Nonalcoholic fatty liver disease (NAFLD) is a component of the metabolic syndrome, with a clinical spectrum ranging from simple fatty liver to steatohepatitis, cirrhosis, and hepatocellular carcinoma. The primary event of NAFLD is the accumulation of triacylglycerols (TAGs) in hepatocytes. In this issue of the JCI, Donnelly et al. report on their use of stable isotope methodology to show that fatty acids stored in adipose tissue and fatty acids newly made within the liver through de novo lipogenesis are the major sources of TAGs in the liver and are secreted as lipoproteins in NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of abnormal results in liver-function tests. This clinical situation is really a continuum of diseases that includes simple (benign) fatty liver, nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (1). NAFLD is defined as liver steatosis in patients who do not consume enough alcohol to cause hepatic injury. Although some drugs or genetic abnormalities can cause NAFLD, the majority of cases are associated with obesity, insulin resistance, and type 2 diabetes. In order to clarify the pathogenesis of this disease and identify potential therapeutic targets, an increased understanding of the dynamics of triacyl-glycerol (TAG) metabolism in the liver in relation to whole-body metabolic status is needed. Sources of hepatic TAGs include dietary TAGs that are transported via chylomicrons from the intestine to adipose tissue or to the liver, where they are secreted via lipoproteins, in addition to TAGs that are synthesized from fatty acids and glycerol in the liver. Fatty acids required for TAG synthesis are available from both the plasma nonesterified fatty acid (NEFA) pool and the pool of fatty acids newly synthesized within the liver through de novo lipogenesis (DNL). TAGs present in the liver may be stored as lipid droplets or secreted into the blood as VLDLs; they may also enter the oxidation pathway (Figure 1). The study by Donnelly et al. in this issue of the JCI examines hepatic lipoprotein metabolism in humans and describes the major sources of hepatic and plasma lipoprotein TAG in NAFLD (2).