Pathogenesis of fatty liver diseases (FLD) and their small animal models
Article Sidebar
Main Article Content
Abstract
Fatty liver disease (FLD), including non-alcoholic (NAFLD) and alcoholic (AFLD) fatty liver diseases, are serious health problems worldwide. Both NAFLD and AFLD have similar pathological spectra, ranging from simple hepatic steatosis to steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. Notably, NAFLD and AFLD are frequently associated with extrahepatic complications, e.g. cardiovascular disease and malignancy. NAFLD is increasingly prevalent and represents a growing challenge in terms of prevention and treatment, despite advances in this field, knowledge on the pathogenesis of NAFLD is still limited. The classical ‘two-hit’ hypothesis, having hepatic accumulation of lipids secondary to sedentary lifestyle, high fat diet, obesity and insulin resistance as the first hit, and sensitization of the liver to inflammation acting as the ‘second hit’, is now outdated. The “multiple hit” hypothesis considers multiple insults acting together on genetically predisposed subjects to induce NAFLD and provides a more accurate explanation of NAFLD pathogenesis. Such “hits” include insulin resistance, hormones secreted from the adipose tissue, nutritional factors, gut microbiota, and genetic/epigenetic factors. Excessive alcohol intake can lead to AFLD through its direct action as a hepatotoxin1 as well as potentiation of other liver diseases including chronic viral hepatitis and NAFLD. Animal models of NAFLD may be divided into two broad categories; those caused by genetic mutation and those with an acquired phenotype produced by dietary or pharmacological manipulation. The genetic leptin-deficient (ob/ob) or leptin-resistant (db/db) mouse and the dietary methionine/choline-deficient model have been employed in the majority of published research. More recently, targeted gene disruption and the use of supra-nutritional diets to induce NAFLD have gained greater prominence as researchers have attempted to bridge the phenotype gap between the available models and the human disease. On the other hand, several models for experimental AFLD exist, including non-human primates, micropigs and rodents. Most researchers employ rodent models of AFLD. Knock-out mice have increased the specificity of the hypotheses that can be directly tested. Based on these models systems, several plausible hypotheses have been applied to explain the pathogenesis of NAFLD and AFLD. However, despite significant advances in our understanding of the mechanisms by development of these models, further studies are still needed in order to translate these to more understandable and specific mechanisms of these diseases to develop new treatments for either NAFLD or AFLD.
Article Details
In the case that some parts are used by others The author must Confirm that obtaining permission to use some of the original authors. And must attach evidence That the permission has been included
References
Adams LA, Angulo P, Lindor KD. Nonalcoholic fatty liver disease. CMAJ 2005; 172(2): 899-903.
Altamirano J, Bataller R. Alcoholic liver disease: pathogenesis and new targets for therapy. Nat Rev Gastroenterol Hepatol 2011; 8: 491-501.
Anstee QM, Daly AK, Day CP. Genetics of alcoholic and nonalcoholic fatty liver disease. Semin Liver Dis 2011; 31: 128-146.
Anstee QM, Day CP. The genetics of NAFLD. Nat Rev Gastroenterol Hepatol 2013; 10: 645-655.
Anstee QM, Goldin RD. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Clin Exp Pathol 2006; 87: 1-16.
Arteel GE. Animal models of alcoholic liver disease. Dig Dis 2010; 28: 729-736.
Ashtari S, Pourhoseingholi A, Zali MR. Non-alcohol fatty liver disease in Asia: Prevention and planning. World J Hepatol 2015; 7(13): 1788-1796.
Basaranoglu M, Basaranoglu G, Bugianesi E. Carbohydrate intake and nonalholic fatty liver disease: fructose as a weapon of a mass destruction. Hepatobiliary Surg Nutr 2015; 4(2): 109-116.
Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 2004; 114(2): 147-152.
Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 2016; 65(8): 1038-1048.
Charlton M, Krishnan A, Viker K. Fast food diet mouse: Novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver physiol 2011; 301(5): G825-G834.
Chen H, Charlat O, Tartaglia LA, et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 1996; 84(3): 491-495.
Coburn CT, Knapp FFJr, Febbraio M, et al Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J Biol Chem 2000; 275: 32523-32529.
Coleman DL. Obese and diabetes: two mutant genes causing diabetes–obesity syndromes in mice. Diabetologia 1978; 14: 141-148.
Cusi K. Role of insulin resistance and lipotoxicity in nonalcoholic steatohepatitis. Clin Liver Dis 2009; 13: 545-563.
Dambach DM, Andrews BA, Moulin F. New technologies and screening strategies for hepatotoxicity: Use of in vitro models. Toxicol Pathol 2005: 33: 17-26.
Dolganiuc A, Szabo G. In vitro and in vivo models of acute alcohol exposure. World J Gastroenterol 2009; 15(10): 1168-1177.
du Plessis J, van Pelt J, Korf H, et al. Association of adipose tissue inflammation with histological severity of nonalcoholic fatty liver disease. Gastroenterology 2005; 149(3): 635-648.
Enomoto N, Ikejima K, Bradford BU, et al. Alcohol causes both tolerance and sensitization of rat Kupffer cells via mechanisms dependent on endotoxin. Gastroenterology 1998; 115(4): 443-451.
Ferramosca A, Zara V. Modulation of hepatic steatosis by dietary fatty acids. World J Gastroenterol 2014; 20(7): 1746-1755.
George J, Liddle C. Nonalcoholic fatty liver disease: pathogenesis and potential for nuclear receptors as therapeutic targets. Mole Pharm 2008; 5: 49-59.
Gomez-Lechon MJ, Donato MT, Castell JV. Human hepatocytes in primary culture: The choice to investigate drug metabolism in man. Curr Drug Metab 2004; 5: 443-462.
Goudriaan JR, Dahlmans VE, Teusink B, et al. CD36 deficiency increases insulin sensitivity in muscle, but induces insulin resistance in the liver in mice. J Lipid Res 2003; 44(12): 2270-2277.
Gregor MF, Hotamisligil GS. Thematic review series: adipocyte biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease. J Lipid Res 2007; 48: 1905-1914.
Hironaka K, Sakaida I, Uchida K, et al. Correlation between stellate cell activation and serum fibrosis markers in choline-deficient L-amino acid-defined diet-induced rat liver fibrosis. Dig Dis Sci 2000; 45(10): 1935-1943.
Jacome-Sos MM, Parks EJ. Fatty acid sources and their fluxes as they contribute to plasma triglyceride concentrations and fatty liver in humans. Curr Opin Lipidol 2014; 25(3): 213-220.
Janorkar AV, Harris LM, Murphey BS. Use of three-dimensional spheroids of hepatocyte-derived reporter cells to study the effects of intracellular fat accumulation and subsequent cytokine exposure. Biotechnol. Bioeng. 2000; 108: 1171-1180.
Kakuma T, Lee Y, Higa M, et al. Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets. Proc Natl Acad Sci USA 2000; 97(15): 8536-8541.
Kanuri G, Bergheim I. In vitro and in vivo models of non-alcoholic fatty liver disease (NAFLD). Int J Mol Sci 2013; 14(6): 11963-11980.
Kanuri G, Landmann M, Priebs J, et al. Moderate alcohol consumption diminishes the development of non-alcoholic fatty liver disease (NAFLD) in ob/ob mice. Eur J Nutr 2016; 55(3): 113-1164.
Kersten S, Seydoux J, Peters JM, et al. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest 1999; 103(11): 1489-1498.
Kirsch R, Clarkson V, Shephard EG, et al. Rodent nutritional model of non-alcoholic steatohepatitis: species, strain and sex difference studies. J Gastroenterol Hepatol 2003; 18(11): 1272-1282.
Klassen LW, Thiele GM, Duryee MJ, et al. An in vitro method of alcoholic liver injury using precision-cut liver slices from rats. Biochem Pharmacol 2008; 76(3): 426-436.
Kono H, Nakagami M, Rusyn I, et al. Development of an animal model of chronic alcohol-induced pancreatitis in the rat. Am J Physiol Gastrointest Liver Physiol 2001; 280(6): G1178-G1186.
Koteish A, Diehl AM. Animal models of steatosis. Sem Liver Dis 2001; 21(1): 89-104.
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: 165-174.
Lewis GF, Carpentier A, Adeli K, et al. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 2002; 23(2): 201-229.
Lieber CS, DeCarli LM. Liquid diet technique of ethanol administration: 1989 update. Alcohol Alcohol 1989; 24(3): 197-211.
Liu CJ. Prevalence and risk factors for non-alcoholic fatty liver disease in Asian people who are not obese. J Gastroenterol Hepatol 2012; 27(10): 1555-1560.
Mancina RM, Matikainen N, Maglio C, et al. Paradoxical dissociation between hepatic fat content and De novo lipogenesis due to PNPLA3 sequence variant. J Clin Endocrinol Metab 2015; 100(5): E821-E825.
Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003; 37(4): 917-923.
Mayer J, Dickie MM, Bates MW, et al. Free selection of nutrients by hereditarily obese mice. Science 1951; 113: 745-746.
Molloy JW, Calcagno CJ, Williams CD, et al. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology 2012; 55(2): 429-436.
Moore JB, Gunn PJ, Fielding BA. The role of dietary sugars and de novo lipogenesis in non-alcoholic fatty liver disease. Nutrients 2014; 6: 5679-5703.
Musso G, Gambino R, Cassader M. Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis. Prog Lipid Res 2013; 52(1): 175-191.
Nalbantoglu I, Brunt EM. Role of Liver Biopsy in Nonalcoholic Fatty Liver Disease. World J Gastroenterol 2014; 20(27): 9026–9037.
Paschos P, Paletas K. Non alcoholic fatty liver disease and metabolic syndrome. Hippokratio Hosp 2009; 13(1): 9-19.
Peverill W, Powell LW, Skoien R. Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int J Mol Sci 2014; 15(5): 8591-8638.
Powell EE, Cooksley WG, Hanson R, et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990; 11(1): 74-80.
Rodd-Henricks ZA, Bell RL, Kuc KA, et al. Effects of ethanol exposure on subsequent acquisition and extinction of ethanol self-administration and expression of alcohol-seeking behavior in adult alcohol-preferring rats. II. Adult exposure. Alcohol Clin Exp Res 2002; 26(11): 1642-1652.
Salaspuro MP, Shaw S, Jayatilleke E, et al. Attenuation of the ethanol-induced hepatic redox change after chronic alcohol consumption in baboons: metabolic consequences in vivo and in vitro. Hepatology 1981; 1(1): 33-8.
Schreuder TC, Verwer BJ, van Nieuwkerk CM, et al. Nonalcoholic fatty liver disease: an overview of current insights in pathogenesis, diagnosis and treatment. World J Gastroenterol 2008; 14(16): 2474-2486.
Seki S, Kitada T, Sakaguchi H. Clinicopathological significance of oxidative cellular damage in non-alcoholic fatty liver diseases. Hepatol Res 2005; 33(2): 132-134.
Shimano H, Horton JD, Hammer RE, et al. Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J Clin Invest 1996; 98(7): 1575-1584.
Shimomura I, Bashmakov Y, Horton JD. Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J Biol Chem 1999; 274(42): 30028-30032.
Shimomura I, Shimano H, Korn BS, et al. Nuclear sterol regulatory element-binding proteins activate genes responsible for the entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver. J Biol Chem 1998; 273(52): 35299-35306.
Shimomura I, Shimano H, Korn BS, et al. Nuclear sterol regulatory element-binding proteins activate genes responsible for the entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver. J Biol Chem 1998; 273: 35299-35306.
Spruss A, Bergheim I. Dietary fructose and intestinal barrier: Potential risk factor in the pathogenesis of nonalcoholic fatty liver disease. J Nutr Biochem 2009; 20(9): 657-662.
Spruss A, Kanuri G, Uebel K. Role of the inducible nitric oxide synthase in the onset of fructose-induced steatosis in mice. Antioxid Redox Signal 2011; 14: 2121-2135.
Streba LAM, Vere CC, Rogoveanu I, Streba CT. Nonalcoholic fatty liver disease, metabolic risk factors, and hepatocellular carcinoma: An open question. World J Gastroenterol 2015; 21(14): 4103-4110.
Summart U, Thinkhamrop B, Chamadol N, Khuntikeo N, Songthamwat M, Kim, CS. Gender differences in the prevalence of nonalcoholic fatty liver disease in the Northeast of Thailand: A population-based cross-sectional study. F1000Res 2017; 6: 1630.
Tartaglia LA, Dembski M, Weng X, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995; 83(7): 1263-1271.
Tian L, Prasad N, Jang YY. In vitro modeling of alcohol-induced liver injury using human-induced pluripotent stem cells. Methods Mol Biol 2014; 1353: 271-283.
Vandamme TF. Use of redents as models of human diseases. J Pharm Bioallied Sci 2014; 6(1): 2-9.
Wang M, Kaufman RJ. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat Rev Cancer 2014; 14(9): 581-597.
Weltman MD, Farrell GC, Liddle C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation. Gastroenterology 1996; 111(6): 1645-1653.
Wheeler MD, Kono H, Rusyn I, et al. Chronic ethanol increases adeno-associated viral transgene expression in rat liver via oxidant and NF-kB-dependent mechanisms. Hepatology 2000; 32(5): 1050-1059.
Wheeler MD, Kono H, Yin M, et al. The role of Kupffer cell oxidant production in early ethanol-induced liver disease. Free Rad Biol Med 2001; 31(12): 1544-1549.
Yao ZM, Vance DE. Reduction in VLDL, but not HDL, in plasma of rats deficient in choline. Biochem Cell Biol 1990; 68(2): 552-558.