title: Deficiency in lysophosphatidylcholine acyltransferase 3 reduces plasma levels of lipids by reducing lipid absorption in mice.
abstract: OBJECTIVE
  Phosphatidylcholines (PCs) are structural and functional constituents of cell membranes. The activity of acyltransferase (lysophosphatidylcholine acyltransferase [LPCAT]) is required for addition of polyunsaturated fatty acids to the sn-2 position of PCs and is therefore required to maintain cell membrane structure and function. LPCAT3 is the most abundant isoform of LPCAT in the small intestine and liver, which are important sites of plasma lipoprotein metabolism. We investigated the effects of Lpcat3 disruption on lipid metabolism in mice.
  
  
  METHODS
  We disrupted the gene Lpcat3 in C57BL/6J mice to create LPCAT3 knockout (KO) mice. Livers and small intestinal tissues were collected from LPCAT3 KO and C57BL/6J parental strain (controls), and levels of LPCAT messenger RNAs and protein were measured. Levels of lipids and lipoproteins were measured in plasma samples. We isolated enterocytes from mice and measured levels of RNAs and proteins involved in lipid uptake by real-time polymerase chain reaction and immunoblot assays, respectively. We assessed lipid absorption and PC subspecies in the enterocyte plasma membrane using liquid chromatography with tandem mass spectometry.
  
  
  RESULTS
  LPCAT3 KO mice survived only 3 weeks after birth. Oil Red O staining showed that the control but not LPCAT3 KO mice accumulated lipids in the small intestine; levels of Niemann-Pick C1-like 1 (NPC1L1) and fatty acid transporter protein 4 (FATP4), which regulate lipid uptake, were greatly reduced in the small intestines of LPCAT3 KO mice. Oral administration of PC and olive oil allowed the LPCAT3 KO mice to survive with the same body weights as controls, but the KO mice had shorter and wider small-intestinal villi and longer and bigger small intestines. Plasma membranes of enterocytes from LPCAT3 KO mice also had significant reductions in the composition of polyunsaturated PCs and reduced levels of NPC1L1, CD36, and FATP4 proteins. These reductions were associated with reduced intestinal uptake of lipid by the small intestine and reduced plasma levels of cholesterol, phospholipid, and triglyceride.
  
  
  CONCLUSIONS
  LPCAT3 KO mice have longer and larger small intestines than control mice, with shorter wide villi, reduced lipid absorption, and lower levels NPC1L1, CD36, and FATP4 proteins. Inhibition of LPCAT3 in the small intestine could be developed as an approach to treat hyperlipidemia.
authors.affiliation: Department of Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, New York; Molecular and Cellular Cardiology Program, VA New York Harbor Healthcare System, Brooklyn, New York.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, New York.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, New York; School of Pharmacy, Fudan University, China.
authors.forename: Tingbo
authors.initials: T
authors.lastname: Ding
authors.affiliation: Department of Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, New York; Guangdong Medical Laboratory Animal Center, Foshan, China.
authors.forename: Caixia
authors.initials: C
authors.lastname: Lou
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana.
authors.forename: Hai H
authors.initials: HH
authors.lastname: Bui
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana.
authors.forename: Ming-Shang
authors.initials: MS
authors.lastname: Kuo
authors.affiliation: Department of Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, New York; Molecular and Cellular Cardiology Program, VA New York Harbor Healthcare System, Brooklyn, New York; School of Pharmacy, Fudan University, China. Electronic address: xjiang@downstate.edu.
authors.forename: Xian-Cheng
authors.initials: XC
authors.lastname: Jiang
mesh_terms: D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000502:physiology; D018955:CD36 Antigens / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D002853:Chromatography, Liquid; D020895:Enterocytes / Q000378:metabolism*; D050612:Fatty Acid Transport Proteins / Q000378:metabolism; D015151:Immunoblotting; D007408:Intestinal Absorption / Q000235:genetics / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000069463:Olive Oil / Q000008:administration & dosage; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D012333:RNA, Messenger; D060888:Real-Time Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D014280:Triglycerides / Q000097:blood
chemical_list: D018955:CD36 Antigens; D050612:Fatty Acid Transport Proteins; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D000069463:Olive Oil; D010713:Phosphatidylcholines; D010743:Phospholipids; D012333:RNA, Messenger; C493572:Slc27a4 protein, mouse; D014280:Triglycerides; C029449:polyene phosphatidylcholine; D002784:Cholesterol; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C000600794:LPCAT3 protein, mouse
keywords: Lipid Regulation; Mouse Model; PUFA; Phosphatidylcholine Remodeling