Abstract 130: Lysophosphatidylcholine Acyltransferase 3 Knockdown-Mediated Liver Lysophosphatidylcholine Accumulation Promotes Very-Low-Density Lipoprotein Production by Enhancing Microsomal Triglyceride Transfer Protein Expression

Abstract

Phospholipids undergo extensive remodeling by the Lands’ Cycle after de novo biosynthesis. Enzymes involved in phospholipid biosynthesis have been studied extensively but not those involved in remodeling. One key enzyme in the Lands’ Cycle is fatty acyl-CoA:lysophosphatidylcholine acyltransferase (LPCAT) which utilizes lysophosphatidylcholine (LysoPC) and fatty acyl-CoA to produce various phosphatidylcholine (PC) species. Four isoforms of LPCAT have been identified. We found, in this study, that LPCAT3 is the major hepatic isoform and its knockdown significantly reduces hepatic LPCAT activity. We also found that adenovirus-shRNA-mediated LPCAT3 knockdown in mice significantly increases different LysoPC with 16:0, 18:0, 18:1, and 18:2 fatty acids and reduces certain PC species in the liver. More importantly, LPCAT3 knockdown significantly reduces hepatic triglyceride levels but induces plasma triglyceride and apoB levels. Lipoprotein production studies indicated that LPCAT3 deficiency enhanced triglyceride-rich apoB-containing lipoprotein assembly and secretion. Further, the knockdown mice had significantly higher microsomal triglyceride transfer protein (MTP) mRNA and protein levels. Mechanistic studies in hepatoma cells revealed that LysoPC enhances secretion of apoB but not apoA-I in a concentration dependent manner. Moreover, LysoPC increased MTP mRNA, protein, and activity levels. In short, these results indicate that hepatic LPCAT3 modulates VLDL production by regulating LysoPC levels and MTP expression.