Figure 2. Mechanisms of Hepatocellular Diacylglycerol Accumulation.

Increases in hepatic diacylglycerol (DAG) content results from an imbalance in rates of fatty acid delivery/uptake relative to rates of mitochondrial fatty acid oxidation and conversion of DAGs to triglycerides (TAGs). Increased energy intake exceeding rates of energy expenditure, is the most common cause of NAFLD and DAG-PKCε induced hepatic insulin resistance, which is most often seen in exogenous obesity. Predisposing genetic factors such as ApoC3 gene variants resulting in increased plasma ApoC3 concentrations results in suppression of lipoprotein lipase activity, increased postprandial chylomicron remnants and increased hepatic fat uptake, increased hepatic DAG content, PKCε-mediated hepatic insulin resistance. Defects in adipocyte fat storage as seen in lipodystrophy or due to genetic alterations (e.g. mutations in PPARγ or perilipin (Agostini et al., 2006; Gandotra et al., 2011) also can result in increased fat delivery to the liver, NAFLD and hepatic insulin resistance. Genetic or acquired defects in mitochondrial fatty acid oxidation may also predispose to NAFLD and DAG-PKCε mediated hepatic insulin resistance. Finally, fatty acids released from adipocytes, can enter the liver through the liver specific fatty acid transport protein 5 (FATP5), resulting in increased long chain fatty acids (LCoAs) (Schaffer and Lodish, 1994), which can then be converted to DAG.