1. Adiponutrin Functions as a Nutritionally Regulated Lysophosphatidic Acid Acyltransferase
- Author
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Harald M. Nagy, Manju Kumari, Gabriele Schoiswohl, Gerald N. Rechberger, Achim Lass, Guenter Haemmerle, H. Alex Brown, Monika Oberer, Ruth Birner-Gruenberger, Ashraf Yusuf Rangrez, Erin E. Kershaw, Sarah A. Scott, Oskar Knittelfelder, Sandra Eder, Irina Cornaciu, Robert Zimmermann, Margret Paar, Pavlina T. Ivanova, Rudolf Zechner, Chandramohan Chitraju, and Nuttaporn Wongsiriroj
- Subjects
Male ,Models, Molecular ,Cirrhosis ,Physiology ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Dietary Sucrose ,Cricetinae ,Lysophosphatidic acid ,Chlorocebus aethiops ,Phospholipids ,Mice, Knockout ,0303 health sciences ,education.field_of_study ,Fatty liver ,Phosphatidic acid ,Hep G2 Cells ,1-Acylglycerol-3-Phosphate O-Acyltransferase ,Lipids ,3. Good health ,Up-Regulation ,Cysteine Endopeptidases ,Liver ,Acyltransferase ,COS Cells ,030211 gastroenterology & hepatology ,lipids (amino acids, peptides, and proteins) ,medicine.medical_specialty ,Phosphatidic Acids ,CHO Cells ,Biology ,Article ,03 medical and health sciences ,Downregulation and upregulation ,Internal medicine ,medicine ,Animals ,Humans ,Adiponutrin ,education ,Molecular Biology ,Triglycerides ,030304 developmental biology ,Polymorphism, Genetic ,Membrane Proteins ,Lipid metabolism ,Cell Biology ,medicine.disease ,Lipid Metabolism ,Fatty Liver ,Endocrinology ,chemistry ,Acyl Coenzyme A ,Lysophospholipids ,Acyltransferases - Abstract
SummaryNumerous 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.
- Published
- 2012
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