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 e xport. When "input" of fats into these systems (either because of increased fatty acid delivery, hepatic fatty acid uptake, or fatty acid synthesis) e xceeds the capacity for fatty acid oxidation or export (i.e., "output"), th en hepatic steatosis occurs. Genetic causes of increased fatty acid input p romote excessive hepatic lipogenesis. These include mutations that cause le ptin deficiency or leptin receptor inhibition and mutations that induce ins ulin, insulin-like growth factors, or insulin-responsive transcription fact ors. Genetic causes of impaired hepatic fatty acid oxidation inhibit the el imination (i.e., output) of fat from the liver. These include mutations tha t inhibit various components of the peroxisomal and/or mitochondrial pathwa ys for fatty acid beta -oxidation. Environmental factors, such as diets and toxins, can also unbalance hepatic fatty acid synthesis and oxidation. Hep atic lipogenesis is increased by dietary sucrose, fructose, or fats and cer tain 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 appe ar to be useful models for human nonalcoholic fatty liver disease in which hyperinsulinemia and defective leptin signaling are conspicuous at early st ages of the disease process.