HNF4a Transcriptionally Regulates PLA₂GXIIB And MTP

Hepatocyte nuclear factor 4α(?HNF4α) is an important transcription factor governing the expression of genes involved in multiple metabolic pathways. Secreted phospholipases A2 GXIIB (PLA2GXIIB) is an atypical member of a class of secreted phospholipases A2. We establish in this study that PLA2GXIIB is a HNF-4αtarget gene. We demonstrate that HNF-4αbinds to a response element on the PLA2GXIIB promoter composed of AGGACAAAGGTGA representing a direct repeat with a 1 base pair spacer (DR1). Moreover, HNF4αagonists and adenovirus-mediated HNF4αover-expression induce PLA2GXIIB expression in human hepatocarcinoma cells. Finally, adenovirus mediated over-expression of HNF4αelevates serum triglyceride level in wild type but not PLA2GXIIB-null mice. Collectively, these evidences suggest that HNF4αis a key physiologically PLA2GXIIB transcriptional regulator and that PLA2GXIIB is a novel mediator of triglyceride metabolism in the liver.Microsomal triglyceride transfer protein (MTP) is a rate-limitting enzyme played a role in the assembly and secretion very low density lipoproteins (VLDLs). Fasting induce MTP expression in C57BL/6J mice. In HepG2 cells, we further demonstrate that starvation induce MTP expression, and also enhance HNF4αmRNA level. We establish that MTP is a HNF4αtarget gene. Moreover, adenovirus mediated HNF4αoverexpression and HNF4αagonists induce MTP expression in HepG2 cells. specific siRNA represses HNF4αand MTP expression. These evidences maybe provide a basis to illuminate the mechanism of lipids secretion from liver in fasting mice.