Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende

Klimawandel und Gesundheit: Was Sie in der Hausarztpraxis wissen müssen und tun können

Die Folgen des Klimwandels haben einen direkten Einfluss auf die Primärversorgung in Deutschland: Hitzeschutz insbesondere bei älteren Patienten, die Zunahme von Infektionen und die Verlängerung der Allergiesesaison spielen medizinisch eine bedeutsame Rolle. Aber auch in der Prävention und der Aufklärung der Patienten kommt den Hausärztinnen und -ärzten eine besondere Rolle zu. Direkt aus der Praxis berichtet im Live-Webinar am 13. Mai von 18 bis 19 Uhr unser Experte Dr. med. Robin Maitra.
Erweiterte Suche
Anmelden
nach oben
Current Hepatology Reports
Erschienen in: Current Hepatology Reports 4/2018

31.10.2018 | Fatty Liver Disease (Z Younossi, Section Editor)

Pathogenesis of NASH: the Impact of Multiple Pathways

verfasst von: Mazen Noureddin, Arun J. Sanyal

Erschienen in: Current Hepatology Reports | Ausgabe 4/2018

Einloggen, um Zugang zu erhalten

Abstract

Purpose of review

Advancing our understanding of the mechanisms that underlie NASH pathogenesis.

Recent findings

Recent findings on NASH pathogenesis have expanded our understanding of its complexity including (1) there are multiple parallel hits that lead to NASH; (2) the microbiota play an important role in pathogenesis, with bacterial species recently shown to accurately differentiate between NAFL and NASH patients; (3) the main drivers of liver cell injury are lipotoxicity caused by free fatty acids (FFAs) and their derivatives combined with mitochondrial dysfunction; (4) decreased endoplasmic reticulum (ER) efficiency with increased demand for protein synthesis/folding/repair results in ER stress, protracted unfolded protein response, and apoptosis; (5) upregulated proteins involved in multiple pathways including JNK, CHOP, PERK, BH3-only proteins, and caspases result in mitochondrial dysfunction and apoptosis; and (6) subtypes of NASH in which these pathophysiological pathways vary may require patient subtype identification to choose effective therapy.

Summary

Recent pathogenesis studies may lead to important therapeutic advances, already seen in patients treated with ACC, ASK1 and SCD1 inhibitors, and FXR agonists. Further, advancing our understanding of mechanisms underlying NASH pathogenesis and the complex interplay between them will be crucial for developing effective therapies.
Literatur
1.
•• Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84 Important updated study on the epidemiology of NAFLD. PubMed
2.
Day CP. Natural history of NAFLD: remarkably benign in the absence of cirrhosis. Gastroenterology. 2005;129:375–8.PubMed
3.
Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–73.PubMed
4.
Wong VW, Wong GL, Choi PC, et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut. 2010;59:969–74.PubMed
5.
•• Setiawan VW, Stram DO, Porcel J, et al. Prevalence of chronic liver disease and cirrhosis by underlying cause in understudied ethnic groups: the multiethnic cohort. Hepatology. 2016;64:1969–77 First study to show NAFLD is the leading cause of cirrhosis in few multiethnic groups. PubMedPubMedCentral
6.
•• Noureddin M, Vipani A, Bresee C, et al. NASH leading cause of liver transplant in women: updated analysis of indications for liver transplant and ethnic and gender variances. Am J Gastroenterol. 2018. https://​doi.​org/​10.​1038/​s41395-018-0088-6. First study to show that NASH is the leading cause of liver transplant in women.
7.
Banini BA, Sanyal AJ. Nonalcoholic fatty liver disease: epidemiology, pathogenesis, natural history, diagnosis, and current treatment options. Clin Med Insights Ther. 2016;8:75–84.PubMedPubMedCentral
8.
•• Mota M, Banini BA, Cazanave SC, et al. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism. 2016;65:1049–61 Comperhensive review on lipotoxicity and glucotoxicity. PubMedPubMedCentral
9.
Caligiuri A, Gentilini A, Marra F. Molecular pathogenesis of NASH. Int J Mol Sci. 2016;17.
10.
Yu J, Marsh S, Hu J, et al. The pathogenesis of nonalcoholic fatty liver disease: interplay between diet, gut microbiota, and genetic background. Gastroenterol Res Pract. 2016;2016:2862173.PubMedPubMedCentral
11.
• BasuRay S, Smagris E, Cohen JC, et al. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology. 2017;66:1111–24 Update on the mechanism of PNPLA3 in NAFLD. PubMedPubMedCentral
12.
• Bruschi FV, Claudel T, Tardelli M, et al. The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells. Hepatology. 2017;65:1875–90 Update on the mechanism of PNPLA3 in NAFLD. PubMed
13.
• Musso G, Cassader M, Paschetta E, et al. TM6SF2 may drive postprandial lipoprotein cholesterol toxicity away from the vessel walls to the liver in NAFLD. J Hepatol. 2016;64:979–81 Update on the mechanism of TM6SF2 in NAFLD. PubMed
14.
Chalasani N, Guo X, Loomba R, et al. Genome-wide association study identifies variants associated with histologic features of nonalcoholic fatty liver disease. Gastroenterology. 2010;139:1567–76 1576 e1561–1566.PubMedPubMedCentral
15.
Di Filippo M, Moulin P, Roy P, et al. Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. J Hepatol. 2014;61:891–902.PubMed
16.
Petta S, Valenti L, Tuttolomondo A, et al. Interferon lambda 4 rs368234815 TT>deltaG variant is associated with liver damage in patients with nonalcoholic fatty liver disease. Hepatology. 2017;66:1885–93.PubMed
17.
Santoro N, Zhang CK, Zhao H, et al. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology. 2012;55:781–9.PubMed
18.
Valenti L, Motta BM, Alisi A, et al. LPIN1 rs13412852 polymorphism in pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2012;54:588–93.PubMed
19.
Abul-Husn NS, Cheng X, Li AH, et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med. 2018;378:1096–106.PubMedPubMedCentral
20.
Sun C, Fan JG, Qiao L. Potential epigenetic mechanism in non-alcoholic fatty liver disease. Int J Mol Sci. 2015;16:5161–79.PubMedPubMedCentral
21.
Murphy SK, Yang H, Moylan CA, et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology. 2013;145:1076–87.PubMedPubMedCentral
22.
Noureddin M, Mato JM, Lu SC. Nonalcoholic fatty liver disease: update on pathogenesis, diagnosis, treatment and the role of S-adenosylmethionine. Exp Biol Med (Maywood). 2015;240:809–20.
23.
Szabo G, Csak T. Role of microRNAs in NAFLD/NASH. Dig Dis Sci. 2016;61:1314–24.PubMed
24.
25.
• Loyer X, Paradis V, Henique C, et al. Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARalpha expression. Gut. 2016;65:1882–94 A study on the role of miRNA in NAFLD. PubMed
26.
Jensen T, Abdelmalek MF, Sullivan S, et al. Fructose and sugar: a major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018;68:1063–75.PubMedPubMedCentral
27.
Leamy AK, Egnatchik RA, Young JD. Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease. Prog Lipid Res. 2013;52:165–74.PubMed
28.
Enjoji M, Yasutake K, Kohjima M, et al. Nutrition and nonalcoholic fatty liver disease: the significance of cholesterol. Int J Hepatol. 2012;2012:925807.PubMedPubMedCentral
29.
Aigner E, Strasser M, Haufe H, et al. A role for low hepatic copper concentrations in nonalcoholic fatty liver disease. Am J Gastroenterol. 2010;105:1978–85.PubMed
30.
Tallino S, Duffy M, Ralle M, et al. Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease. J Nutr Biochem. 2015;26:996–1006.PubMedPubMedCentral
31.
Nelson JE, Klintworth H, Kowdley KV. Iron metabolism in nonalcoholic fatty liver disease. Curr Gastroenterol Rep. 2012;14:8–16.PubMed
32.
• Zelber-Sagi S, Ivancovsky-Wajcman D, Fliss Isakov N, et al. High red and processed meat consumption is associated with non-alcoholic fatty liver disease and insulin resistance. J Hepatol. 2018;68:1239–46 Update on diet association with NAFLD. PubMed
33.
Meek TH, Morton GJ. The role of leptin in diabetes: metabolic effects. Diabetologia. 2016;59:928–32.PubMed
34.
Ikejima K, Honda H, Yoshikawa M, et al. Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001;34:288–97.PubMed
35.
Polyzos SA, Aronis KN, Kountouras J, et al. Circulating leptin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Diabetologia. 2016;59:30–43.PubMed
36.
Polyzos SA, Kountouras J, Mantzoros CS, et al. Effects of combined low-dose spironolactone plus vitamin E vs vitamin E monotherapy on insulin resistance, non-invasive indices of steatosis and fibrosis, and adipokine levels in non-alcoholic fatty liver disease: a randomized controlled trial. Diabetes Obes Metab. 2017;19:1805–9.PubMed
37.
Kamran F, Rother KI, Cochran E, et al. Consequences of stopping and restarting leptin in an adolescent with lipodystrophy. Horm Res Paediatr. 2012;78:320–5.PubMedPubMedCentral
38.
Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346:570–8.PubMed
39.
Park JY, Chong AY, Cochran EK, et al. Type 1 diabetes associated with acquired generalized lipodystrophy and insulin resistance: the effect of long-term leptin therapy. J Clin Endocrinol Metab. 2008;93:26–31.PubMed
40.
Safar Zadeh E, Lungu AO, Cochran EK, et al. The liver diseases of lipodystrophy: the long-term effect of leptin treatment. J Hepatol. 2013;59:131–7.PubMed
41.
Dadson K, Liu Y, Sweeney G. Adiponectin action: a combination of endocrine and autocrine/paracrine effects. Front Endocrinol (Lausanne). 2011;2:62.
42.
Kusminski CM, Scherer PE. Mitochondrial dysfunction in white adipose tissue. Trends Endocrinol Metab. 2012;23:435–43.PubMedPubMedCentral
43.
Otani H. Oxidative stress as pathogenesis of cardiovascular risk associated with metabolic syndrome. Antioxid Redox Signal. 2011;15:1911–26.PubMed
44.
Polyzos SA, Kountouras J, Zavos C. Nonlinear distribution of adiponectin in patients with nonalcoholic fatty liver disease limits its use in linear regression analysis. J Clin Gastroenterol. 2010;44:229–30 author reply 230-221.PubMed
45.
van der Poorten D, Samer CF, Ramezani-Moghadam M, et al. Hepatic fat loss in advanced nonalcoholic steatohepatitis: are alterations in serum adiponectin the cause? Hepatology. 2013;57:2180–8.PubMed
46.
Joshi-Barve S, Kirpich I, Cave MC, et al. Alcoholic, nonalcoholic, and toxicant-associated steatohepatitis: mechanistic similarities and differences. Cell Mol Gastroenterol Hepatol. 2015;1:356–67.PubMedPubMedCentral
47.
Boursier J, Mueller O, Barret M, et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology. 2016;63:764–75.PubMedPubMedCentral
48.
Farhadi A, Gundlapalli S, Shaikh M, et al. Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis. Liver Int. 2008;28:1026–33.PubMedPubMedCentral
49.
Schneider KM, Bieghs V, Heymann F, et al. CX3CR1 is a gatekeeper for intestinal barrier integrity in mice: limiting steatohepatitis by maintaining intestinal homeostasis. Hepatology. 2015;62:1405–16.PubMed
50.
Bashiardes S, Shapiro H, Rozin S, et al. Non-alcoholic fatty liver and the gut microbiota. Mol Metab. 2016;5:782–94.PubMedPubMedCentral
51.
•• Loomba R, Seguritan V, Li W, et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab. 2017;25:1054–1062 e1055 Study on the role of gut microbiome in NAFLD and assication with severity of the disease. PubMedPubMedCentral
52.
Mouzaki M, Comelli EM, Arendt BM, et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology. 2013;58:120–7.PubMed
53.
Zhu L, Baker SS, Gill C, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology. 2013;57:601–9.PubMed
54.
Wong VW, Wong GL, Chan HY, et al. Bacterial endotoxin and non-alcoholic fatty liver disease in the general population: a prospective cohort study. Aliment Pharmacol Ther. 2015;42:731–40.PubMed
55.
Oseini AM, Sanyal AJ. Therapies in non-alcoholic steatohepatitis (NASH). Liver Int. 2017;37 Suppl 1:97–103.PubMed
56.
Rotman Y, Sanyal AJ. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease. Gut. 2017;66:180–90.PubMed
57.
Puri P, Baillie RA, Wiest MM, et al. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology. 2007;46:1081–90.PubMed
58.
Arguello G, Balboa E, Arrese M, et al. Recent insights on the role of cholesterol in non-alcoholic fatty liver disease. Biochim Biophys Acta. 2015;1852:1765–78.PubMed
59.
Ferreira DM, Afonso MB, Rodrigues PM, et al. c-Jun N-terminal kinase 1/c-Jun activation of the p53/microRNA 34a/sirtuin 1 pathway contributes to apoptosis induced by deoxycholic acid in rat liver. Mol Cell Biol. 2014;34:1100–20.PubMedPubMedCentral
60.
Lim JS, Mietus-Snyder M, Valente A, et al. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol. 2010;7:251–64.PubMed
61.
Kunde SS, Roede JR, Vos MB, et al. Hepatic oxidative stress in fructose-induced fatty liver is not caused by sulfur amino acid insufficiency. Nutrients. 2011;3:987–1002.PubMedPubMedCentral
62.
Pooranaperundevi M, Sumiyabanu MS, Viswanathan P, et al. Insulin resistance induced by high-fructose diet potentiates carbon tetrachloride hepatotoxicity. Toxicol Ind Health. 2010;26:89–104.PubMed
63.
Sivaraman K, Senthilkumar GP, Sankar P, et al. Attenuation of oxidative stress, inflammation and insulin resistance by allium sativum in fructose-fed male rats. J Clin Diagn Res. 2013;7:1860–2.
64.
Wei Y, Pagliassotti MJ. Hepatospecific effects of fructose on c-Jun NH2-terminal kinase: implications for hepatic insulin resistance. Am J Physiol Endocrinol Metab. 2004;287:E926–33.PubMed
65.
Iruarrizaga-Lejarreta M, Varela-Rey M, Fernandez-Ramos D, et al. Role of Aramchol in steatohepatitis and fibrosis in mice. Hepatol Commun. 2017;1:911–27.PubMedPubMedCentral
66.
67.
Koliaki C, Szendroedi J, Kaul K, et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab. 2015;21:739–46.PubMed
68.
Fromenty B, Robin MA, Igoudjil A, et al. The ins and outs of mitochondrial dysfunction in NASH. Diabetes Metab. 2004;30:121–38.PubMed
69.
Gariani K, Menzies KJ, Ryu D, et al. Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology. 2016;63:1190–204.PubMed
70.
Penke M, Larsen PS, Schuster S, et al. Hepatic NAD salvage pathway is enhanced in mice on a high-fat diet. Mol Cell Endocrinol. 2015;412:65–72.PubMed
71.
Emery MG, Fisher JM, Chien JY, et al. CYP2E1 activity before and after weight loss in morbidly obese subjects with nonalcoholic fatty liver disease. Hepatology. 2003;38:428–35.PubMed
72.
Weltman MD, Farrell GC, Hall P, et al. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology. 1998;27:128–33.PubMed
73.
• Win S, Than TA, Le BH, et al. Sab (Sh3bp5) dependence of JNK mediated inhibition of mitochondrial respiration in palmitic acid induced hepatocyte lipotoxicity. J Hepatol. 2015;62:1367–74 New study that gives insight into the JNK-mitochodria pathway in NAFLD. PubMedPubMedCentral
74.
McCommis KS, Hodges WT, Brunt EM, et al. Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis. Hepatology. 2017;65:1543–56.PubMedPubMedCentral
75.
Feldstein AE, Werneburg NW, Canbay A, et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology. 2004;40:185–94.PubMed
76.
Li Z, Berk M, McIntyre TM, et al. The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity. Hepatology. 2008;47:1495–503.PubMedPubMedCentral
77.
Schwarz DS, Blower MD. The endoplasmic reticulum: structure, function and response to cellular signaling. Cell Mol Life Sci. 2016;73:79–94.PubMed
78.
Szegezdi E, Logue SE, Gorman AM, et al. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 2006;7:880–5.PubMedPubMedCentral
79.
Volmer R, van der Ploeg K, Ron D. Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains. Proc Natl Acad Sci U S A. 2013;110:4628–33.PubMedPubMedCentral
80.
Puri P, Mirshahi F, Cheung O, et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology. 2008;134:568–76.PubMed
81.
Lovering F, Morgan P, Allais C, et al. Rational approach to highly potent and selective apoptosis signal-regulating kinase 1 (ASK1) inhibitors. Eur J Med Chem. 2018;145:606–21.PubMed
82.
•• Loomba R, Lawitz E, Mantry PS, et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology. 2017. https://​doi.​org/​10.​1002/​hep.​29514. Role of ASK1 inhibtors in humans with NASH.
83.
•• Wang PX, Ji YX, Zhang XJ, et al. Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates. Nat Med. 2017;23:439–49 New study on new pathways in NASH. PubMed
84.
•• Zhang P, Wang PX, Zhao LP, et al. The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis. Nat Med. 2018;24:84–94 New study on new pathways related to ASK1 in NASH. PubMed
85.
Kakisaka K, Cazanave SC, Fingas CD, et al. Mechanisms of lysophosphatidylcholine-induced hepatocyte lipoapoptosis. Am J Physiol Gastrointest Liver Physiol. 2012;302:G77–84.PubMed
86.
Zhang J, Singh N, Robinson-Taylor KS, et al. Hepatocyte autophagy is linked to C/EBP-homologous protein, Bcl2-interacting mediator of cell death, and BH3-interacting domain death agonist gene expression. J Surg Res. 2015;195:588–95.PubMed
87.
Feldstein AE, Canbay A, Angulo P, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology. 2003;125:437–43.PubMed
88.
Hirsova P, Gores GJ. Death receptor-mediated cell death and proinflammatory signaling in nonalcoholic steatohepatitis. Cell Mol Gastroenterol Hepatol. 2015;1:17–27.PubMed
89.
Schuster S, Cabrera D, Arrese M, et al. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol. 2018;15:349–64.PubMed
90.
91.
Meli R, Mattace Raso G, Calignano A. Role of innate immune response in non-alcoholic fatty liver disease: metabolic complications and therapeutic tools. Front Immunol. 2014;5:177.PubMedPubMedCentral
92.
Miura K, Yang L, van Rooijen N, et al. Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology. 2013;57:577–89.PubMedPubMedCentral
93.
Rahman K, Desai C, Iyer SS, et al. Loss of junctional adhesion molecule a promotes severe steatohepatitis in mice on a diet high in saturated fat, fructose, and cholesterol. Gastroenterology. 2016;151:733–746 e712.PubMedPubMedCentral
94.
Jia L, Vianna CR, Fukuda M, et al. Hepatocyte toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nat Commun. 2014;5:3878.PubMedPubMedCentral
95.
Okin D, Medzhitov R. The effect of sustained inflammation on hepatic mevalonate pathway results in hyperglycemia. Cell. 2016;165:343–56.PubMedPubMedCentral
96.
Spruss A, Kanuri G, Wagnerberger S, et al. Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology. 2009;50:1094–104.PubMed
97.
Palsson-McDermott EM, Doyle SL, McGettrick AF, et al. TAG, a splice variant of the adaptor TRAM, negatively regulates the adaptor MyD88-independent TLR4 pathway. Nat Immunol. 2009;10:579–86.PubMed
98.
Wang Y, Chen T, Han C, et al. Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4. Blood. 2007;110:962–71.PubMed
99.
Zhang N, Liang H, Farese RV, et al. Pharmacological TLR4 inhibition protects against acute and chronic fat-induced insulin resistance in rats. PLoS One. 2015;10:e0132575.PubMedPubMedCentral
100.
•• Zhao GN, Zhang P, Gong J, et al. Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4. Nat Med. 2017;23:742–52 A study exploring new pathways in NASH related to TLR4. PubMed
101.
Mridha AR, Wree A, Robertson AAB, et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J Hepatol. 2017;66:1037–46.PubMedPubMedCentral
102.
Verdelho Machado M, Diehl AM. The hedgehog pathway in nonalcoholic fatty liver disease. Crit Rev Biochem Mol Biol. 2018;53:264–78.PubMed
103.
Syn WK, Oo YH, Pereira TA, et al. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology. 2010;51:1998–2007.PubMedPubMedCentral
104.
Guy CD, Suzuki A, Zdanowicz M, et al. Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology. 2012;55:1711–21.PubMedPubMedCentral
105.
Guy CD, Suzuki A, Abdelmalek MF, et al. Treatment response in the PIVENS trial is associated with decreased Hedgehog pathway activity. Hepatology. 2015;61:98–107.PubMed
106.
Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65:1038–48.PubMed
107.
108.
Fuchs CD, Traussnigg SA, Trauner M. Nuclear receptor modulation for the treatment of nonalcoholic fatty liver disease. Semin Liver Dis. 2016;36:69–86.PubMed
109.
Francque S, Verrijken A, Caron S, et al. PPARalpha gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J Hepatol. 2015;63:164–73.PubMed
110.
Shan W, Nicol CJ, Ito S, et al. Peroxisome proliferator-activated receptor-beta/delta protects against chemically induced liver toxicity in mice. Hepatology. 2008;47:225–35.PubMed
111.
• Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150:1147–1159 e1145 Role of peroxisome proliferator-activated receptor-alpha and -delta in humans with NASH. PubMed
112.
Kunne C, Acco A, Duijst S, et al. FXR-dependent reduction of hepatic steatosis in a bile salt deficient mouse model. Biochim Biophys Acta. 2014;1842:739–46.PubMed
113.
Cipriani S, Mencarelli A, Palladino G, et al. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res. 2010;51:771–84.PubMedPubMedCentral
114.
Ma Y, Huang Y, Yan L, et al. Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm Res. 2013;30:1447–57.PubMedPubMedCentral
115.
•• Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956–65 Role of FXR agnosits in humans with NASH. PubMed
116.
Degirolamo C, Modica S, Vacca M, et al. Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation. Hepatology. 2015;61:161–70.PubMed
117.
Fu L, John LM, Adams SH, et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology. 2004;145:2594–603.PubMed
118.
Tomlinson E, Fu L, John L, et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology. 2002;143:1741–7.PubMed
119.
Fang S, Suh JM, Reilly SM, et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 2015;21:159–65.PubMedPubMedCentral
120.
Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14:397–411.PubMed
121.
Bansal R, van Baarlen J, Storm G, et al. The interplay of the notch signaling in hepatic stellate cells and macrophages determines the fate of liver fibrogenesis. Sci Rep. 2015;5:18272.PubMedPubMedCentral
122.
Borthwick LA, Mann DA. Liver: Osteopontin and HMGB1: novel regulators of HSC activation. Nat Rev Gastroenterol Hepatol. 2016;13:320–2.PubMed
123.
Schnabl B, Bradham CA, Bennett BL, et al. TAK1/JNK and p38 have opposite effects on rat hepatic stellate cells. Hepatology. 2001;34:953–63.PubMed
124.
•• Alonso C, Fernandez-Ramos D, Varela-Rey M, et al. Metabolomic identification of subtypes of nonalcoholic steatohepatitis. Gastroenterology. 2017;152:1449–1461 e1447 A study exploring the NASH-subtypes in humans. PubMedPubMedCentral
Metadaten
Titel
Pathogenesis of NASH: the Impact of Multiple Pathways
verfasst von
Mazen Noureddin
Arun J. Sanyal
Publikationsdatum
31.10.2018
Verlag
Springer US
Erschienen in
Current Hepatology Reports / Ausgabe 4/2018
Elektronische ISSN: 2195-9595
DOI
https://doi.org/10.1007/s11901-018-0425-7

Weitere Artikel der Ausgabe 4/2018

Current Hepatology Reports 4/2018 Zur Ausgabe

Fatty Liver Disease (Z Younossi, Section Editor)

The Clinical and Economic Burden of Nonalcoholic Steatohepatitis

Portal Hypertension (J Gonzalez-Abraldes and E Tsochatzis, Section Editors)

Portal Cavernoma Cholangiopathy

Hepatic Cancer (A Singal and A Mufti, Section Editors)

The Impact of Direct-acting Antiviral Therapy for Hepatitis C on Hepatocellular Carcinoma Risk

Portal Hypertension (J Gonzalez-Abraldes and E Tsochatzis, Section Editors)

Small Esophageal Varices in Patients with Cirrhosis—Should We Treat Them?

Hepatitis B (J Lim, Section Editor)

Prevention and Management of HBV Infection in Patients with Chronic Kidney Disease Requiring Renal Transplantation

Hepatitis B (J Lim, Section Editor)

Long-term Outcomes in Patients with HBV Treated with Antiviral Agents

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Battle of Experts: Sport vs. Spritze bei Adipositas und Typ-2-Diabetes

11.05.2024 DDG-Jahrestagung 2024 Kongressbericht

Im Battle of Experts traten zwei Experten auf dem Diabeteskongress gegeneinander an: Die eine vertrat die Auffassung „Sport statt Spritze“ bei Adipositas und Typ-2-Diabetes, der andere forderte „Spritze statt Sport!“ Am Ende waren sie sich aber einig: Die Kombination aus beidem erzielt die besten Ergebnisse.

Triglyzeridsenker schützt nicht nur Hochrisikopatienten

10.05.2024 Hypercholesterinämie Nachrichten

Patienten mit Arteriosklerose-bedingten kardiovaskulären Erkrankungen, die trotz Statineinnahme zu hohe Triglyzeridspiegel haben, profitieren von einer Behandlung mit Icosapent-Ethyl, und zwar unabhängig vom individuellen Risikoprofil.

Gibt es eine Wende bei den bioresorbierbaren Gefäßstützen?

10.05.2024 Periphere arterielle Verschlusskrankheit Nachrichten

In den USA ist erstmals eine bioresorbierbare Gefäßstütze – auch Scaffold genannt – zur Rekanalisation infrapoplitealer Arterien bei schwerer PAVK zugelassen worden. Das markiert einen Wendepunkt in der Geschichte dieser speziellen Gefäßstützen.

Vorsicht, erhöhte Blutungsgefahr nach PCI!

10.05.2024 Koronare Herzerkrankung Nachrichten

Nach PCI besteht ein erhöhtes Blutungsrisiko, wenn die Behandelten eine verminderte linksventrikuläre Ejektionsfraktion aufweisen. Das Risiko ist umso höher, je stärker die Pumpfunktion eingeschränkt ist.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen
Bildnachweise