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-4α-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.

CONCLUSIONS

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.