Serum TAG Analysis Differentiates Between Genetic and Obesity-Associated NAFLD

Nonalcoholic fatty liver disease (NAFLD) occurs in 20–30% of Americans and is the most prevalent form of liver disease (1,2). NAFLD is commonly linked to hepatic and whole-body insulin resistance and, in some individuals NAFLD can lead to steatohepatitis, cirrhosis, and cancer (3). The selective hepatic insulin resistance that typically accompanies NAFLD results in increased hepatic glucose production, hepatic lipogenesis, and very low-density lipoprotein (VLDL) secretion, thereby contributing to the hyperglycemia and triglyceridemia observed in insulin-resistant and type 2 diabetic subjects. Despite their close association, NAFLD and insulin resistance can be uncoupled, suggesting that not all NAFLD is the same (4). Although dietary and environmental factors have a large influence, genetics alone or in combination with external factors also influence NAFLD etiology. A point mutation in PNPLA3 (also known as adiponutrin) is prevalent in ∼20–50% of people depending upon ethnicity and is the single best genetic predictor of NAFLD (5). A recent meta-analysis of nearly 3,000 subjects showed that carriers of the I148M mutant have 73% higher liver triacylglycerol (TAG) content compared with those with the normal I148I allele (6). In addition, the I148M variant has been associated with complications or progression of NAFLD, including development of nonalcoholic steatohepatitis, alcoholic liver disease and its progression to cirrhosis, and the severity of hepatitis C–induced steatosis (7). Despite its important role in NAFLD etiology, the physiological function of wild-type and variant PNPLA3 remains under intense debate. …