Hepatocyte nuclear factor‐4 alpha regulates liver triglyceride metabolism in part through secreted phospholipase A 2 GXIIB

Hepatocyte nuclear factor‐4 alpha (HNF‐4α) is an important transcription factor governing the expression of genes involved in multiple metabolic pathways. Secreted phospholipase A 2 GXIIB (PLA 2 GXIIB) is an atypical member of a class of secreted phospholipases A 2 . We establish in this study that PLA 2 GXIIB is an HNF‐4α target gene. We demonstrate that HNF‐4α binds to a response element on the PLA 2 GXIIB promoter. Moreover, HNF‐4α agonists induce PLA 2 GXIIB expression in human hepatocarcinoma cells. Importantly, PLA 2 GXIIB ‐null mice accumulate triglyceride, cholesterol, and fatty acids in the liver and develop severe hepatosteatosis resembling some of the phenotypes of liver‐specific HNF ‐ 4 α–null mice. These defects are in part due to compromised hepatic very low‐density lipoprotein secretion. Finally, adenovirus‐mediated overexpression of HNF‐4α elevates serum triglyceride level in wild‐type but not PLA 2 GXIIB ‐null mice. Conclusion: Collectively, these evidences suggest that HNF‐4α is a key physiological PLA 2 GXIIB transcriptional regulator and that PLA 2 GXIIB is a novel mediator of triglyceride metabolism in the liver. (H EPATOLOGY 2011;53:458‐466)