Understanding the Role of Liver Acetyl-CoA Carboxylases in Normal Physiology, Metabolic Disease, and Liver Cancer

Abstract

The liver has a high capacity to store excess nutrients, primarily in the form of fat. However, excess lipid deposition in the liver can be problematic, as it is associated with metabolic disorders including fatty liver disease, type II diabetes, and liver cancer. The acetyl-CoA carboxylase (ACC) enzymes are major regulators of liver lipid content by catalyzing the conversion of excess glucose in the liver to fat, and by inhibiting mitochondrial fat oxidation. Thus, the ACC enzymes are potential drug targets because altering their activity could correct disease states associated with excess fat deposition. Using mice with genetic inhibition of liver ACC activity, we have uncovered a novel role for these enzymes in regulating protein acetylation that contributes to broad changes in cellular metabolism. At the level of whole-body physiology, we found that when a source of dietary fat was absent, LDKO mice have increased glucose disposal into the liver, reduction of peripheral adiposity, and improved whole-body glucose tolerance compared to controls. Under high-fat diet conditions, LDKO mice are protected from diet-induced fatty liver. However, a decrease in liver fat in this case is not sufficient to ameliorate diet-induced glucose intolerance. Finally, we investigated the role of ACC activity in tumorigenesis. Unexpectedly, inhibition of ACC activity increased susceptibility to carcinogen-induced liver tumor. Increased liver antioxidant defenses in LDKO mice protected cells from carcinogen-induced apoptosis and promoted tumor cell proliferation. This study identifies a protective role for ACC enzymes against tumorigenesis. Taken together, this work increases our understanding of liver nutrient metabolism and ACC activity, and highlights the complexity of liver metabolic compensatory mechanisms.