Abstract
After de novo biosynthesis phospholipids undergo extensive remodeling by the Lands' cycle. Enzymes involved in phospholipid biosynthesis have been studied extensively but not those involved in reacylation of lysophosphopholipids. 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. In this study we found that LPCAT3 is the major hepatic isoform, and its knockdown significantly reduces hepatic LPCAT activity. Moreover, we report that hepatic LPCAT3 knockdown increases certain species of LysoPCs and decreases certain species of PC. A surprising observation was that LPCAT3 knockdown significantly reduces hepatic triglycerides. Despite this, these mice had higher plasma triglyceride and apoB levels. Lipoprotein production studies indicated that reductions in LPCAT3 enhanced assembly and secretion of triglyceride-rich apoB-containing lipoproteins. Furthermore, these mice had 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. In short, these results indicate that hepatic LPCAT3 modulates VLDL production by regulating LysoPC levels and MTP expression.
Highlights
LPCAT3 is involved in liver PC remodeling
We obtained the same results from Huh7 cells, another human hepatoma cell line [23]. These results suggested that LPCAT3 is the major enzyme contributing to lysophosphatidylcholine acyltransferase (LPCAT) activity in liver cells and is consistent with its highest expression in the human liver [23]
We show that liver-specific LPCAT3 knockdown can significantly 1) increase certain species of LysoPC and total LysoPC levels and decrease certain species of PC but not total PC levels, 2) decrease hepatic triglyceride levels, and 3) increase plasma triglyceride and apoB levels
Summary
LPCAT3 is involved in liver PC remodeling. Results: LPCAT3 knockdown in the liver significantly accumulates LysoPC, which promotes VLDL production by enhancing liver MTP expression. Lipoprotein production studies indicated that reductions in LPCAT3 enhanced assembly and secretion of triglyceride-rich apoB-containing lipoproteins These mice had higher microsomal triglyceride transfer protein. LysoPC increased MTP mRNA, protein, and activity These results indicate that hepatic LPCAT3 modulates VLDL production by regulating LysoPC levels and MTP expression. Microsomal triglyceride transfer protein (MTP) plays a crucial role in the lipidation of this nascent peptide by physically interacting with it and depositing lipids on it, resulting a primordial lipoprotein [3] This process is referred to as “first step of lipidation” of apoB (4 – 6). Liver LPCAT3 Knockdown Increases VLDL Production assembly, as exemplified by studies with hepatic cells treated with n-3 fatty acids [13, 14] or insulin [15], where active TG synthesis does not always enhance VLDL production. We show for the first time that liver LPCAT3 activity directly regulates VLDL production by increasing MTP expression
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