7). Incidentally, PLA2GXIIB is expressed in the small intestine where HNF-4α is functionally active14; therefore, HNF-4α also likely drives PLA2GXIIB expression in the small intestine. Although both HNF4αLivKO and PLA2GXIIB-null mice share many common phenotypes such as fatty liver and reduced serum lipid levels, they have other unique characteristics. HNF-4α regulates PEPCK to guide gluconeogenesis, short-heterodimer partner (SHP) to govern bile acid homeostasis, and ornithine transcarbamylase (OTC) to regulate ureagenesis; not surprisingly, the serum glucose check details and

urea levels of HNF4αLivKO-null mice are lowered whereas bile acids and ammonia levels are elevated compared to their wild-type counterparts.6 However, these serum biochemical parameters were not significantly altered in PLA2GXIIB-null

mice (Table 1; Supporting Information Fig. 5; data not shown). On the other hand, the serum free fatty acids level was significantly lowered in PLA2GXIIB-null buy Pritelivir but not in HNF4αLivKO mice (Table 1).6 Because PLA2GXIIB is a secreted protein, its action may extend to tissues other than the liver to affect the homeostasis of fatty acids. Although hepatic VLDL-TG secretion is inhibited by PLA2GXIIB deficiency, the mechanistic connection is still an open question. Intriguingly, MTP-null mice also have lowered serum TG, cholesterol, and phospholipids levels as in PLA2GXIIB-null mice (Table 1) and develop mild hepatosteatosis.15 Nevertheless, the mRNA expression level of MTP, which is an HNF-4α target gene, remained normal in PLA2GXIIB-null mice (Supporting Information Fig. 6A). Beside, the expression levels of two other HNF-4α target genes PEPCK and G6P were not altered (Supporting Information Fig. 6B),

implying that HNF-4α activity remains intact Carbohydrate in PLA2GXIIB-null mice. Hepatic VLDL-TG secretion not only depends on the function of MTP but also plasma phospholipid transfer protein (PLTP).16 We found that the liver mRNA expression level of PLTP was not significantly altered in PLA2GXIIB-null mice (Supporting Information Fig. 6). Bile acids can regulate both gluconeogenesis and VLDL-TG secretion through suppressing HNF-4α activity. Our preliminary analysis indicated that the amounts of hepatic, urinary, fecal, and gallbladder bile acids did not significantly differ between wild-type and PLA2GXIIB-null mice (Supporting Information Fig. 5). As demonstrated by their respective knockout mice, the functions of HNF-4α and its target genes MTP and PLA2GXIIB are indispensable for VLDL-TG secretion. In a complementary analysis, overexpression of MTP by adenovirus elevated serum TG levels and the rate of hepatic VLDL-TG secretion.17 Remarkably, we showed that overexpression of PLA2GXIIB by adenovirus also affected these parameters (Fig. 6). Based on these observations, we propose that HNF-4α acts upstream to control MTP- and PLA2GXIIB-dependent pathways that are independent but acting in parallel to drive hepatic VLDL-TG secretion (Fig. 7).