Endocrine Abstracts

Nonalcoholic fatty liver disease (NAFLD) is becoming a master component of the epidemic of obesity and metabolic syndrome worldwide due to excessive caloric intake. The spectrum of NAFLD ranges from simple fatty liver with benign prognosis to a potentially progressive form, nonalcoholic steatohepatitis (NASH), which may lead to liver fibrosis and cirrhosis resulting in increased morbidity and mortality. Development of hepatic steatosis and its progression to steatohepatitis may be the consequence of dysfunction of several metabolic pathways, such as triglyceride synthesis, VLDL secretion and fatty acid β-oxidation. One main determinant in the pathogenesis of fatty liver seems to be an increment in the serum fatty acid pool. The sources of fat contributing to fatty liver are peripheral TGs stored in white adipose tissue that are driven to the liver in form of plasma non-esterified fatty acids (NEFAs), dietary fatty acids, and hepatic de novo lipogenesis (DNL). The metabolic partitioning of fatty acids between mitochondrial β-oxidation and TG synthesis is critically regulated. In the liver, fatty acid β-oxidation is normally inhibited by food intake by the action of insulin, which is the main regulator of DNL due to its direct activation of SREBP1c. Recent studies focused on the transcriptional regulatory proteins that drive mitochondrial biogenesis and oxidative metabolism, lipogenesis and triglyceride (TG) secretion. We will present novel data from tissue-specific mouse models that bolster the concept that a combined non-insulin driven hepatic specific action on lipid synthesis and secretion, as well as, on mitochondrial biogenesis and function could protect against fatty liver and insulin resistance.