Animal models of nonalcoholic fatty liver disease

In 1980, Ludwig and colleagues described a series of patients with liver histology characterized by the accumulation of fat and the presence of hepatic necroinflammation in the absence of a history of excessive alcohol consumption. They coined the term nonalcoholic steatohepatitis (NASH), which today is regarded as one of the most common causes of liver disease in affluent countries. NASH is a subset of a larger spectrum of diseases termed fatty liver disease (including alcoholic and nonalcoholic fatty liver disease; AFLD and NAFLD, respectively). NAFLD and NASH are linked to visceral adiposity, insulin resistance, dyslipidemia and type 2 diabetes, and are increasing due to the prevalence of the metabolic syndrome. In this context, research has been undertaken using animals to model human steatosis and NAFLD to NASH disease progression. This Review discusses the prevalent dietary and inflammation-based genetic animal models described in recent years.

[1]  I. Leclercq,et al.  Intrahepatic insulin resistance in a murine model of steatohepatitis: effect of PPARγ agonist pioglitazone , 2007, Laboratory Investigation.

[2]  I. Leclercq,et al.  CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. , 2000, The Journal of clinical investigation.

[3]  L. N. Valenti,et al.  Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. , 2010, The New England journal of medicine.

[4]  Victor M Montori,et al.  Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. , 2007, Journal of the American College of Cardiology.

[5]  M. Manns,et al.  Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus , 2008, Hepatology.

[6]  Claudio Cobelli,et al.  Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men , 2006, Proceedings of the National Academy of Sciences.

[7]  B. Paigen,et al.  Variation in susceptibility to atherosclerosis among inbred strains of mice. , 1985, Atherosclerosis.

[8]  J. Breslow,et al.  Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice. , 1990, Science.

[9]  A. Chervonsky,et al.  Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice. , 2010, The Journal of clinical investigation.

[10]  J. Chiang,et al.  Transgenic expression of cholesterol 7α‐hydroxylase in the liver prevents high‐fat diet–induced obesity and insulin resistance in mice , 2010, Hepatology.

[11]  I. Leclercq,et al.  COX‐2 induction in mice with experimental nutritional steatohepatitis: Role as pro‐inflammatory mediator , 2006, Hepatology.

[12]  M. Czaja,et al.  Jnk1 but not jnk2 promotes the development of steatohepatitis in mice , 2006, Hepatology.

[13]  Y. Kondo,et al.  Possible involvement and the mechanisms of excess trans-fatty acid consumption in severe NAFLD in mice. , 2010, Journal of hepatology.

[14]  A. Colell,et al.  Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. , 2006, Cell metabolism.

[15]  Chris Day,et al.  A position statement on NAFLD/NASH based on the EASL 2009 special conference. , 2010, Journal of hepatology.

[16]  Michael J Thun,et al.  Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. , 2003, The New England journal of medicine.

[17]  G. Trautwein Pathology and Pathogenesis of the Disease , 1988 .

[18]  S. Shoelson,et al.  Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB , 2005, Nature Medicine.

[19]  I. Leclercq,et al.  Pro-oxidant-mediated hepatic fibrosis and effects of antioxidant intervention in murine dietary steatohepatitis. , 2009, International journal of molecular medicine.

[20]  K. Moore,et al.  Role of scavenger receptor A and CD36 in diet-induced nonalcoholic steatohepatitis in hyperlipidemic mice. , 2010, Gastroenterology.

[21]  I. Leclercq,et al.  Central role of PPARα‐dependent hepatic lipid turnover in dietary steatohepatitis in mice , 2003, Hepatology.

[22]  B. S. Mohammed,et al.  Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. , 2008, Gastroenterology.

[23]  K. Walsh,et al.  Adiponectin Promotes Macrophage Polarization toward an Anti-inflammatory Phenotype* , 2009, The Journal of Biological Chemistry.

[24]  G. Shulman,et al.  The role of muscle insulin resistance in the pathogenesis of atherogenic dyslipidemia and nonalcoholic fatty liver disease associated with the metabolic syndrome. , 2010, Annual review of nutrition.

[25]  K. Iwaisako,et al.  c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice. , 2009, Gastroenterology.

[26]  C. Day,et al.  Non‐alcoholic steatohepatitis: Definitions and pathogenesis , 2002, Journal of gastroenterology and hepatology.

[27]  A. Greenberg,et al.  Obesity and the role of adipose tissue in inflammation and metabolism. , 2006, The American journal of clinical nutrition.

[28]  J. Lefkowitch Morphology of alcoholic liver disease. , 2005, Clinics in liver disease.

[29]  M. Yeh,et al.  MCD-induced steatohepatitis is associated with hepatic adiponectin resistance and adipogenic transformation of hepatocytes. , 2008, Journal of hepatology.

[30]  B. Neuschwander‐Tetri,et al.  Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions , 1999, American Journal of Gastroenterology.

[31]  A. Sanyal,et al.  Recent advances in nonalcoholic fatty liver disease , 2010, Current opinion in gastroenterology.

[32]  R. Green,et al.  Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet , 2008 .

[33]  S. Bischoff,et al.  Toll‐like receptor 4 is involved in the development of fructose‐induced hepatic steatosis in mice , 2009, Hepatology.

[34]  D. Brenner,et al.  Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. , 2010, Gastroenterology.

[35]  T. Hibi,et al.  Hepatic AdipoR2 signaling plays a protective role against progression of nonalcoholic steatohepatitis in mice , 2008, Hepatology.

[36]  I. Leclercq,et al.  Administration of the potent PPARα agonist, Wy‐14,643, reverses nutritional fibrosis and steatohepatitis in mice , 2004, Hepatology.

[37]  K. Jeong,et al.  Mild hepatic fibrosis in cholesterol and sodium cholate diet-fed rats. , 2005, The Journal of veterinary medical science.

[38]  N. Maeda,et al.  Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis , 2008, Hepatology.

[39]  C. Kahn,et al.  Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle. , 2000, The Journal of clinical investigation.

[40]  T. Luedde,et al.  Deletion of NEMO/IKKγ in Liver Parenchymal Cells Causes Steatohepatitis and Hepatocellular Carcinoma , 2007 .

[41]  J. George,et al.  Pathogenesis of NASH: animal models. , 2007, Clinics in liver disease.

[42]  Yuichi Akasaki,et al.  Sfrp5 Is an Anti-Inflammatory Adipokine That Modulates Metabolic Dysfunction in Obesity , 2010, Science.

[43]  S. Kihara,et al.  Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin. , 2003, Gastroenterology.

[44]  E. Fisher,et al.  Lipid peroxidation and oxidant stress regulate hepatic apolipoprotein B degradation and VLDL production. , 2004, The Journal of clinical investigation.

[45]  Alexander Pertsemlidis,et al.  Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease , 2008, Nature Genetics.

[46]  Christophe Benoist,et al.  Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters , 2009, Nature Medicine.

[47]  N. Maeda,et al.  Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates. , 2006, Journal of hepatology.

[48]  S. Kihara,et al.  Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model. , 2007, Journal of hepatology.

[49]  M. Czaja,et al.  Hepatocyte CYP2E1 Overexpression and Steatohepatitis Lead to Impaired Hepatic Insulin Signaling* , 2005, Journal of Biological Chemistry.

[50]  A. Saltiel,et al.  Obesity induces a phenotypic switch in adipose tissue macrophage polarization. , 2007, The Journal of clinical investigation.

[51]  Jonathan C. Cohen,et al.  Patatin‐like phospholipase domain‐containing 3 and the pathogenesis and progression of pediatric nonalcoholic fatty liver disease , 2010, Hepatology.

[52]  Chien-Jen Chen,et al.  Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. , 2008, Gastroenterology.

[53]  A. Suzuki,et al.  Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease , 2010, Hepatology.

[54]  D. Koop,et al.  Steatohepatitis induced by intragastric overfeeding in mice , 2005, Hepatology.

[55]  J. Schwarz,et al.  The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome , 2010, Nature Reviews Gastroenterology &Hepatology.

[56]  K. Reue,et al.  Cholesterol and Cholate Components of an Atherogenic Diet Induce Distinct Stages of Hepatic Inflammatory Gene Expression* , 2003, Journal of Biological Chemistry.

[57]  O. Cummings,et al.  Design and validation of a histological scoring system for nonalcoholic fatty liver disease , 2005, Hepatology.

[58]  K. Zatloukal,et al.  Mallory body—A disease‐associated type of sequestosome , 2002, Hepatology.

[59]  E. Brunt,et al.  Nonalcoholic fatty liver disease: pathology and pathogenesis. , 2010, Annual review of pathology.

[60]  A. Vercesi,et al.  Overexpression of apolipoprotein CIII increases and CETP reverses diet-induced obesity in transgenic mice , 2007, International Journal of Obesity.

[61]  angesichts der Corona-Pandemie,et al.  UPDATE , 1973, The Lancet.

[62]  C. Sempoux,et al.  Curcumin inhibits NF-kappaB activation and reduces the severity of experimental steatohepatitis in mice. , 2004, Journal of hepatology.

[63]  I. Leclercq,et al.  Lipid peroxidation, stellate cell activation and hepatic fibrogenesis in a rat model of chronic steatohepatitis. , 2003, Journal of hepatology.

[64]  B. Neuschwander‐Tetri,et al.  Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. , 2008, American journal of physiology. Gastrointestinal and liver physiology.

[65]  Y. Huang,et al.  High-fat emulsion-induced rat model of nonalcoholic steatohepatitis. , 2006, Life sciences.

[66]  D. Brenner,et al.  Toll‐like receptors and adaptor molecules in liver disease: Update , 2008, Hepatology.

[67]  R. Goldin,et al.  Mouse models in non‐alcoholic fatty liver disease and steatohepatitis research , 2006, International journal of experimental pathology.

[68]  A. Dolganiuc,et al.  VSL#3 probiotic treatment attenuates fibrosis without changes in steatohepatitis in a diet‐induced nonalcoholic steatohepatitis model in mice , 2009, Hepatology.

[69]  I. Leclercq,et al.  NF-kappaB activation, rather than TNF, mediates hepatic inflammation in a murine dietary model of steatohepatitis. , 2005, Gastroenterology.

[70]  J. Girard,et al.  Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. , 2008, The Journal of clinical investigation.

[71]  Leah Hennings,et al.  A new model for nonalcoholic steatohepatitis in the rat utilizing total enteral nutrition to overfeed a high-polyunsaturated fat diet. , 2008, American journal of physiology. Gastrointestinal and liver physiology.

[72]  M. Honda,et al.  Lipid‐induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet , 2007, Hepatology.

[73]  T. Luedde,et al.  Hepatic NF-κB essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis , 2008, Proceedings of the National Academy of Sciences.

[74]  M. Weltman,et al.  Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation. , 1996, Gastroenterology.

[75]  S. Shoelson,et al.  Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. , 2005, Nature medicine.

[76]  T. Kadowaki,et al.  CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity , 2009, Nature Medicine.

[77]  A. Feldstein,et al.  Diagnosis of Nonalcoholic Fatty Liver Disease: Invasive versus Noninvasive , 2008, Seminars in liver disease.

[78]  Shobha Ghosh,et al.  Improved Insulin Sensitivity in High Fat- and High Cholesterol-fed Ldlr−/− Mice with Macrophage-specific Transgenic Expression of Cholesteryl Ester Hydrolase , 2010, The Journal of Biological Chemistry.

[79]  M. Sasaki,et al.  Phospholipase D2 Mediates Acute Aldosterone Secretion in Response to Angiotensin Ii in Adrenal Glomerulosa Cells Spironolactone Improves Glucose and Lipid Metabolism by Ameliorating Hepatic Steatosis and Inflammation and Suppressing Enhanced Gluconeogenesis Induced by High-fat and High-fructose Diet , 2022 .

[80]  Jun Hee Lee,et al.  Dietary and Genetic Obesity Promote Liver Inflammation and Tumorigenesis by Enhancing IL-6 and TNF Expression , 2010, Cell.

[81]  Michael Karin,et al.  A central role for JNK in obesity and insulin resistance , 2002, Nature.

[82]  G. Gores,et al.  Free fatty acids promote hepatic lipotoxicity by stimulating TNF‐α expression via a lysosomal pathway , 2004 .

[83]  T. Shike,et al.  Animal models. , 2001, Contributions to nephrology.

[84]  P. Schauer,et al.  Adipocyte Apoptosis, a Link between Obesity, Insulin Resistance, and Hepatic Steatosis* , 2009, The Journal of Biological Chemistry.

[85]  J. Kuroda,et al.  Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. , 2006, European journal of pharmacology.

[86]  C. McClain,et al.  Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. , 2008, Journal of hepatology.

[87]  S. McCall,et al.  Fructose consumption as a risk factor for non-alcoholic fatty liver disease. , 2008, Journal of hepatology.

[88]  G. Tell,et al.  Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis. , 2008, Trends in molecular medicine.

[89]  T. Kadowaki,et al.  Adiponectin knockout mice on high fat diet develop fibrosing steatohepatitis , 2009, Journal of gastroenterology and hepatology.

[90]  J. Ludwig,et al.  Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. , 1980, Mayo Clinic proceedings.

[91]  Z. Younossi,et al.  Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. , 1999, Gastroenterology.

[92]  K. Yoshizato,et al.  A human-type nonalcoholic steatohepatitis model with advanced fibrosis in rabbits. , 2010, The American journal of pathology.

[93]  D. Nakae Endogenous liver carcinogenesis in the rat * , 1999, Pathology international.

[94]  R. Green,et al.  The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance. , 2004, Journal of hepatology.

[95]  R. McCuskey,et al.  Hepatic microvascular dysfunction during evolution of dietary steatohepatitis in mice , 2004, Hepatology.

[96]  E. Brunt Histopathology of non-alcoholic fatty liver disease. , 2009, Clinics in liver disease.

[97]  Y. Konishi,et al.  Comparative Changes in the Liver of Female Fischer-344 Rats after Short-Term Feeding of a Semipurified or a Semisynthetic L-Amino Acid-Defined Choline-Deficient Diet , 1995, Toxicologic pathology.

[98]  K. Mak,et al.  Model of nonalcoholic steatohepatitis. , 2004, The American journal of clinical nutrition.

[99]  Nick V. Grishin,et al.  A Sequence Variation (I148M) in PNPLA3 Associated with Nonalcoholic Fatty Liver Disease Disrupts Triglyceride Hydrolysis , 2009, The Journal of Biological Chemistry.

[100]  T. Luedde,et al.  Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. , 2007, Cancer cell.

[101]  L. Samuelson,et al.  Lessons from genetically engineered animal models. III. Lessons learned from gastrin gene deletion in mice. , 1999, The American journal of physiology.