Animal Models of Steatosis

ABSTRACT

The lipid content of hepatocytes is regulated by the integrated activities of cellular enzymes that catalyze lipid uptake, synthesis, oxidation, and export. When ``input'' of fats into these systems (either because of increased fatty acid delivery, hepatic fatty acid uptake, or fatty acid synthesis) exceeds the capacity for fatty acid oxidation or export (i.e., ``output''), then hepatic steatosis occurs. Genetic causes of increased fatty acid input promote excessive hepatic lipogenesis. These include mutations that cause leptin deficiency or leptin receptor inhibition and mutations that induce insulin, insulin-like growth factors, or insulin-responsive transcription factors. Genetic causes of impaired hepatic fatty acid oxidation inhibit the elimination (i.e., output) of fat from the liver. These include mutations that inhibit various components of the peroxisomal and/or mitochondrial pathways for fatty acid β-oxidation. Environmental factors, such as diets and toxins, can also unbalance hepatic fatty acid synthesis and oxidation. Hepatic lipogenesis is increased by dietary sucrose, fructose, or fats and certain toxins, such as ethanol. Hepatic fatty acid oxidation is inhibited by choline- or methionine-deficient diets and other toxins, such as etomoxir. Animals with genetic or environmental induction of hepatic lipogenesis appear to be useful models for human nonalcoholic fatty liver disease in which hyperinsulinemia and defective leptin signaling are conspicuous at early stages of the disease process.

KEYWORD

Leptin - insulin - mitochondria - peroxisomes - energy

REFERENCES

• 1 Fromenty B, Pessayre D. Impaired mitochondrial function in microvesicular steatosis. Effects of drugs, ethanol, hormones and cytokines.  J Hepatol . 1997;  26(suppl 2) 43-53
• 2 Leone T C, Weinheimer C J, Kelly D P. A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPAR alpha-null mouse as a model of fatty acid oxidation disorders.  Proc Natl Acad Sci U S A . 1999;  96 7473-7478
• 3 Kersten S, Seydoux J, Peters J M. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting.  J Clin Invest . 1999;  103 1489-1498
• 4 Fan C Y, Pan J, Chu R, Lee D. Hepatocellular and hepatic peroxisomal alterations in mice with a disrupted peroxisomal fatty acyl-coenzyme A oxidase gene.  J Biol Chem . 1996;  271 24698-24670
• 5 Fan C-Y, Pan J, Chu R, Lee D. Targeted disruption of the peroxisomal fatty acyl-CoA oxidase gene: generation of a mouse model of pseudoneonatal adrenoleukodystrophy.  Ann N Y Acad Sci . 1996;  530-540
• 6 Coste P, Legendre C, More J. Peroxisome proliferator-activated receptor alpha-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis.  J Biol Chem . 1998;  273 29577-29585
• 7 Djouadi F, Weinheimer C J, Saffitz J E. A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor alpha-deficient mice.  J Clin Invest . 1998;  102 1083-1091
• 8 Fan C-Y, Pan J, Usuda N. Steatohepatitis, spontaneous peroxisome proliferation and tumors in mice lacking peroxisomal and fatty acyl-CoA oxidase.  J Biol Chem . 1998;  273 15639-15645
• 9 Shimomura I, Bashmakow Y, Horton J D. Increased levels of nuclear SREP-1c associated with fatty livers in two mouse models of diabetes mellitus.  J Biol Chem . 1999;  274 30028-30032
• 10 Sawka-Verhelle D, Tartare-Deckert S, Decaux J F. Stat 5B, activated by insulin in a Jak- independent fashion, plays a role in glucokinase gene transcription.  Endocrinology . 2000;  141 1977-1988
• 11 Roduit R, Morin J, Masse F. Glucose down regulates the expression of the PPAR alpha gene in the pancreatic beta cell.  J Biol Chem . 2000;  275 35799-35806
• 12 Edvardsson U, Alexandersson M, Brockenhuus von Lowenhielm H. A proteome analysis of livers from obese (ob/ob) mice treated with the peroxisome proliferator WY 14,643.  Electrophoresis . 1999;  20 935-942
• 13 Boni-Schnetzler M, Hauri C, Zapf J. Leptin is suppressed during infusion of recombinant human insulin-like growth factor I (rhIGFI) in normal rats.  Diabetologia . 1999;  42 160-166
• 14 Kok N, Roberfroid M, Delzenne N. Dietary oligofructose modifies the impact of fructose on hepatic triacylglycerol metabolism.  Metabolism . 1996;  45 1547-1550
• 15 Shimano H, Horton J D, Hammer R E. Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a.  J Clin Invest . 1996;  98 1575-1584
• 16 Shimomura I, Hammer R E, Richardson J A. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREP-1c in adipose tissue: model for congenital generalized lipodystrophy.  Genes Dev . 1998;  12 3182-3194s
• 17 Shimomura I, Hammer R E, Ikemoto S. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy.  Nature . 1999;  401 73-76
• 18 Moitra J, Mason M M, Olive M. Life without white fat: a transgenic mouse.  Genes Dev . 1998;  12 3168-3181
• 19 Lekstrom-Himes J, Xanthopoulos K G. Biological role of the CCAAT enhancer-binding protein family of transcription factors.  J Biol Chem . 1998;  273 28545-28548
• 20 Wang N D, Finegold M J, Bradley A. Impaired energy homeostasis in C/EBP alpha knockout mice.  Science . 1995;  269 1108-1112
• 21 Darlington G J, Wang N, Hanson R W. C/EBP alpha: a critical regulator of genes governing integrative metabolic processes.  Curr Opin Genet Dev . 1995;  5 565-570
• 22 Ross S R, Graves R A, Spiegelman B M. Targeted expression of a toxin gene to adipose tissue: transgenic mice resistant to obesity.  Genes Dev . 1993;  7 1318-1324
• 23 Burant C F, Sreenan S, Hirano K. Troglitazone action is independent of adipose tissue.  J Clin Invest . 1997;  100 2900-2908
• 24 Akira S. Functional roles of STAT family proteins: lessons from knockout mice.  Stem Cells . 1999;  17 138-146
• 25 Swaka-Verhell D, Tartare-Deckert S, Decaux J F. Stat 5B, activated by insulin in a Jak- independent fashion, plays a role in glucokinase gene transcription.  Endocrinology . 2000;  141 1977-1988
• 26 Udy G B, Towers R P, Snell R G. Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression.  Proc Natl Acad Sci U S A . 1997;  94 7239-7244
• 27 Devedjian J C, George M, Casellas A. Transgenic mice overexpressing insulin-like growth factor-II in beta cells develop type 2 diabetes.  J Clin Invest . 2000;  105 731-740
• 28 Campfield L A, Smith F J, Burn P. The OB protein (leptin) pathway-a link between adipose tissue mass and central neural networks.  Horm Metab Res . 1996;  28 619-632
• 29 Pelleymounter M A, Cullen M F, Baker M B. Effects of the obese gene product on body weight regulation in ob/ob mice.  Science . 1995;  269 540-543
• 30 Yang S Q, Lin H Z, Lane M D. Obesity increases sensitivity to endotoxin liver injury: implications for pathogenesis of steatohepatitis.  Proc Natl Acad Sci U S A . 1997;  94 2557-2562
• 31 Chavin K, Yang S Q, Lin H Z. Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion.  J Biol Chem . 1999;  274 5692-5700
• 32 Faggioni R, Fantuzzi G, Gabay C. Leptin deficiency enhances sensitivity to endotoxin-induced lethality.  Am J Physiol . 1999;  276 R136-R142
• 33 Hotamisligil G S, Peraldi S P, Budavari A. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance.  Science . 1996;  271 665-668
• 34 Lin H Z, Yang S Q, Kujhada F. Metformin reverses nonalcoholic fatty liver disease in obese leptin-deficient mice.  Nat Med . 2000;  6 998-1003
• 35 Boss O, Muzzin P, Giacobino J P. The uncoupling proteins, a review.  Eur J Endocrinol . 1998;  139 1-9
• 36 Skulachev V P. Uncoupling: new approaches to an old problem of bioenergetics.  Biochim Biophys Acta . 1998;  1363 100-124
• 37 Enriquez A, Leclercq I, Farrell G C. Altered expression of hepatic Cyp2E1 and Cyp4A in obese, diabetic ob/ob mice, and fa/fa Zucker rats.  Biochem Biophys Res Commun . 1999;  255 300-306
• 38 Tartaglia L A, Dembski M, Weng X. Identification and expression cloning of a leptin receptor, OB-R.  Cell . 1995;  83 1263-1271
• 39 Ghilardi N, Ziegler S, Wiestner A. Defective STAT signaling by the leptin receptor in diabetic mice.  Proc Natl Acad Sci U S A . 1996;  93 6321-6235
• 40 Chen H, Charlat O, Tartaglia L A. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice.  Cell . 1996;  84 491-495
• 41 Shimabukaro M, Zhou Y T, Lee Y. Induction of UCP2 mRNA by troglitazone in pancreatic islets of Zucker diabetic fatty rats.  Biochem Biophys Res Commun . 1997;  237 359-361
• 42 Zhou Y T, Shimabukuro M, Koyama K. Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation.  Proc Natl Acad Sci U S A . 1997;  94 6386-6390
• 43 Seufert J, Kieffer T J, Habener J F. Leptin inhibits insulin gene transcription and reverses hyperinsulinemia in leptin-deficient ob/ob mice.  Proc Natl Acad Sci U S A . 1999;  96 674-679
• 44 Kieffer T J, Heller R S, Leech C A. Leptin suppression of insulin secretion by the activation of ATP-sensitive K⁺ channels in pancreatic beta cells.  Diabetes . 1997;  46 10087-1093
• 45 Spanswick D, Smith M A, Groppi V E. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels.  Nature . 1997;  390 521-525
• 46 Zhou Y-T, Want Z-W, Higa M. Reversing adipocyte differentiation: implications for treatment of obesity.  Proc Natl Acad Sci U S A . 1999;  96 2391-2395
• 47 Edvardsson U, Bergstrom M, Alexandersson M. Rosiglitazone (BRL49653), a PPAR gamma-selective agonist, causes peroxisome proliferator-like liver effects in obese mice.  J Lipid Res . 1999;  40 1177-1184
• 48 DeFronzo R A, Barzilai N, Simonson D C. Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects.  J Clin Endocrinol Metab . 1991;  73 1294-1301
• 49 Cortez-Pinto H, Yang S Q, Lin H Z. Bacterial lipopolysaccharide induces uncoupling protein- 2 in hepatocytes via a tumor necrosis alpha-dependent mechanism.  Biochem Biophys Res Commun . 1998;  251 313-319
• 50 Loftus T M, Jaworsky D E, Frehywot G L. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors.  Science . 2000;  288 2379-2381
• 51 Lee G H, Proenca R, Montez J M. Abnormal splicing of the leptin receptor in diabetic mice.  Nature . 1996;  379 632-635
• 52 Phillips M S, Liu Q, Hammond H A. Leptin receptor missense mutation in the fatty Zucker rat.  Nat Genet . 1996;  13 18-19
• 53 Wildman H F, Chua S, Leibel R L. Effects of leptin and cholecystokinin in rats with a null mutation of the leptin receptor Lepr-fak.  Am J Physiol . 2000;  278 R1518-R1523
• 54 Kakuma T, Lee Y, Higa M. Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets.  Proc Natl Acad Sci U S A . 2000;  97 8536-8541
• 55 Fan W, Boston B A, Kesterson R A. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome.  Nature . 1997;  385 165-168
• 56 Odaka H, Shino A, Ikeda H. Antiobesity and antidiabetic actions of a new potent disaccharidase inhibitor in genetically obese-diabetic mice, KKAy.  J Nutr Sci Vitaminol . 1992;  38 27-37
• 57 Angulo P, Deach J C, Batts K P. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis.  Hepatology . 1999;  30 1356-1362
• 58 Ratziu V, Giral P, Charlotte F. Liver fibrosis in overweight patients.  Gastroenterology . 2000;  118 1117-1123
• 59 Harrold J A, Widdowson P S, Clapham J C. Individual severity of dietary obesity in unselected Wistar rats: relationship with hyperphagia.  Am J Physiol . 2000;  279 E340-E347
• 60 Poulsom R. Morphological changes of organs after sucrose or fructose feeding.  Prog Biochem Pharmacol . 1986;  21 104-134
• 61 Bogin E, Avidar Y, Meron M. Biochemical changes in liver and blood during liver fattening in rats.  J Clin Chem Clin Biochem . 1986;  24 621-626
• 62 Novikoff P M. Fatty liver induced in Zucker ``fatty'' (ff) rats by a semisynthetic diet rich in sucrose.  Proc Natl Acad Sci U S A . 1977;  74 3550-3554
• 63 Katayama T. Hypolipidemic action of phytic acid (IP6): prevention of fatty liver.  Anticancer Res . 1999;  19 3695-3698
• 64 Novikoff P M, Roheim P S, Novikoff A B. Production and prevention of fatty liver in rats fed clofibrate and orotic acid diets containing sucrose.  Lab Invest . 1974;  30 732-750
• 65 El-Haschimi K, Pierroz D D, Hileman S M. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity.  J Clin Invest . 2000;  105 1827-1832
• 66 Hancock R L, Dickie M M. Biochemical, pathological, and genetic aspects of a spontaneous mouse hepatoma.  J Natl Cancer Inst . 1969;  43 407-415
• 67 Heston W, Vlhakis G. Genetic obesity and neoplasia.  J Natl Cancer Inst . 1962;  29 197-209
• 68 Han L-K, Takaku T, Li J. Anti-obesity action of oo-long tea.  Int J Obes . 1999;  23 98-105
• 69 Milner J A, Hassan A S. Species specificity of arginine deficiency-induced hepatic steatosis.  J Nutr . 1981;  111 1067-1073
• 70 Loria R M, Kibrick S, Madge G E. Infection of hypercholesterolemic mice with Coxsackie virus B.  J Infect Dis . 1976;  133 655-662
• 71 Moriya K, Yotsuyanagi H, Shintani Y. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice.  J Gen Virol . 1997;  78 1527-1531
• 72 Moriya K, Fujie H, Shintani Y. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice.  Nat Med . 1998;  4 1065-1067
• 73 Foss I, Trygstad O. Lipoatrophy produced in mice and rabbits by a fraction prepared from the urine from patients with congenital generalized lipodystrophy.  Acta Endocrinol . 1975;  80 398-416
• 74 Reitman M L, Mason M M, Moitra J. Transgenic mice lacking white fat: models for understanding human lipoatrophic diabetes.  Ann N Y Acad Sci . 1999;  289-296
• 75 Lieber C S. Biochemical factors in alcoholic liver disease.  Semin Liv Dis . 1993;  13 136-147
• 76 Seitz H K, Xu Y, Simanowski U A. Effect of age and gender on in vivo ethanol elimination, hepatic alcohol dehydrogenase activity, and NAD⁺ availability in F344 rats.  Res Exp Med . 1992;  192 205-212
• 77 Lieber C S, DeCarli L M. Quantitative relationship between amount of dietary fat and severity of alcoholic fatty liver.  Am J Clin Nutr . 1970;  23 474-478
• 78 Theuer R C, Martin W H, Friday T J. Regression of alcoholic fatty liver in the rat by medium-chain triglycerides.  Am J Clin Nutr . 1972;  25 175-181
• 79 Karpe F, Wejke J, Anggard E. Dietary arachidonic acid protects mice against the fatty liver induced by a high fat diet and by ethanol.  Acta Pharmacol Toxicol . 1984;  55 95-99
• 80 Lieber C S, DeCarli L M. The feeding of alcohol in liquid diets: two decades of applications and 1982 update.  Alcohol Clin Exp Res . 1982;  6 523-531
• 81 Tsukamoto H, Towner S J, Ciofalo L M. Ethanol-induced liver fibrosis in rats fed high fat diets.  Hepatology . 1986;  6 814-822
• 82 McClain C J, Hill D B, Schmidt J. Cytokines and alcoholic liver disease.  Semin Liver Dis . 1993;  13 170-182
• 83 Cao Q, Batey R, Pang G. Altered T-lymphocyte responsiveness to polyclonal cell activators is responsible for liver cell necrosis in alcohol-fed rats.  Alcohol Clin Exp Res . 1998;  22 723-729
• 84 Trautwein C, Rakemann T, Brenner D A. Concanavalin A-induced liver cell damage: activation of intracellular pathways triggered by tumor necrosis factor in mice.  Gastroenterology . 1998;  114 1035-1045
• 85 Tsukamoto H, Horne W, Kamimura S. Experimental liver cirrhosis induced by alcohol and iron.  J Clin Invest . 1995;  96 620-630
• 86 Adachi Y, Moore L E, Bradford B U. Antibiotics prevent liver injury in rats following long-term exposure to ethanol.  Gastroenterology . 1995;  108 218-224
• 87 Nanji A A, Khettry U, Sadrzadeh S M. Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver disease.  Proc Soc Exp Biol Med . 1994;  205 243-247
• 88 Iimuro Y, Gallucci R M, Luster M I. Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat.  Hepatology . 1997;  26 1530-1537
• 89 Yin M, Wheeler M D, Kono H. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice.  Gastroenterology . 1999;  117 942-952
• 90 Schulze-Osthoff K, Bakker A C, Vanhaesebroeck B. Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation.  J Biol Chem . 1992;  267 5317-5323
• 91 Hennet T, Richter C, Peterhans E. Tumour necrosis factor-alpha induces superoxide anion generation in mitochondria of L929 cells.  Biochem J . 1993;  289 587-592
• 92 Pastorino J G, Simbula G, Yamamoto K. The cytotoxicity of tumor necrosis factor depends on induction of the mitochondrial permeability transition.  J Biol Chem . 1996;  271 29792-29798
• 93 Lieber C S, Leo M A, Aleynik S I. Polyenylphosphatidylcholine decreases alcohol-induced oxidative stress in the baboon.  Alcohol Clin Exp Res . 1997;  21 375-379
• 94 Nemoto Y, Toda K, Ono M. Altered expression of fatty acid-metabolizing enzymes in aromatase-deficient mice.  J Clin Invest . 2000;  105 1819-1825
• 95 Saibara T, Onishi S, Ogawa Y. Bezafibrate for tamoxifen-induced non-alcoholic steatohepatitis.  Lancet . 1999;  353 1802
• 96 Koizumi T, Nikaido H, Hayakawa J. Infantile disease with microvesicular fatty infiltration of viscera spontaneously occurring in the C3H-H-2 strain of mouse with similarities to Reye's syndrome.  Lab Anim . 1988;  22 83-87
• 97 Kuwajima M, Kono N, Horiuchi M. Animal model of systemic carnitine deficiency: analysis in C3H-2 strain of mouse associated with juvenile visceral steatosis.  Biochem Biophys Res Commun . 1991;  174 1090-1094
• 98 Miyagawa J, Kuwajima M, Hanafusa T. Mitochondrial abnormalities of muscle tissue in mice with juvenile visceral steatosis associated with systemic carnitine deficiency.  Virchows Arch . 1995;  426 271-279
• 99 Weltman M D, Farrell G C, Liddle C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation.  Gastroenterology . 1996;  111 1645-1653
• 100 Leclercq I A, Farrell G C, Field J. Cyp2E1 and Cyp4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis.  J Clin Invest . 2000;  105 1067-1075
• 101 Oien K A, Moffat D, Curry G W. Cirrhosis with steatohepatitis after adjuvant tamoxifen.  Lancet . 1999;  353 36-37
• 102 Pratt D S, Knox T A, Erban J. Tamoxifen-induced steatohepatitis.  Ann Intern Med . 1995;  123 236-239
• 103 Pinto H C, Baptista A, Camilo M E. Tamoxifen-associated steatohepatitis: report of three cases.  J Hepatol . 1995;  23 95-97
• 104 Van Hoof M, Rahier J, Horsmans Y. Tamoxifen-induced steatohepatitis.  Ann Intern Med . 1996;  124 855-856
• 105 Grimbert S, Fisch C, Deschamps D. Effects of female sex hormones on mitochondria: possible role in acute fatty liver of pregnancy.  Am J Physiol . 1995;  31 G107-G115
• 106 Letteron P, Brahimi-Bourouina N, Robin M A. Glucocorticoids inhibit mitochondrial matrix acyl-CoA dehydrogenases and fatty acid beta oxidation.  Am J Physiol . 1997;  35 G1141-G1150
• 107 Cortez-Pinto H, Lin H Z, Yang S Q. Lipids up-regulate uncoupling protein-2 expression in rat hepatocytes.  Gastroenterology . 1999;  116 1184-1193