title: Lysophosphatidylcholine acyltransferase 3 knockdown-mediated liver lysophosphatidylcholine accumulation promotes very low density lipoprotein production by enhancing microsomal triglyceride transfer protein expression.
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.
authors.affiliation: Molecular and Cellular Cardiology Program, Veterans Affairs New York Harbor Healthcare System, Brooklyn, New York 11209, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Li
authors.forename: Tingbo
authors.initials: T
authors.lastname: Ding
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Pan
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Ruohan
authors.initials: R
authors.lastname: Li
authors.forename: Philip E
authors.initials: PE
authors.lastname: Sanders
authors.forename: Ming-Shang
authors.initials: MS
authors.lastname: Kuo
authors.forename: M Mahmood
authors.initials: MM
authors.lastname: Hussain
authors.forename: Guoqing
authors.initials: G
authors.lastname: Cao
authors.forename: Xian-Cheng
authors.initials: XC
authors.lastname: Jiang
mesh_terms: D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D055785:Gene Knockdown Techniques; D008079:Lipoproteins, VLDL / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D008297:Male; D051379:Mice; D014176:Protein Biosynthesis / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism*
chemical_list: C415826:Apob protein, mouse; D016632:Apolipoprotein A-I; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D002352:Carrier Proteins; D008079:Lipoproteins, VLDL; D008244:Lysophosphatidylcholines; D012333:RNA, Messenger; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D008243:1-Acylglycerophosphocholine O-Acyltransferase