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Protocols for Mitochondria as the Target of Pharmacological Therapy in the Context of Nonalcoholic Fatty Liver Disease (NAFLD)

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Mitochondrial Regulation

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2310))

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent metabolic chronic liver diseases in developed countries and puts the populations at risk of progression to liver necro-inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Mitochondrial dysfunction is involved in the onset of NAFLD and contributes to the progression from NAFLD to nonalcoholic steatohepatitis (NASH). Thus, liver mitochondria could become the target for treatments for improving liver function in NAFLD patients. This chapter describes the most important steps used for potential therapeutic interventions in NAFLD patients, discusses current options gathered from both experimental and clinical evidence, and presents some novel options for potentially improving mitochondrial function in NAFLD.

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Abbreviations

ANG:

Angiotensin

ATP :

Adenosine triphosphate

BCAA :

Branched-chain amino acids

DAG:

Diacylglycerol

ER:

Endoplasmic reticulum

Fe/S:

Iron-sulfur

FFA:

Free fatty acid

GPD2 :

Glycerol phosphatase dehydrogenase-2

GFP :

Green-fluorescence protein

GSH:

Glutathione

HCC:

Hepatocellular carcinoma

iNOs:

Inducible nitric oxide synthase

KGDH:

α-ketoglutarate dehydrogenase

LCFA :

Long-chain fatty acids

MAM:

Mitochondria-associated membranes

MPC:

Mitochondrial pyruvate carrier

mtDNA :

Mitochondrial DNA

MPTP :

Mitochondrial permeability transition pore

NAFL:

Nonalcoholic fatty liver

NAFLD :

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

NO:

Nitric oxide

NOX4:

NADPH oxidase-4

PDH:

Pyruvate dehydrogenase

PSSG:

Protein mixed disulfides

PSH:

Protein sulfhydryl

ROS :

Reactive oxygen species

SAME :

S-adenosyl-L-methionine

SOD :

Superoxide dismutase

TCA :

Tricarboxylic acids

TFAM :

Transcription factor A

TG:

Triglycerides

TNF-α:

tumor necrosis factor-alpha

References

  1. Eslam M, Newsome PN, Sarin SK et al (2020) A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol 73(1):202–209

    Article  PubMed  Google Scholar 

  2. Williams CD, Stengel J, Asike MI et al (2011) Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140:124–131

    Article  PubMed  Google Scholar 

  3. Vernon G, Baranova A, Younossi ZM (2011) Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 34:274–285

    Article  CAS  PubMed  Google Scholar 

  4. Lazo M, Hernaez R, Eberhardt MS et al (2013) Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994. Am J Epidemiol 178:38–45

    Article  PubMed  PubMed Central  Google Scholar 

  5. Younossi ZM, Stepanova M, Afendy M et al (2011) Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 9:524–530.e1; quiz e560

    Article  PubMed  Google Scholar 

  6. Molina-Molina E, Lunardi Baccetto R, Wang DQ, de Bari O, Krawczyk M, Portincasa P (2018) Exercising the hepatobiliary-gut axis. The impact of physical activity performance. Eur J Clin Invest 48:e12958

    Article  PubMed  PubMed Central  Google Scholar 

  7. Molina-Molina E, Krawczyk M, Stachowska E, Lammert F, Portincasa P (2019) Non-alcoholic fatty liver disease in non-obese individuals: prevalence, pathogenesis and treatment. Clin Res Hepatol Gastroenterol 43:638–645

    Article  CAS  PubMed  Google Scholar 

  8. Zhou J, Zhou F, Wang W et al (2020) Epidemiological feature of NAFLD from 1999 to 2018 in China. Hepatology 71(5):1851–1864

    Article  PubMed  Google Scholar 

  9. Loomba R, Sanyal AJ (2013) The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 10:686–690

    Article  CAS  PubMed  Google Scholar 

  10. Krawczyk M, Bonfrate L, Portincasa P (2010) Nonalcoholic fatty liver disease. Best Pract Res Clin Gastroenterol 24:695–708

    Article  CAS  PubMed  Google Scholar 

  11. Krawczyk M, Grünhage F, Mihalache F, Acalovschi M, Lammert F (2010) The common adiponutrin variant p. I148M, a common genetic risk factor for severe forms of NAFLD and ALD, in gallstone patients. Zeitschrift für Gastroenterologie 48:P408

    Article  Google Scholar 

  12. Ludwig J, Viggiano TR, McGill DB, Oh BJ (1980) Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 55:434–438

    CAS  PubMed  Google Scholar 

  13. Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ (1999) Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 29:664–669

    Article  CAS  PubMed  Google Scholar 

  14. Browning JD, Kumar KS, Saboorian MH, Thiele DL (2004) Ethnic differences in the prevalence of cryptogenic cirrhosis. Am J Gastroenterol 99:292–298

    Article  PubMed  Google Scholar 

  15. Nasr P, Ignatova S, Kechagias S, Ekstedt M (2018) Natural history of nonalcoholic fatty liver disease: a prospective follow-up study with serial biopsies. Hepatol Commun 2:199–210

    Article  CAS  PubMed  Google Scholar 

  16. Younossi Z, Anstee QM, Marietti M et al (2018) Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 15:11–20

    Article  PubMed  Google Scholar 

  17. Mittal S, El-Serag HB, Sada YH et al (2016) Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 14:124–131.e1

    Article  CAS  PubMed  Google Scholar 

  18. Lindenmeyer CC, McCullough AJ (2018) The Natural History of Nonalcoholic Fatty Liver Disease-An Evolving View. Clin Liver Dis 22:11–21

    Article  PubMed  PubMed Central  Google Scholar 

  19. Rinella ME, Sanyal AJ (2016) Management of NAFLD: a stage-based approach. Nat Rev Gastroenterol Hepatol 13:196–205

    Article  CAS  PubMed  Google Scholar 

  20. Chalasani N, Younossi Z, Lavine JE et al (2018) The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67:328–357

    Article  PubMed  Google Scholar 

  21. National Institute of Alcohol Abuse and Alcoholism (NIH). https://pubs.niaaa.nih.gov/publications/practitioner/pocketguide/pocket_guide2.htm (last access March 12, 2021)

  22. Chen Z, Yu Y, Cai J, Li H (2019) Emerging molecular targets for treatment of nonalcoholic fatty liver disease. Trends Endocrinol Metab 30:903–914

    Article  PubMed  CAS  Google Scholar 

  23. Bai L, Li H (2019) Innate immune regulatory networks in hepatic lipid metabolism. J Mol Med (Berl) 97:593–604

    Article  CAS  Google Scholar 

  24. Samuel VT, Shulman GI (2018) Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell metabolism 27:22–41

    Article  CAS  PubMed  Google Scholar 

  25. Arab JP, Arrese M, Trauner M (2018) Recent insights into the pathogenesis of nonalcoholic fatty liver disease. Annu Rev Pathol 13:321–350

    Article  CAS  PubMed  Google Scholar 

  26. Arab JP, Karpen SJ, Dawson PA, Arrese M, Trauner M (2017) Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives. Hepatology 65:350–362

    Article  PubMed  Google Scholar 

  27. Di Ciaula A, Garruti G, Lunardi Baccetto R et al (2017) Bile acid physiology. Ann Hepatol 16:s4–s14

    Article  PubMed  CAS  Google Scholar 

  28. Neuschwander-Tetri BA, Loomba R, Sanyal AJ et al (2015) Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385:956–965

    Article  CAS  PubMed  Google Scholar 

  29. Marra F, Svegliati-Baroni G (2018) Lipotoxicity and the gut-liver axis in NASH pathogenesis. J Hepatol 68:280–295

    Article  CAS  PubMed  Google Scholar 

  30. Portincasa P, Wang DQH (2017) Nonalcoholic fatty liver and gallstone disease. In: DQH W, Portincasa P (eds) Gallstones. Recent advances in epidemiology, pathogenesis, diagnosis and management. Nova Science Publisher Inc., New York, pp 387–414

    Google Scholar 

  31. Grattagliano I, De Bari O, Di Palo D et al (2018) Mitochondria in liver diseases. In: Oliveira P (ed) Mitochondrial biology and experimental therapeutics. Springer Nature, Cham, pp 91–126. https://doi.org/10.1007/978-3-319-73344-9

    Chapter  Google Scholar 

  32. Sunny NE, Parks EJ, Browning JD, Burgess SC (2011) Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab 14:804–810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ (2014) Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology 146:726–735

    Article  CAS  PubMed  Google Scholar 

  34. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ (2005) Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 115:1343–1351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Han MS, Park SY, Shinzawa K et al (2008) Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes. J Lipid Res 49:84–97

    Article  CAS  PubMed  Google Scholar 

  36. Mota M, Banini BA, Cazanave SC, Sanyal AJ (2016) Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism 65:1049–1061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Pagadala M, Kasumov T, McCullough AJ, Zein NN, Kirwan JP (2012) Role of ceramides in nonalcoholic fatty liver disease. Trends Endocrinol Metab 23:365–371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ioannou GN (2016) The role of cholesterol in the pathogenesis of NASH. Trends Endocrinol Metab 27:84–95

    Article  CAS  PubMed  Google Scholar 

  39. Bellanti F, Mitarotonda D, Tamborra R et al (2014) Oxysterols induce mitochondrial impairment and hepatocellular toxicity in non-alcoholic fatty liver disease. Free Radic Biol Med 75(Suppl 1):S16–S17

    Article  PubMed  Google Scholar 

  40. Müller FA, Sturla SJ (2019) Human in vitro models of nonalcoholic fatty liver disease. Curr Opin Toxicol 16:9–16

    Article  Google Scholar 

  41. Fu S, Watkins SM, Hotamisligil GS (2012) The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab 15:623–634

    Article  CAS  PubMed  Google Scholar 

  42. Perry RJ, Samuel VT, Petersen KF, Shulman GI (2014) The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510:84–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ertunc ME, Hotamisligil GS (2016) Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment. J Lipid Res 57:2099–2114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cai J, Xu M, Zhang X, Li H (2019) Innate immune signaling in nonalcoholic fatty liver disease and cardiovascular diseases. Annu Rev Pathol 14:153–184

    Article  CAS  PubMed  Google Scholar 

  45. Cai J, Zhang XJ, Li H (2019) The Role of Innate Immune Cells in Nonalcoholic Steatohepatitis. Hepatology 70:1026–1037

    Article  PubMed  Google Scholar 

  46. Wang XA, Zhang R, She ZG et al (2014) Interferon regulatory factor 3 constrains IKKbeta/NF-kappaB signaling to alleviate hepatic steatosis and insulin resistance. Hepatology 59:870–885

    Article  CAS  PubMed  Google Scholar 

  47. Guerrieri F, Nicoletti C, Adorisio E et al (2000) Correlation between decreased expression of mitochondrial F0F1-ATP synthase and low regenerating capability of the liver after partial hepatectomy in hypothyroid rats. J Bioenerg Biomembr 32:183–191

    Article  CAS  PubMed  Google Scholar 

  48. Chen Z, Tian R, She Z, Cai J, Li H (2020) Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease. Free Radic Biol Med 152:116–141

    Article  CAS  PubMed  Google Scholar 

  49. Lopaschuk GD, Belke DD, Gamble J, Itoi T, Schonekess BO (1994) Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta 1213:263–276

    Article  CAS  PubMed  Google Scholar 

  50. Kerner J, Hoppel C (2000) Fatty acid import into mitochondria. Biochim Biophys Acta 1486:1–17

    Article  CAS  PubMed  Google Scholar 

  51. Serviddio G, Giudetti AM, Bellanti F et al (2011) Oxidation of hepatic carnitine palmitoyl transferase-I (CPT-I) impairs fatty acid beta-oxidation in rats fed a methionine-choline deficient diet. PLoS One 6:e24084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Schmid AI, Szendroedi J, Chmelik M, Krssak M, Moser E, Roden M (2011) Liver ATP synthesis is lower and relates to insulin sensitivity in patients with type 2 diabetes. Diabetes Care 34:448–453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Peng KY, Watt MJ, Rensen S et al (2018) Mitochondrial dysfunction-related lipid changes occur in nonalcoholic fatty liver disease progression. J Lipid Res 59:1977–1986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Koliaki C, Szendroedi J, Kaul K et al (2015) Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab 21:739–746

    Article  CAS  PubMed  Google Scholar 

  55. Fletcher JA, Deja S, Satapati S, Fu X, Burgess SC, Browning JD (2019) Impaired ketogenesis and increased acetyl-CoA oxidation promote hyperglycemia in human fatty liver. JCI Insight 5:e127737

    Article  Google Scholar 

  56. Pessayre D, Fromenty B (2005) NASH: a mitochondrial disease. J Hepatol 42:928–940

    Article  CAS  PubMed  Google Scholar 

  57. Pessayre D, Berson A, Fromenty B, Mansouri A (2001) Mitochondria in steatohepatitis. Semin Liver Dis 21:57–69

    Article  CAS  PubMed  Google Scholar 

  58. Sunny NE, Bril F, Cusi K (2017) Mitochondrial adaptation in nonalcoholic fatty liver disease: novel mechanisms and treatment strategies. Trends Endocrinol Metab 28:250–260

    Article  CAS  PubMed  Google Scholar 

  59. Grattagliano I, Bonfrate L, Oliveira PJ et al (2013) Breath tests with novel 13C-substrates for clinical studies of liver mitochondrial function in health and disease. Eur Rev Med Pharmacol Sci 17(Suppl 2):72–81

    PubMed  Google Scholar 

  60. Grattagliano I, Bonfrate L, Lorusso M, Castorani L, de Bari O, Portincasa P (2015) Exploring liver mitochondrial function by (1)(3)C-stable isotope breath tests: implications in clinical biochemistry. Methods Mol Biol 1241:137–152

    Article  CAS  PubMed  Google Scholar 

  61. Bonfrate L, Grattagliano I, Palasciano G, Portincasa P (2015) Dynamic carbon 13 breath tests for the study of liver function and gastric emptying. Gastroenterol Rep (Oxf) 3:12–21

    Article  Google Scholar 

  62. Portincasa P, Grattagliano I, Lauterburg BH, Palmieri VO, Palasciano G, Stellaard F (2006) Liver breath tests non-invasively predict higher stages of non-alcoholic steatohepatitis. Clin Sci (Lond) 111:135–143

    Article  CAS  Google Scholar 

  63. Begriche K, Massart J, Robin MA, Borgne-Sanchez A, Fromenty B (2011) Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver. J Hepatol 54:773–794

    Article  CAS  PubMed  Google Scholar 

  64. Yin X, Zheng F, Pan Q et al (2015) Glucose fluctuation increased hepatocyte apoptosis under lipotoxicity and the involvement of mitochondrial permeability transition opening. J Mol Endocrinol 55:169–181

    Article  CAS  PubMed  Google Scholar 

  65. Navarro CDC, Figueira TR, Francisco A et al (2017) Redox imbalance due to the loss of mitochondrial NAD(P)-transhydrogenase markedly aggravates high fat diet-induced fatty liver disease in mice. Free Radic Biol Med 113:190–202

    Article  CAS  PubMed  Google Scholar 

  66. King AL, Swain TM, Mao Z et al (2014) Involvement of the mitochondrial permeability transition pore in chronic ethanol-mediated liver injury in mice. Am J Physiol Gastrointest Liver Physiol 306:G265–G277

    Article  CAS  PubMed  Google Scholar 

  67. Martel C, Allouche M, Esposti DD et al (2012) GSK3-mediated VDAC phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation. Hepatology 57(1):93–102

    Article  CAS  Google Scholar 

  68. Win S, Than TA, Le BH, Garcia-Ruiz C, Fernandez-Checa JC, Kaplowitz N (2015) Sab (Sh3bp5) dependence of JNK mediated inhibition of mitochondrial respiration in palmitic acid induced hepatocyte lipotoxicity. J Hepatol 62:1367–1374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Gariani K, Menzies KJ, Ryu D et al (2016) Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology 63:1190–1204

    Article  CAS  PubMed  Google Scholar 

  70. Vecchione G, Grasselli E, Cioffi F et al (2017) The nutraceutic silybin counteracts excess lipid accumulation and ongoing oxidative stress in an in vitro model of non-alcoholic fatty liver disease progression. Front Nutr 4:42

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Petrosillo G, Portincasa P, Grattagliano I et al (2007) Mitochondrial dysfunction in rat with nonalcoholic fatty liver Involvement of complex I, reactive oxygen species and cardiolipin. Biochim Biophys Acta 1767:1260–1267

    Article  CAS  PubMed  Google Scholar 

  72. Satapati S, Kucejova B, Duarte JA et al (2015) Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. J Clin Invest 125:4447–4462

    Article  PubMed  PubMed Central  Google Scholar 

  73. Kagan VE, Bayir HA, Belikova NA et al (2009) Cytochrome c/cardiolipin relations in mitochondria: a kiss of death. Free Radic Biol Med 46:1439–1453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Haouzi D, Lekehal M, Moreau A et al (2000) Cytochrome P450-generated reactive metabolites cause mitochondrial permeability transition, caspase activation, and apoptosis in rat hepatocytes. Hepatology 32:303–311

    Article  CAS  PubMed  Google Scholar 

  75. Bonora M, Morganti C, Morciano G et al (2017) Mitochondrial permeability transition involves dissociation of F1FO ATP synthase dimers and C-ring conformation. EMBO Rep 18:1077–1089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Elustondo PA, Nichols M, Negoda A et al (2016) Mitochondrial permeability transition pore induction is linked to formation of the complex of ATPase C-subunit, polyhydroxybutyrate and inorganic polyphosphate. Cell Death Discov 2:16070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. He J, Carroll J, Ding S, Fearnley IM, Walker JE (2017) Permeability transition in human mitochondria persists in the absence of peripheral stalk subunits of ATP synthase. Proc Natl Acad Sci U S A 114:9086–9091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. He J, Ford HC, Carroll J, Ding S, Fearnley IM, Walker JE (2017) Persistence of the mitochondrial permeability transition in the absence of subunit c of human ATP synthase. Proc Natl Acad Sci U S A 114:3409–3414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Papucci L, Formigli L, Schiavone N et al (2004) Apoptosis shifts to necrosis via intermediate types of cell death by a mechanism depending on c-myc and bcl-2 expression. Cell Tissue Res 316:197–209

    Article  CAS  PubMed  Google Scholar 

  80. Musso G, Gambino R, De Michieli F et al (2007) Nitrosative stress predicts the presence and severity of nonalcoholic fatty liver at different stages of the development of insulin resistance and metabolic syndrome: possible role of vitamin A intake. Am J Clin Nutr 86:661–671

    Article  CAS  PubMed  Google Scholar 

  81. Afonso MB, Rodrigues PM, Simao AL et al (2016) Activation of necroptosis in human and experimental cholestasis. Cell Death Dis 7:e2390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Caldwell SH, Crespo DM (2004) The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver diseasePowell EE, Cooksley WGE, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years [Hepatology 1990; 11: 74–80]. J Hepatol 40:578–584

    Article  PubMed  Google Scholar 

  83. Mantena SK, King AL, Andringa KK, Landar A, Darley-Usmar V, Bailey SM (2007) Novel interactions of mitochondria and reactive oxygen/nitrogen species in alcohol mediated liver disease. World J Gastroenterol 13:4967–4973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Vanni E, Marengo A, Mezzabotta L, Bugianesi E (2015) Systemic complications of nonalcoholic fatty liver disease: when the liver is not an innocent bystander. In: Seminars in liver disease. vol 03. Thieme Medical Publishers, pp 236–249

    Google Scholar 

  85. Simoes ICM, Fontes A, Pinton P, Zischka H, Wieckowski MR (2018) Mitochondria in non-alcoholic fatty liver disease. Int J Biochem Cell Biol 95:93–99

    Article  CAS  PubMed  Google Scholar 

  86. Sunny NE, Kalavalapalli S, Bril F et al (2015) Cross-talk between branched-chain amino acids and hepatic mitochondria is compromised in nonalcoholic fatty liver disease. Am J Physiol Endocrinol Metab 309:E311–E319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sanyal AJ, Campbell-Sargent C, Mirshahi F et al (2001) Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120:1183–1192

    Article  CAS  PubMed  Google Scholar 

  88. Mehta R, Jeiran K, Koenig AB et al (2016) The role of mitochondrial genomics in patients with non-alcoholic steatohepatitis (NASH). BMC Med Genet 17:63

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S (2020) Nonalcoholic steatohepatitis: a review. JAMA 323:1175–1183

    Article  CAS  PubMed  Google Scholar 

  90. Ekstedt M, Franzen LE, Holmqvist M et al (2009) Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease. Scand J Gastroenterol 44:366–374

    Article  CAS  PubMed  Google Scholar 

  91. Chen X, Zhang Z, Li H et al (2020) Endogenous ethanol produced by intestinal bacteria induces mitochondrial dysfunction in non-alcoholic fatty liver disease. J Gastroenterol Hepatol 35(11):2009–2019

    Article  CAS  PubMed  Google Scholar 

  92. Cerqueira FM, FMD C, Silva CC et al (2011) Redox state, insulin sensitivity and aging. Resumos. FeSBE, São Paulo

    Google Scholar 

  93. Kowaltowski AJ (2011) Caloric restriction and redox state: does this diet increase or decrease oxidant production? Redox Rep 16:237–241

    Article  CAS  PubMed  Google Scholar 

  94. Walsh ME, Shi Y, Van Remmen H (2014) The effects of dietary restriction on oxidative stress in rodents. Free Radic Biol Med 66:88–99

    Article  CAS  PubMed  Google Scholar 

  95. Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander-Tetri BA (2008) Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am J Physiol Gastrointest Liver Physiol 295:G987–G995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Romero-Gomez M, Zelber-Sagi S, Trenell M (2017) Treatment of NAFLD with diet, physical activity and exercise. J Hepatol 67:829–846

    Article  PubMed  Google Scholar 

  97. Goncalves IO, Passos E, Rocha-Rodrigues S et al (2015) Physical exercise antagonizes clinical and anatomical features characterizing Lieber-DeCarli diet-induced obesity and related metabolic disorders. Clin Nutr 34:241–247

    Article  CAS  PubMed  Google Scholar 

  98. Promrat K, Kleiner DE, Niemeier HM et al (2010) Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 51:121–129

    Article  CAS  PubMed  Google Scholar 

  99. Keating SE, Hackett DA, George J, Johnson NA (2012) Exercise and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 57:157–166

    Article  CAS  PubMed  Google Scholar 

  100. Keating SE, Hackett DA, Parker HM et al (2015) Effect of aerobic exercise training dose on liver fat and visceral adiposity. J Hepatol 63:174–182

    Article  PubMed  Google Scholar 

  101. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L et al (2015) Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 149:367–378.e5; quiz e314-365

    Article  PubMed  Google Scholar 

  102. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI (2005) Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54:603–608

    Article  CAS  PubMed  Google Scholar 

  103. Musso G, Cassader M, Rosina F, Gambino R (2012) Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 55:885–904

    Article  CAS  PubMed  Google Scholar 

  104. Bower G, Toma T, Harling L et al (2015) Bariatric surgery and non-alcoholic fatty liver disease: a systematic review of liver biochemistry and histology. Obes Surg 25:2280–2289

    Article  PubMed  Google Scholar 

  105. Mathurin P, Hollebecque A, Arnalsteen L et al (2009) Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology 137:532–540

    Article  CAS  PubMed  Google Scholar 

  106. Dixon JB, Bhathal PS, Hughes NR, O’Brien PE (2004) Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology 39:1647–1654

    Article  PubMed  Google Scholar 

  107. Clark JM, Alkhuraishi AR, Solga SF, Alli P, Diehl AM, Magnuson TH (2005) Roux-en-Y gastric bypass improves liver histology in patients with non-alcoholic fatty liver disease. Obes Res 13:1180–1186

    Article  PubMed  Google Scholar 

  108. Tai CM, Huang CK, Hwang JC et al (2012) Improvement of nonalcoholic fatty liver disease after bariatric surgery in morbidly obese Chinese patients. Obes Surg 22:1016–1021

    Article  PubMed  Google Scholar 

  109. Lee Y, Doumouras AG, Yu J et al (2018) Complete resolution of nonalcoholic fatty liver disease after bariatric surgery: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 17(6):1040–1060.e11

    Article  PubMed  Google Scholar 

  110. de Almeida SR, Rocha PR, Sanches MD et al (2006) Roux-en-Y gastric bypass improves the nonalcoholic steatohepatitis (NASH) of morbid obesity. Obes Surg 16:270–278

    Article  PubMed  Google Scholar 

  111. Lassailly G, Caiazzo R, Buob D et al (2015) Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology 149:379–388; quiz e315-376

    Article  PubMed  Google Scholar 

  112. Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T, Mendez-Sanchez N, Lizardi-Cervera J, Uribe M (2010) Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev 2010(1):CD007340

    PubMed Central  Google Scholar 

  113. Miele L, Valenza V, La Torre G et al (2009) Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49:1877–1887

    Article  CAS  PubMed  Google Scholar 

  114. Di Palo DM, Garruti G, Di Ciaula A et al (2020) Increased colonic permeability and lifestyles as contributing factors to obesity and liver steatosis. Nutrients 12:E564

    Article  PubMed  CAS  Google Scholar 

  115. Rotman Y, Sanyal AJ (2017) Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease. Gut 66:180–190

    Article  CAS  PubMed  Google Scholar 

  116. Sanyal AJ, Chalasani N, Kowdley KV et al (2010) Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 362:1675–1685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Barreyro FJ, Holod S, Finocchietto PV et al (2015) The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int 35:953–966

    Article  CAS  PubMed  Google Scholar 

  118. Alkhouri N, Carter-Kent C, Feldstein AE (2011) Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications. Expert Rev Gastroenterol Hepatol 5:201–212

    Article  PubMed  PubMed Central  Google Scholar 

  119. Rakoski MO, Singal AG, Rogers MA, Conjeevaram H (2010) Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther 32:1211–1221

    Article  CAS  PubMed  Google Scholar 

  120. Li Y, Liu L, Wang B, Wang J, Chen D (2013) Metformin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Biomed Rep 1:57–64

    Article  CAS  PubMed  Google Scholar 

  121. Aithal GP, Thomas JA, Kaye PV et al (2008) Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 135:1176–1184

    Article  CAS  PubMed  Google Scholar 

  122. Belfort R, Harrison SA, Brown K et al (2006) A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 355:2297–2307

    Article  CAS  PubMed  Google Scholar 

  123. Cusi K, Orsak B, Bril F et al (2016) Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med 165:305–315

    Article  PubMed  Google Scholar 

  124. Sanyal AJ, Mofrad PS, Contos MJ et al (2004) A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2:1107–1115

    Article  CAS  PubMed  Google Scholar 

  125. Mahady SE, Wong G, Craig JC, George J (2012) Pioglitazone and vitamin E for nonalcoholic steatohepatitis: a cost utility analysis. Hepatology 56:2172–2179

    Article  CAS  PubMed  Google Scholar 

  126. Singh S, Khera R, Allen AM, Murad MH, Loomba R (2015) Comparative effectiveness of pharmacological interventions for nonalcoholic steatohepatitis: a systematic review and network meta-analysis. Hepatology 62:1417–1432

    Article  CAS  PubMed  Google Scholar 

  127. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR (2003) Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 38:1008–1017

    Article  CAS  PubMed  Google Scholar 

  128. Ratziu V, Charlotte F, Bernhardt C et al (2010) Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 51:445–453

    Article  CAS  PubMed  Google Scholar 

  129. Ratziu V, Giral P, Jacqueminet S et al (2008) Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 135:100–110

    Article  CAS  PubMed  Google Scholar 

  130. European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO) (2016) EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 64:1388–1402

    Article  Google Scholar 

  131. Rinella ME, Lominadze Z, Loomba R et al (2016) Practice patterns in NAFLD and NASH: real life differs from published guidelines. Therap Adv Gastroenterol 9:4–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Armstrong MJ, Hull D, Guo K et al (2016) Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol 64:399–408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Brighton CA, Rievaj J, Kuhre RE et al (2015) Bile acids trigger GLP-1 release predominantly by accessing basolaterally located G protein-coupled bile acid receptors. Endocrinology 156:3961–3970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Jinnouchi H, Sugiyama S, Yoshida A et al (2015) Liraglutide, a glucagon-like peptide-1 analog, increased insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp examination in patients with uncontrolled type 2 diabetes mellitus. J Diabetes Res 2015:706416

    Article  PubMed  PubMed Central  Google Scholar 

  135. Armstrong MJ, Gaunt P, Aithal GP et al (2016) Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387:679–690

    Article  CAS  PubMed  Google Scholar 

  136. Harriman G, Greenwood J, Bhat S et al (2016) Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. Proc Natl Acad Sci U S A 113:E1796–E1805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Chow JD, Lawrence RT, Healy ME et al (2014) Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation. Mol Metab 3:419–431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Goedeke L, Bates J, Vatner DF et al (2018) Acetyl-C o A carboxylase inhibition reverses NAFLD and hepatic insulin resistance but promotes hypertriglyceridemia in rodents. Hepatology 68:2197–2211

    Article  CAS  PubMed  Google Scholar 

  139. Loomba R, Kayali Z, Noureddin M et al (2018) GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease. Gastroenterology 155(1463-1473):e1466

    Google Scholar 

  140. Kim CW, Addy C, Kusunoki J et al (2017) Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation. Cell Metab 26:576

    Article  CAS  PubMed  Google Scholar 

  141. Verschueren KHG, Blanchet C, Felix J et al (2019) Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle. Nature 568:571–575

    Article  CAS  PubMed  Google Scholar 

  142. Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M (2019) From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol 16:411–428

    Article  PubMed  Google Scholar 

  143. Mudaliar S, Henry RR, Sanyal AJ et al (2013) Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145:574–582.e1

    Article  CAS  PubMed  Google Scholar 

  144. Ratziu V, Sanyal AJ, Loomba R et al (2019) REGENERATE: Design of a pivotal, randomised, phase 3 study evaluating the safety and efficacy of obeticholic acid in patients with fibrosis due to nonalcoholic steatohepatitis. Contemp Clin Trials 84:105803

    Article  PubMed  Google Scholar 

  145. Min HK, Kapoor A, Fuchs M et al (2012) Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metab 15:665–674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Ajmera VH, Cachay E, Ramers C et al (2019) MRI assessment of treatment response in HIV-associated NAFLD: a randomized trial of a stearoyl-coenzyme-A-desaturase-1 inhibitor (ARRIVE Trial). Hepatology 70:1531–1545

    Article  CAS  PubMed  Google Scholar 

  147. Iruarrizaga-Lejarreta M, Varela-Rey M, Fernandez-Ramos D et al (2017) Role of Aramchol in steatohepatitis and fibrosis in mice. Hepatol Commun 1:911–927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Safadi R, Konikoff FM, Mahamid M et al (2014) The fatty acid–bile acid conjugate aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 12:2085–2091.e1

    Article  CAS  PubMed  Google Scholar 

  149. Nies VJ, Sancar G, Liu W et al (2015) Fibroblast growth factor signaling in metabolic regulation. Front Endocrinol (Lausanne) 6:193

    Google Scholar 

  150. Fu L, John LM, Adams SH et al (2004) Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology 145:2594–2603

    Article  CAS  PubMed  Google Scholar 

  151. Harrison SA, Rinella ME, Abdelmalek MF et al (2018) NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 391:1174–1185

    Article  CAS  PubMed  Google Scholar 

  152. Kharitonenkov A, Shiyanova TL, Koester A et al (2005) FGF-21 as a novel metabolic regulator. J Clin Invest 115:1627–1635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Staiger H, Keuper M, Berti L, Hrabe de Angelis M, Haring HU (2017) Fibroblast growth factor 21-metabolic role in mice and men. Endocr Rev 38:468–488

    Article  PubMed  Google Scholar 

  154. Staels B, Rubenstrunk A, Noel B et al (2013) Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 58:1941–1952

    Article  CAS  PubMed  Google Scholar 

  155. Hanf R, Millatt LJ, Cariou B et al (2014) The dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 exerts anti-diabetic effects in db/db mice without peroxisome proliferator-activated receptor gamma–associated adverse cardiac effects. Diab Vasc Dis Res 11:440–447

    Article  CAS  PubMed  Google Scholar 

  156. Cariou B, Hanf R, Lambert-Porcheron S et al (2013) Dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 36:2923–2930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Ratziu V, Harrison SA, Francque S et al (2016) Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and –delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150:1147–1159.e5

    Article  CAS  PubMed  Google Scholar 

  158. Alvarado TF, Puliga E, Preziosi M et al (2016) Thyroid hormone receptor beta agonist induces beta-catenin-dependent hepatocyte proliferation in mice: implications in hepatic regeneration. Gene Expr 17:19–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ogawa Y, Yoneda M, Kobayashi T et al (2019) Present and emerging pharmacotherapies for non-alcoholic steatohepatitis in adults. Expert Opin Pharmacother 20:69–82

    Article  CAS  PubMed  Google Scholar 

  160. Bai L, Chen MM, Chen ZD et al (2019) F-box/WD repeat-containing protein 5 mediates the ubiquitination of apoptosis signal-regulating kinase 1 and exacerbates nonalcoholic steatohepatitis in mice. Hepatology 70:1942–1957

    Article  CAS  PubMed  Google Scholar 

  161. Loomba R, Lawitz E, Mantry PS et al (2018) The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology 67:549–559

    Article  CAS  PubMed  Google Scholar 

  162. Zhang P, Wang PX, Zhao LP et al (2018) The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis. Nat Med 24:84–94

    Article  CAS  PubMed  Google Scholar 

  163. Wang P-X, Ji Y-X, Zhang X-J et al (2017) Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates. Nature medicine 23:439

    Article  CAS  PubMed  Google Scholar 

  164. Friedman SL, Ratziu V, Harrison SA et al (2018) A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology 67:1754–1767

    Article  CAS  PubMed  Google Scholar 

  165. Wang PX, Zhang XJ, Luo PC et al (2016) Hepatocyte TRAF3 promotes liver steatosis and systemic insulin resistance through targeting TAK1-dependent signalling. Nat Commun 7:1–22

    Google Scholar 

  166. Ji YX, Huang Z, Yang X et al (2018) The deubiquitinating enzyme cylindromatosis mitigates nonalcoholic steatohepatitis. Nat Med 24:213–223

    Article  CAS  PubMed  Google Scholar 

  167. Chalasani N, Abdelmalek MF, Garcia-Tsao G et al (2020) Effects of belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension. Gastroenterology 158:1334–1345.e5

    Article  CAS  PubMed  Google Scholar 

  168. Carino A, Cipriani S, Marchiano S et al (2017) BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis. Sci Rep 7:42801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Puri P, Sanyal AJ (2018) The intestinal microbiome in nonalcoholic fatty liver disease. Clin Liver Dis 22:121–132

    Article  PubMed  Google Scholar 

  170. Georgescu EF, Georgescu M (2007) Therapeutic options in non-alcoholic steatohepatitis (NASH). Are all agents alike? Results of a preliminary study. J Gastrointestin Liver Dis 16:39–46

    PubMed  Google Scholar 

  171. Hyogo H, Tazuma S, Arihiro K et al (2008) Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia. Metabolism 57:1711–1718

    Article  CAS  PubMed  Google Scholar 

  172. Dongiovanni P, Petta S, Mannisto V et al (2015) Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol 63:705–712

    Article  CAS  PubMed  Google Scholar 

  173. Echeverria F, Valenzuela R, Bustamante A et al (2019) High-fat diet induces mouse liver steatosis with a concomitant decline in energy metabolism: attenuation by eicosapentaenoic acid (EPA) or hydroxytyrosol (HT) supplementation and the additive effects upon EPA and HT co-administration. Food Funct 10:6170–6183

    Article  CAS  PubMed  Google Scholar 

  174. Parker HM, Johnson NA, Burdon CA, Cohn JS, O’Connor HT, George J (2012) Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 56:944–951

    Article  CAS  PubMed  Google Scholar 

  175. Sofi F, Giangrandi I, Cesari F et al (2010) Effects of a 1-year dietary intervention with n-3 polyunsaturated fatty acid-enriched olive oil on non-alcoholic fatty liver disease patients: a preliminary study. Int J Food Sci Nutr 61:792–802

    Article  CAS  PubMed  Google Scholar 

  176. Simon TG, Henson J, Osganian S et al (2019) Daily aspirin use associated with reduced risk for fibrosis progression in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 17:2776–2784.e4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Lombardi R, Onali S, Thorburn D, Davidson BR, Gurusamy KS, Tsochatzis E (2017) Pharmacological interventions for non-alcohol related fatty liver disease (NAFLD): an attempted network meta-analysis. Cochrane Database Syst Rev 3:CD011640

    PubMed  Google Scholar 

  178. Thoma C, Day CP, Trenell MI (2012) Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J Hepatol 56:255–266

    Article  PubMed  Google Scholar 

  179. Li Z, Li Y, Zhang HX et al (2019) Mitochondria-mediated pathogenesis and therapeutics for non-alcoholic fatty liver disease. Mol Nutr Food Res 63:e1900043

    Article  PubMed  CAS  Google Scholar 

  180. Sun L, Yuan Q, Xu T et al (2017) Pioglitazone improves mitochondrial function in the remnant kidney and protects against renal fibrosis in 5/6 nephrectomized rats. Front Pharmacol 8:545

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. He L, Sabet A, Djedjos S et al (2009) Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 137:635–646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Tong W, Ju L, Qiu M et al (2016) Liraglutide ameliorates non-alcoholic fatty liver disease by enhancing mitochondrial architecture and promoting autophagy through the SIRT1/SIRT3-FOXO3a pathway. Hepatol Res 46:933–943

    Article  CAS  PubMed  Google Scholar 

  183. Chen YS, Liu HM, Lee TY (2019) Ursodeoxycholic acid regulates hepatic energy homeostasis and white adipose tissue macrophages polarization in leptin-deficiency obese mice. Cells 8:253

    Article  CAS  PubMed Central  Google Scholar 

  184. Xie C, Jiang C, Shi J et al (2017) An intestinal farnesoid X receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice. Diabetes 66:613–626

    Article  CAS  PubMed  Google Scholar 

  185. Ferramosca A, Di Giacomo M, Zara V (2017) Antioxidant dietary approach in treatment of fatty liver: new insights and updates. World J Gastroenterol 23:4146–4157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Ding S, Jiang J, Zhang G, Bu Y, Zhang G, Zhao X (2017) Resveratrol and caloric restriction prevent hepatic steatosis by regulating SIRT1-autophagy pathway and alleviating endoplasmic reticulum stress in high-fat diet-fed rats. PLoS One 12:e0183541

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Tian Y, Ma J, Wang W et al (2016) Resveratrol supplement inhibited the NF-κB inflammation pathway through activating AMPKα-SIRT1 pathway in mice with fatty liver. Mol Cell Biochem 422:75–84

    Article  CAS  PubMed  Google Scholar 

  188. Shang J, Chen LL, Xiao FX, Sun H, Ding HC, Xiao H (2008) Resveratrol improves non-alcoholic fatty liver disease by activating AMP-activated protein kinase. Acta Pharmacol Sin 29:698–706

    Article  CAS  PubMed  Google Scholar 

  189. Asin-Cayuela J, Manas AR, James AM, Smith RA, Murphy MP (2004) Fine-tuning the hydrophobicity of a mitochondria-targeted antioxidant. FEBS Lett 571:9–16

    Article  CAS  PubMed  Google Scholar 

  190. Rokitskaya TI, Klishin SS, Severina II, Skulachev VP, Antonenko YN (2008) Kinetic analysis of permeation of mitochondria-targeted antioxidants across bilayer lipid membranes. J Membr Biol 224:9–19

    Article  CAS  PubMed  Google Scholar 

  191. Smith RA, Porteous CM, Gane AM, Murphy MP (2003) Delivery of bioactive molecules to mitochondria in vivo. Proc Natl Acad Sci U S A 100:5407–5412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Grattagliano I, Diogo CV, Mastrodonato M et al (2013) A silybin-phospholipids complex counteracts rat fatty liver degeneration and mitochondrial oxidative changes. World J Gastroenterol 19:3007–3017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Vecchione G, Grasselli E, Voci A et al (2016) Silybin counteracts lipid excess and oxidative stress in cultured steatotic hepatic cells. World J Gastroenterol 22:6016–6026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Wu N, Zu Y, Fu Y et al (2010) Antioxidant activities and xanthine oxidase inhibitory effects of extracts and main polyphenolic compounds obtained from Geranium sibiricum L. J Agric Food Chem 58:4737–4743

    Article  CAS  PubMed  Google Scholar 

  195. Ling WH, Shen TR, Tang XL, Jiang XW (2016) Anthocyanins improved mitochondrial dysfunction in mice of non-alcoholic fatty liver disease induced by high fat diet. Faseb Journal 30:915.929

    Google Scholar 

  196. Tang X, Shen T, Jiang X et al (2015) Purified anthocyanins from bilberry and black currant attenuate hepatic mitochondrial dysfunction and steatohepatitis in mice with methionine and choline deficiency. J Agric Food Chem 63:552–561

    Article  CAS  PubMed  Google Scholar 

  197. Zeng X, Yang J, Hu O et al (2019) Dihydromyricetin ameliorates nonalcoholic fatty liver disease by improving mitochondrial respiratory capacity and redox homeostasis through modulation of SIRT3 signaling. Antioxid Redox Signal 30:163–183

    Article  CAS  PubMed  Google Scholar 

  198. Teodoro JS, Duarte FV, Gomes AP et al (2013) Berberine reverts hepatic mitochondrial dysfunction in high-fat fed rats: a possible role for SirT3 activation. Mitochondrion 13:637–646

    Article  CAS  PubMed  Google Scholar 

  199. Schwimmer JB, Lavine JE, Wilson LA et al (2016) In children with nonalcoholic fatty liver disease, cysteamine bitartrate delayed release improves liver enzymes but does not reduce disease activity scores. Gastroenterology 151:1141–1154.e9

    Article  CAS  PubMed  Google Scholar 

  200. Dohil R, Schmeltzer S, Cabrera BL et al (2011) Enteric-coated cysteamine for the treatment of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther 33:1036–1044

    Article  CAS  PubMed  Google Scholar 

  201. Ye JH, Chao J, Chang ML et al (2016) Pentoxifylline ameliorates non-alcoholic fatty liver disease in hyperglycaemic and dyslipidaemic mice by upregulating fatty acid beta-oxidation. Sci Rep 6:33102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Zein CO, Lopez R, Yerian L, Anderson KA, McCullough AJ, Rinella ME (2012) 932 pentoxifylline improves non-invasive serum markers of fibrosis: combined results from 2 randomized, placebo-controlled trials. Gastroenterology 142:S-936

    Article  Google Scholar 

  203. Zein CO, Yerian LM, Gogate P et al (2011) Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 54:1610–1619

    Article  CAS  PubMed  Google Scholar 

  204. Rendon DA (2015) Letter to the Editor: the bioenergetics of hepatic mitochondria isolated from avocado oil-treated rats: typical experimental errors in the study of the bioenergetics of isolated mitochondria. J Bioenerg Biomembr 47:451–453

    Article  CAS  PubMed  Google Scholar 

  205. Ortiz-Avila O, Gallegos-Corona MA, Sanchez-Briones LA et al (2015) Protective effects of dietary avocado oil on impaired electron transport chain function and exacerbated oxidative stress in liver mitochondria from diabetic rats. J Bioenerg Biomembr 47:337–353

    Article  CAS  PubMed  Google Scholar 

  206. Garcia-Berumen CI, Olmos-Orizaba BE, Marquez-Ramirez CA et al (2019) Avocado oil ameliorates non-alcoholic fatty liver disease by down-regulating inflammatory cytokines and improving mitochondrial dynamics. Faseb J 33:660.666

    Article  Google Scholar 

  207. Fu A, Shi X, Zhang H, Fu B (2017) Mitotherapy for fatty liver by intravenous administration of exogenous mitochondria in male mice. Front Pharmacol 8:241

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  208. Ajith TA (2018) Role of mitochondria and mitochondria-targeted agents in non-alcoholic fatty liver disease. Clin Exp Pharmacol Physiol 45:413–421

    Article  CAS  PubMed  Google Scholar 

  209. Dai J, Liang K, Zhao S et al (2018) Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis. Proc Natl Acad Sci U S A 115:E5896–E5905

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  210. Fazzari M, Chartoumpekis D, Li L et al (2017) Nitro-oleic acid protects mice from diet-induced hepatic steatosis and insulin resistance without the adverse side effects of thiazolidinediones. Free Radic Biol Med 112:152–152

    Article  Google Scholar 

  211. Cho J, Zhang Y, Park S-Y et al (2017) Mitochondrial ATP transporter depletion protects mice against liver steatosis and insulin resistance. Nat Commun 8:1–12

    Article  CAS  Google Scholar 

  212. Amanat S, Eftekhari MH, Fararouei M, Bagheri Lankarani K, Massoumi SJ (2018) Genistein supplementation improves insulin resistance and inflammatory state in non-alcoholic fatty liver patients: a randomized, controlled trial. Clin Nutr 37:1210–1215

    Article  CAS  PubMed  Google Scholar 

  213. Miele L, Grieco A, Armuzzi A et al (2003) Hepatic mitochondrial beta-oxidation in patients with nonalcoholic steatohepatitis assessed by 13 C-octanoate breath test. Am J Gastroenterol 98:2335

    Article  PubMed  Google Scholar 

  214. Festi D, Capodicasa S, Sandri L et al (2005) Measurement of hepatic functional mass by means of 13C-methacetin and 13C-phenylalanine breath tests in chronic liver disease: comparison with Child-Pugh score and serum bile acid levels. World J Gastroenterol 11:142–148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Grattagliano I, Lauterburg BH, Palasciano G, Portincasa P (2010) 13C-breath tests for clinical investigation of liver mitochondrial function. Eur J Clin Invest 40:843–850

    Article  CAS  PubMed  Google Scholar 

  216. Palmieri VO, Grattagliano I, Minerva F, Pollice S, Palasciano G, Portincasa P (2009) Liver function as assessed by breath tests in patients with hepatocellular carcinoma. JSurgRes 157:199–207

    Google Scholar 

  217. Perri F, Bellini M, Portincasa P et al (2010) (13)C-octanoic acid breath test (OBT) with a new test meal (EXPIROGer): toward standardization for testing gastric emptying of solids. Dig Liver Dis 42:549–553

    Article  PubMed  Google Scholar 

  218. Wei Y, Clark SE, Thyfault JP et al (2009) Oxidative stress-mediated mitochondrial dysfunction contributes to angiotensin II-induced nonalcoholic fatty liver disease in transgenic Ren2 rats. Am J Pathol 174:1329–1337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Yan J, Jiang J, He L, Chen L (2020) Mitochondrial superoxide/hydrogen peroxide: an emerging therapeutic target for metabolic diseases. Free Radic Biol Med 152:33–42

    Article  CAS  PubMed  Google Scholar 

  220. Little JP, Safdar A, Benton CR, Wright DC (2011) Skeletal muscle and beyond: the role of exercise as a mediator of systemic mitochondrial biogenesis. Appl Physiol Nutr Metab 36:598–607

    Article  CAS  PubMed  Google Scholar 

  221. Stevanovic J, Beleza J, Coxito P, Ascensao A, Magalhaes J (2020) Physical exercise and liver “fitness”: Role of mitochondrial function and epigenetics-related mechanisms in non-alcoholic fatty liver disease. Mol Metab 32:1–14

    Article  CAS  PubMed  Google Scholar 

  222. Venditti P, Di Meo S (1996) Antioxidants, tissue damage, and endurance in trained and untrained young male rats. Arch Biochem Biophys 331:63–68

    Article  CAS  PubMed  Google Scholar 

  223. Ascensao A, Martins MJ, Santos-Alves E et al (2013) Modulation of hepatic redox status and mitochondrial metabolism by exercise: therapeutic strategy for liver diseases. Mitochondrion 13:862–870

    Article  CAS  PubMed  Google Scholar 

  224. Rector RS, Thyfault JP, Laye MJ et al (2008) Cessation of daily exercise dramatically alters precursors of hepatic steatosis in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. J Physiol 586:4241–4249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Rector RS, Thyfault JP, Morris RT et al (2008) Daily exercise increases hepatic fatty acid oxidation and prevents steatosis in Otsuka Long-Evans Tokushima Fatty rats. Am J Physiol Gastrointest Liver Physiol 294:G619–G626

    Article  CAS  PubMed  Google Scholar 

  226. Sun L, Shen W, Liu Z, Guan S, Liu J, Ding S (2010) Endurance exercise causes mitochondrial and oxidative stress in rat liver: effects of a combination of mitochondrial targeting nutrients. Life Sci 86:39–44

    Article  CAS  PubMed  Google Scholar 

  227. Samuel VT, Shulman GI (2012) Mechanisms for insulin resistance: common threads and missing links. Cell 148:852–871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Cohen JC, Horton JD, Hobbs HH (2011) Human fatty liver disease: old questions and new insights. Science 332:1519–1523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Chastin SF, Buck C, Freiberger E et al (2015) Systematic literature review of determinants of sedentary behaviour in older adults: a DEDIPAC study. Int J Behav Nutr Phys Act 12:127

    Article  PubMed  PubMed Central  Google Scholar 

  230. Gross B, Pawlak M, Lefebvre P, Staels B (2017) PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD. Nat Rev Endocrinol 13:36–49

    Article  CAS  PubMed  Google Scholar 

  231. Pawlak M, Lefebvre P, Staels B (2015) Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol 62:720–733

    Article  CAS  PubMed  Google Scholar 

  232. Musso G, Gambino R, Cassader M, Pagano G (2010) A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology 52:79–104

    Article  CAS  PubMed  Google Scholar 

  233. Bojic LA, Huff MW (2013) Peroxisome proliferator-activated receptor delta: a multifaceted metabolic player. Curr Opin Lipidol 24:171–177

    Article  CAS  PubMed  Google Scholar 

  234. Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A et al (2008) Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab 7:496–507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Riserus U, Sprecher D, Johnson T et al (2008) Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes 57:332–339

    Article  CAS  PubMed  Google Scholar 

  236. Promrat K, Lutchman G, Uwaifo GI et al (2004) A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 39:188–196

    Article  CAS  PubMed  Google Scholar 

  237. Colca JR, McDonald WG, Cavey GS et al (2013) Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)--relationship to newly identified mitochondrial pyruvate carrier proteins. PLoS One 8:e61551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Kalavalapalli S, Bril F, Koelmel JP et al (2018) Pioglitazone improves hepatic mitochondrial function in a mouse model of nonalcoholic steatohepatitis. Am J Physiol Endocrinol Metab 315:E163–E173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. McCommis KS, Chen Z, Fu X et al (2015) Loss of mitochondrial pyruvate carrier 2 in the liver leads to defects in gluconeogenesis and compensation via pyruvate-alanine cycling. Cell Metab 22:682–694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Shannon CE, Daniele G, Galindo C, Abdul-Ghani MA, DeFronzo RA, Norton L (2017) Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes. FEBS J 284:451–465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Cui J, Philo L, Nguyen P et al (2016) Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial. J Hepatol 65:369–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Joy TR, McKenzie CA, Tirona RG et al (2017) Sitagliptin in patients with non-alcoholic steatohepatitis: a randomized, placebo-controlled trial. World J Gastroenterol 23:141–150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Wu PB, Song Q, Yu YJ, Yu HG, Luo HS, Tan SY (2020) Effect of metformin on mitochondrial pathway of apoptosis and oxidative stress in cell model of nonalcoholic fatty liver disease. Zhonghua Gan Zang Bing Za Zhi 28:64–68

    CAS  PubMed  Google Scholar 

  244. Yu X, Hao M, Liu Y et al (2019) Liraglutide ameliorates non-alcoholic steatohepatitis by inhibiting NLRP3 inflammasome and pyroptosis activation via mitophagy. Eur J Pharmacol 864:172715

    Article  CAS  PubMed  Google Scholar 

  245. Watanabe M, Houten SM, Wang L et al (2004) Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 113:1408–1418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Porez G, Prawitt J, Gross B, Staels B (2012) Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease thematic review series: new lipid and lipoprotein targets for the treatment of cardiometabolic diseases. J Lipid Res 53:1723–1737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Calkin AC, Tontonoz P (2012) Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol 13:213–224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. de Aguiar Vallim TQ, Tarling EJ, Edwards PA (2013) Pleiotropic roles of bile acids in metabolism. Cell Metab 17:657–669

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  249. Jahn D, Rau M, Hermanns HM, Geier A (2015) Mechanisms of enterohepatic fibroblast growth factor 15/19 signaling in health and disease. Cytokine Growth Factor Rev 26:625–635

    Article  CAS  PubMed  Google Scholar 

  250. Lazaridis KN, Gores GJ, Lindor KD (2001) Ursodeoxycholic acid ‘mechanisms of action and clinical use in hepatobiliary disorders’. J Hepatol 35:134–146

    Article  CAS  PubMed  Google Scholar 

  251. Laurin J, Lindor KD, Crippin JS et al (1996) Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 23:1464–1467

    Article  CAS  PubMed  Google Scholar 

  252. Mueller M, Thorell A, Claudel T et al (2015) Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity. J Hepatol 62:1398–1404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Krahenbuhl S, Talos C, Fischer S, Reichen J (1994) Toxicity of bile acids on the electron transport chain of isolated rat liver mitochondria. Hepatology 19:471–479

    CAS  PubMed  Google Scholar 

  254. Krahenbuhl S, Talos C, Lauterburg BH, Reichen J (1995) Reduced antioxidative capacity in liver mitochondria from bile duct ligated rats. Hepatology 22:607–612

    CAS  PubMed  Google Scholar 

  255. Rolo AP, Oliveira PJ, Moreno AJ, Palmeira CM (2000) Bile acids affect liver mitochondrial bioenergetics: possible relevance for cholestasis therapy. Toxicol Sci 57:177–185

    Article  CAS  PubMed  Google Scholar 

  256. Krahenbuhl S, Fischer S, Talos C, Reichen J (1994) Ursodeoxycholate protects oxidative mitochondrial metabolism from bile acid toxicity: dose-response study in isolated rat liver mitochondria. Hepatology 20:1595–1601

    Article  CAS  PubMed  Google Scholar 

  257. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ (2018) Mechanisms of NAFLD development and therapeutic strategies. Nat Med 24:908–922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Luangmonkong T, Suriguga S, Mutsaers HAM, Groothuis GMM, Olinga P, Boersema M (2018) Targeting oxidative stress for the treatment of liver fibrosis. Rev Physiol Biochem Pharmacol 175:71–102. https://doi.org/10.1007/112_2018_10

    Article  CAS  PubMed  Google Scholar 

  259. Jiang C, Xie C, Li F et al (2015) Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 125:386–402

    Article  PubMed  Google Scholar 

  260. Chachay VS, Macdonald GA, Martin JH et al (2014) Resveratrol does not benefit patients with nonalcoholic fatty liver disease. Clini Gastroenterol Hepatol 12:2092–2103.e6

    Article  CAS  Google Scholar 

  261. Feillet-Coudray C, Fouret G, Ebabe Elle R et al (2014) The mitochondrial-targeted antioxidant MitoQ ameliorates metabolic syndrome features in obesogenic diet-fed rats better than Apocynin or Allopurinol. Free Radic Res 48:1232–1246

    Article  PubMed  Google Scholar 

  262. Fouret G, Tolika E, Lecomte J et al (2015) The mitochondrial-targeted antioxidant, MitoQ, increases liver mitochondrial cardiolipin content in obesogenic diet-fed rats. Biochim Biophys Acta 1847:1025–1035

    Article  CAS  PubMed  Google Scholar 

  263. Mercer JR, Yu E, Figg N et al (2012) The mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+/-/ApoE-/- mice. Free Radic Biol Med 52:841–849

    Article  CAS  PubMed  Google Scholar 

  264. Dhanasekaran A, Kotamraju S, Kalivendi SV et al (2004) Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis. J Biol Chem 279:37575–37587

    Article  CAS  PubMed  Google Scholar 

  265. Gane EJ, Weilert F, Orr DW et al (2010) The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients. Liver Int 30:1019–1026

    Article  CAS  PubMed  Google Scholar 

  266. Baselga-Escudero L, Souza-Mello V, Pascual-Serrano A et al (2017) Beneficial effects of the Mediterranean spices and aromas on non-alcoholic fatty liver disease. Trends Food Sci Technol 61:141–159

    Article  CAS  Google Scholar 

  267. Saller R, Meier R, Brignoli R (2001) The use of silymarin in the treatment of liver diseases. Drugs 61:2035–2063

    Article  CAS  PubMed  Google Scholar 

  268. Trappoliere M, Caligiuri A, Schmid M et al (2009) Silybin, a component of sylimarin, exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells. J Hepatol 50:1102–1111

    Article  CAS  PubMed  Google Scholar 

  269. Solhi H, Ghahremani R, Kazemifar AM, Hoseini Yazdi Z (2014) Silymarin in treatment of non-alcoholic steatohepatitis: a randomized clinical trial. Caspian J Intern Med 5:9–12

    PubMed  PubMed Central  Google Scholar 

  270. Loguercio C, Andreone P, Brisc C et al (2012) Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial. Free Radic Biol Med 52:1658–1665

    Article  CAS  PubMed  Google Scholar 

  271. Colman E (2007) Dinitrophenol and obesity: an early twentieth-century regulatory dilemma. Regul Toxicol Pharmacol 48:115–117

    Article  CAS  PubMed  Google Scholar 

  272. Zhang R, Chu K, Zhao N et al (2019) Corilagin alleviates nonalcoholic fatty liver disease in high-fat diet-induced C57BL/6 mice by ameliorating oxidative stress and restoring autophagic flux. Front Pharmacol 10:1693

    Article  CAS  PubMed  Google Scholar 

  273. Perry RJ, Zhang D, Zhang XM, Boyer JL, Shulman GI (2015) Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science 347:1253–1256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Dobrzyn P, Dobrzyn A, Miyazaki M et al (2004) Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver. Proc Natl Acad Sci U S A 101:6409–6414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Dobrzyn A, Ntambi JM (2005) Stearoyl-CoA desaturase as a new drug target for obesity treatment. Obes Rev 6:169–174

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

These projects received funding from the European Union’s Horizon 2020 Research and Innovation program under the Marie Skłodowska-Curie Grant Agreement No. 722619 (FOIE GRAS) and Grant Agreement No. 734719 (mtFOIE GRAS). EMM and HS are recipients of Marie Skłodowska-Curie Grant Agreement No. 722619. This chapter is dedicated to Prof. Giuseppe Palasciano and Prof. Sergio Papa (University of Bari, Italy), Prof. Hermon Dowling (University of London, UK), Prof. Gerard P. vanBerge-Henegouwen (Utrecht University, The Netherlands), and Prof. Tom LaMont (Harvard Medical School, Boston, USA). We are indebted to Prof. Salvatore Passarella (University of Foggia, Italy) for helpful scientific discussion.

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Authors and Affiliations

  1. Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy

    Ignazio Grattagliano, Agostino Di Ciaula, Emilio Molina-Molina, Harshitha Shanmugam & Piero Portincasa

  2. Italian College of General Practitioners and Primary Care, Bari, Italy

    Ignazio Grattagliano

  3. Department of Anatomy, Medical University of Lublin, Lublin, Poland

    Jacek Baj

  4. Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, Bari, Italy

    Gabriella Garruti

  5. Division of Gastroenterology and Liver Diseases, Department of Medicine and Genetics, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, USA

    David Q. -H. Wang

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  1. Ignazio Grattagliano
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  7. David Q. -H. Wang
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  8. Piero Portincasa
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Correspondence to Piero Portincasa .

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Editors and Affiliations

  1. Department of Life Sciences, University of Coimbra, Coimbra, Portugal

    Carlos M. Palmeira

  2. Department of Life Sciences, University of Coimbra, Coimbra, Portugal

    Anabela P. Rolo

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Grattagliano, I. et al. (2021). Protocols for Mitochondria as the Target of Pharmacological Therapy in the Context of Nonalcoholic Fatty Liver Disease (NAFLD). In: Palmeira, C.M., Rolo, A.P. (eds) Mitochondrial Regulation. Methods in Molecular Biology, vol 2310. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1433-4_12

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  • DOI: https://doi.org/10.1007/978-1-0716-1433-4_12

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