Animal models of steatosis.
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 beta-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.
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Johns Hopkins University, 912 Ross Bldg., 720 Rutland Street, Baltimore, MD 21205, USA.
Diehl
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D000818:Animals; D004032:Diet; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics; D020738:Leptin / Q000172:deficiency / Q000627:therapeutic use; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D023421:Models, Animal; D010084:Oxidation-Reduction; D051381:Rats; D011924:Rats, Zucker; D014118:Toxins, Biological / Q000009:adverse effects
D005227:Fatty Acids; D020738:Leptin; D014118:Toxins, Biological