title: Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase.
abstract: Numerous studies in humans link a nonsynonymous genetic polymorphism (I148M) in adiponutrin (ADPN) to various forms of fatty liver disease and liver cirrhosis. Despite its high clinical relevance, the molecular function of ADPN and the mechanism by which I148M variant affects hepatic metabolism are unclear. Here we show that ADPN promotes cellular lipid synthesis by converting lysophosphatidic acid (LPA) into phosphatidic acid. The ADPN-catalyzed LPA acyltransferase (LPAAT) reaction is specific for LPA and long-chain acyl-CoAs. Wild-type mice receiving a high-sucrose diet exhibit substantial upregulation of Adpn in the liver and a concomitant increase in LPAAT activity. In Adpn-deficient mice, this diet-induced increase in hepatic LPAAT activity is reduced. Notably, the I148M variant of human ADPN exhibits increased LPAAT activity leading to increased cellular lipid accumulation. This gain of function provides a plausible biochemical mechanism for the development of liver steatosis in subjects carrying the I148M variant.
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Manju
authors.initials: M
authors.lastname: Kumari
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schoiswohl
authors.forename: Chandramohan
authors.initials: C
authors.lastname: Chitraju
authors.forename: Margret
authors.initials: M
authors.lastname: Paar
authors.forename: Irina
authors.initials: I
authors.lastname: Cornaciu
authors.forename: Ashraf Y
authors.initials: AY
authors.lastname: Rangrez
authors.forename: Nuttaporn
authors.initials: N
authors.lastname: Wongsiriroj
authors.forename: Harald M
authors.initials: HM
authors.lastname: Nagy
authors.forename: Pavlina T
authors.initials: PT
authors.lastname: Ivanova
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Scott
authors.forename: Oskar
authors.initials: O
authors.lastname: Knittelfelder
authors.forename: Gerald N
authors.initials: GN
authors.lastname: Rechberger
authors.forename: Ruth
authors.initials: R
authors.lastname: Birner-Gruenberger
authors.forename: Sandra
authors.initials: S
authors.lastname: Eder
authors.forename: H Alex
authors.initials: HA
authors.lastname: Brown
authors.forename: Guenter
authors.initials: G
authors.lastname: Haemmerle
authors.forename: Monika
authors.initials: M
authors.lastname: Oberer
authors.forename: Achim
authors.initials: A
authors.lastname: Lass
authors.forename: Erin E
authors.initials: EE
authors.lastname: Kershaw
authors.forename: Robert
authors.initials: R
authors.lastname: Zimmermann
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D000214:Acyl Coenzyme A / Q000235:genetics / Q000378:metabolism; D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D019422:Dietary Sucrose / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008055:Lipids / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D010712:Phosphatidic Acids / Q000235:genetics / Q000378:metabolism; D010743:Phospholipids / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000214:Acyl Coenzyme A; D019422:Dietary Sucrose; D008055:Lipids; D008246:Lysophospholipids; D008565:Membrane Proteins; D010712:Phosphatidic Acids; D010743:Phospholipids; D014280:Triglycerides; C436316:adiponutrin; D000217:Acyltransferases; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C439972:ABHD5 protein, human; C492986:Abhd5 protein, mouse; C018764:2-acylglycerophosphate acyltransferase; D003546:Cysteine Endopeptidases; C056657:cysteine proteinase I; C032881:lysophosphatidic acid