Hepatic triglyceride synthesis and nonalcoholic fatty liver disease
- 1 June 2008
- journal article
- review article
- Published by Ovid Technologies (Wolters Kluwer Health) in Current Opinion in Lipidology
- Vol. 19 (3), 295-300
- https://doi.org/10.1097/mol.0b013e3282ff5e55
Abstract
Nonalcoholic fatty liver disease is a spectrum of diseases ranging from simple steatosis to cirrhosis. The hallmark of nonalcoholic fatty liver disease is hepatocyte accumulation of triglycerides. We will review the role of triglyceride synthesis in nonalcoholic fatty liver disease progression and summarize recent findings about triglyceride synthesis inhibition and prevention of progressive disease. Attempts to inhibit triglyceride synthesis in animal models have resulted in improvement in hepatic steatosis. Studies in animal models of nonalcoholic fatty liver disease demonstrate that inhibition of acyl-coenzyme A:diacylglycerol acyltransferase, the enzyme that catalyzes the final step in triglyceride synthesis, results in improvement in hepatic steatosis and insulin sensitivity. We recently confirmed that hepatic specific inhibition of acyl-coenzyme A:diacylglycerol acyltransferase with antisense oligonucleotides improves hepatic steatosis in obese, diabetic mice but, unexpectedly, exacerbated injury and fibrosis in that model of progressive nonalcoholic fatty liver disease. When hepatocyte triglyceride synthesis was inhibited, free fatty acids accumulated in the liver, leading to induction of fatty acid oxidizing systems that increased hepatic oxidative stress and liver damage. These findings suggest that the ability to synthesize triglycerides may, in fact, be protective in obesity. Nonalcoholic fatty liver disease is strongly associated with obesity and peripheral insulin resistance. Peripheral insulin resistance increases lipolysis in adipose depots, promoting increased free fatty acid delivery to the liver. In states of energy excess, such as obesity, the latter normally triggers hepatic triglyceride synthesis. When hepatic triglyceride synthesis is unable to accommodate increased hepatocyte free fatty acid accumulation, however, lipotoxicity results. Thus, rather than being hepatotoxic, liver triglyceride accumulation is actually hepato-protective in obese, insulin-resistant individuals.Keywords
This publication has 43 references indexed in Scilit:
- Nonalcoholic Fatty Liver Disease as a Complication of Insulin ResistanceMedical Clinics of North America, 2007
- Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicityHepatology, 2004
- Adipose Tissue as a Regulator of Energy BalanceCurrent Drug Targets, 2004
- Minireview: The Adipocyte—At the Crossroads of Energy Homeostasis, Inflammation, and AtherosclerosisEndocrinology, 2003
- Insulin Resistance Syndrome and Nonalcoholic Fatty Liver DiseaseEndocrine Practice, 2003
- Nonalcoholic Fatty Liver DiseaseJAMA, 2003
- Adipobiology of Disease: Adipokines and Adipokine-Targeted PharmacologyCurrent Pharmaceutical Design, 2003
- Nonalcoholic Fatty Liver DiseaseNew England Journal of Medicine, 2002
- Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: Further evidence for an etiologic associationHepatology, 2002
- Steatohepatitis: A tale of two “hits”?Gastroenterology, 1998