Horm Metab Res 2013; 45(11): 795-801
DOI: 10.1055/s-0033-1353209
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Olive Oil Attenuates the Cholesterol-induced Development of Nonalcoholic Steatohepatitis Despite Increased Insulin Resistance in a Rodent Model

R. Buettner
1   Department of Internal Medicine I, University Medical Center Regensburg, Regensburg, Germany
,
M. Ascher
1   Department of Internal Medicine I, University Medical Center Regensburg, Regensburg, Germany
,
E. Gäbele
1   Department of Internal Medicine I, University Medical Center Regensburg, Regensburg, Germany
,
C. Hellerbrand
1   Department of Internal Medicine I, University Medical Center Regensburg, Regensburg, Germany
,
R. Kob
2   Institute for Biomedicine of Aging, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nürnberg, Germany
,
T. Bertsch
3   Institute of Clinical Chemistry, Laboratory Medicine and Transfusion Medicine, Nürnberg Hospital, Nürnberg, Germany
4   Institute of Clinical Chemistry, University Hospital Mannheim, Mannheim, Germany
,
L. C. Bollheimer
2   Institute for Biomedicine of Aging, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nürnberg, Germany
› Author Affiliations
Further Information

Publication History

received 17 January 2013

accepted 29 July 2013

Publication Date:
30 August 2013 (online)

Abstract

It is indefinite whether nonalcoholic steatohepatitis (NASH) results as by-product from general metabolic perturbations and adipokine dysregulations or whether defined dietary factors also play a pathogenetic role. Here, we examine the effects of a modification of dietary lipids in a NASH inducing diet on metabolic changes as well as hepatic steatosis, inflammation, and fibrosis in rats. Male Wistar rats were fed with variations of the atherogenic diet (AD), which induces pathophysiological changes resembling human NASH. Dietary variants (AD without cholesterol, cholate, or choline; change of neutral fat to olive oil or coconut oil) were fed for 8 weeks. Insulin resistance, adipokine profile, liver histology, and lipid content as well as expression of proinflammatory and profibrogenic genes were examined. AD led to clear signs of hepatic steatosis and inflammation together with an increase in TNF and collagen type 1 expression. AD without cholesterol showed markedly less liver damage without changes of insulin action and adipokine profile. AD with olive oil and AD without cholate clearly attenuated hepatic inflammation, whereas fat deposition and features of the metabolic syndrome were increased in these animals. Insulin resistance and hepatic fat deposition per se do not cause significant hepatic inflammation in this rodent model. However, dietary cholesterol is an important causal agent for the development of NASH. Olive oil plays a protective role in this respect, which might be due to the high content of monounsaturated fatty acids.

 
  • References

  • 1 Poonawala A, Nair SP, Thuluvath PJ. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study. Hepatology 2000; 32: 689-692
  • 2 Williams CH, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA. Prevalence of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among a Largely Middle-Aged Population Utilizing Ultrasound and Liver Biopsy: A Prospective Study. Gastroenterology 2011; 140: 124-131
  • 3 de Oliveira CP, de Mello ES, Alves VA, Saviero SM, Strauss E. Changes in histological criteria lead to different prevalences of nonalcoholic steatohepatitis in severe obesity. Ann Hepatol 2007; 6: 255-261
  • 4 Brunt EM. Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2010; 7: 195-203
  • 5 Wierzbicki AS, Oben J. Nonalcoholic fatty liver disease and lipids. Curr Opin Lipidol 2012; 23: 345-352
  • 6 Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 2008; 134: 424-431
  • 7 Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 2010; 52: 774-788
  • 8 Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest 2008; 118: 829-838
  • 9 Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis 2008; 28: 370-379
  • 10 Marra F, Bertolani C. Adipokines in liver diseases. Hepatology 2009; 50: 957-969
  • 11 Musso G, Gambino R, De Michieli F, Cassader M, Rizzetto M, Durazzo M, Faga E, Silli B, Pagano G. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 2003; 37: 909-916
  • 12 Toshimitsu K, Matsuura B, Ohkubo I, Niiya T, Furukawa S, Hiasa Y, Kawamura M, Ebihara K, Onji M. Dietary habits and nutrient intake in non-alcoholic steatohepatitis. Nutrition 2007; 23: 46-52
  • 13 Buettner R, Parhofer KG, Woenckhaus M, Wrede CE, Kunz-Schughart LA, Scholmerich J, Bollheimer LC. Defining high-fat-diet rat models: metabolic and molecular effects of different fat types. J Mol Endocrinol 2006; 36: 485-501
  • 14 Gentile CL, Pagliassotti MJ. The role of fatty acids in the development and progression of nonalcoholic fatty liver disease. J Nutr Biochem 2008; 19: 567-576
  • 15 Wei Y, Wang D, Topczewski F, Pagliassotti MJ. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol Metab 2006; 291: E275-E281
  • 16 Paigen B, Morrow A, Brandon C, Mitchell D, Holmes P. Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis 1985; 57: 65-73
  • 17 Matsuzawa N, Takamura T, Kurita S, Misu H, Ota T, Ando H, Yokoyama M, Honda M, Zen Y, Nakanuma Y, Miyamoto K, Kaneko S. Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology 2007; 46: 1392-1403
  • 18 Puri P, Baillie RA, Wiest MM, Mirshahi F, Choudhury J, Cheung O, Sargeant C, Contos MJ, Sanyal AJ. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 2007; 46: 1081-1090
  • 19 Liao F, Andalibi A, deBeer FC, Fogelman AM, Lusis AJ. Genetic control of inflammatory gene induction and NF-kappa B-like transcription factor activation in response to an atherogenic diet in mice. J Clin Invest 1993; 91: 2572-2579
  • 20 Dorn C, Riener MO, Kirovski G, Saugspier M, Steib K, Weiss TS, Gabele E, Kristiansen G, Hartmann A, Hellerbrand C. Expression of fatty acid synthase in nonalcoholic fatty liver disease. Int J Clin Exp Pathol 2010; 3: 505-514
  • 21 Caballero F, Fernandez A, De Lacy AM, Fernandez-Checa JC, Caballeria J, Garcia-Ruiz C. Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH. J Hepatol 2009; 50: 789-796
  • 22 Vinaixa M, Rodriguez MA, Rull A, Beltran R, Blade C, Brezmes J, Canellas N, Joven J, Correig X. Metabolomic assessment of the effect of dietary cholesterol in the progressive development of fatty liver disease. J Proteome Res 2010; 9: 2527-2538
  • 23 Bieghs V, Wouters K, van Gorp PJ, Gijbels MJ, de Winther MP, Binder CJ, Lutjohann D, Febbraio M, Moore KJ, van Bilsen M, Hofker MH, Shiri-Sverdlov R. Role of scavenger receptor A and CD36 in diet-induced nonalcoholic steatohepatitis in hyperlipidemic mice. Gastroenterology 2010; 138: 2477-2486 2486.e1–2486.e3
  • 24 Wouters K, van Gorp PJ, Bieghs V, Gijbels MJ, Duimel H, Lütjohann D, Kerksiek A, van Kruchten R, Maeda N, Staels B, van Bilsen M, Shiri-Sverdlov R, Hofker MH. Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis. Hepatology 2008; 48: 474-486
  • 25 Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: A randomized placebo-controlled trial. J Clin Gastroenterol 2009; 43: 990-994
  • 26 Basciano H, Miller AE, Naples M, Baker C, Kohen R, Xu E, Su Q, Allister EM, Wheeler MB, Adeli K. Metabolic effects of dietary cholesterol in an animal model of insulin resistance and hepatic steatosis. Am J Physiol Endocrinol Metab 2009; 297: E462-E473
  • 27 Malhi H, Gores GJ. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis 2008; 28: 360-369
  • 28 Hussein O, Grosovski M, Lasri E, Svalb S, Ravid U, Assy N. Monounsaturated fat decreases hepatic lipid content in non-alcoholic fatty liver disease in rats. World J Gastroenterol 2007; 13: 361-368
  • 29 Cazanave SC, Mott JL, Elmi NA, Bronk SF, Werneburg NW, Akazawa Y, Kahraman A, Garrison SP, Zambetti GP, Charlton MR, Gores GJ. JNK1-dependent PUMA expression contributes to hepatocyte lipoapoptosis. J Biol Chem 2009; 284: 26591-26602
  • 30 Malhi H, Bronk SF, Werneburg NW, Gores GJ. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem 2006; 281: 12093-12101
  • 31 Wei Y, Wang D, Pagliassotti MJ. Saturated fatty acid-mediated endoplasmic reticulum stress and apoptosis are augmented by trans-10, cis-12-conjugated linoleic acid in liver cells. Mol Cell Biochem 2007; 303: 105-113
  • 32 Aguilera CM, Mesa MD, Ramirez-Tortosa MC, Quiles JL, Gil A. Virgin olive and fish oils enhance the hepatic antioxidant defence system in atherosclerotic rabbits. Clin Nutr 2003; 22: 379-384
  • 33 Perona JS, Arcemis C, Ruiz-Gutierrez V, Catala A. Effect of dietary high-oleic-acid oils that are rich in antioxidants on microsomal lipid peroxidation in rats. J Agric Food Chem 2005; 53: 730-735
  • 34 Kasdallah-Grissa A, Nakbi A, Koubaa N, El-Fazaa S, Gharbi N, Kamoun A, Hammami M. Dietary virgin olive oil protects against lipid peroxidation and improves antioxidant status in the liver of rats chronically exposed to ethanol. Nutr Res 2008; 28: 472-479
  • 35 Lambert MS, Avella MA, Botham KM, Mayes PA. The type of dietary fat alters the hepatic uptake and biliary excretion of cholesterol from chylomicron remnants. Br J Nutr 2000; 83: 431-438
  • 36 Li Y, Hou MJ, Ma J, Tang ZH, Zhu HL, Ling WH. Dietary fatty acids regulate cholesterol induction of liver CYP7alpha1 expression and bile acid production. Lipids 2005; 40: 455-462
  • 37 Mawatari S, Ohnishi Y, Kaji Y, Maruyama T, Murakami K, Tsutsui K, Fujino T. High-cholesterol diets induce changes in lipid composition of rat erythrocyte membrane including decrease in cholesterol, increase in alpha-tocopherol and changes in fatty acids of phospholipids. Biosci Biotechnol Biochem 2003; 67: 1457-1464
  • 38 Ferramosca A, Savy V, Zara V. Olive oil increases the hepatic triacyl­glycerol content in mice by a distinct influence on the synthesis and oxidation of fatty acids. Biosci Biotechnol Biochem 2008; 72: 62-69