The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Soumik BasuRayHelen H Hobbs

Abstract

A sequence variation (I148M) in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is strongly associated with fatty liver disease, but the underlying mechanism remains obscure. In this study, we used knock-in (KI) mice (Pnpla3148M/M ) to examine the mechanism responsible for accumulation of triglyceride (TG) and PNPLA3 in hepatic lipid droplets (LDs). No differences were found between Pnpla3148M/M and Pnpla3+/+ mice in hepatic TG synthesis, utilization, or secretion. These results are consistent with TG accumulation in the Pnpla3148M/M mice being caused by impaired TG mobilization from LDs. Sucrose feeding, which is required to elicit fatty liver in KI mice, led to a much larger and more persistent increase in PNPLA3 protein in the KI mice than in wild-type (WT) mice. Inhibition of the proteasome (bortezomib), but not macroautophagy (3-methyladenine), markedly increased PNPLA3 levels in WT mice, coincident with the appearance of ubiquitylated forms of the protein. Bortezomib did not increase PNPLA3 levels in Pnpla3148M/M mice, and only trace amounts of ubiquitylated PNPLA3 were seen in these animals. These results are consistent with the notion that the 148M variant disrupts ubiquitylation and proteasomal degradat...Continue Reading

References

Mar 1, 1982·Proceedings of the National Academy of Sciences of the United States of America·P O Seglen, P B Gordon
Nov 20, 2004·Science·Robert ZimmermannRudolf Zechner
Jul 5, 2005·Journal of Lipid Research·John S MillarJeffrey T Billheimer
Aug 24, 2005·The Journal of Biological Chemistry·Guoheng XuConstantine Londos
Oct 8, 2008·Journal of Lipid Research·Young-Ah MoonJay D Horton
Jul 8, 2009·The Journal of Biological Chemistry·Hong-Ping GuanGuosheng Liang
Apr 14, 2010·Proceedings of the National Academy of Sciences of the United States of America·Yongcheng HuangHelen H Hobbs
Jul 22, 2010·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Weiqin ChenLawrence Chan
Aug 6, 2010·The Journal of Biological Chemistry·Nargis NasrinLaura Bordone
Nov 12, 2010·Journal of Lipid Research·Mahesh K BasantaniErin E Kershaw
Jun 28, 2011·Science·Jonathan C CohenHelen H Hobbs
Sep 1, 2011·The Journal of Biological Chemistry·Yongcheng HuangHelen H Hobbs
Oct 2, 2012·The Journal of Clinical Investigation·John Zhong LiHelen H Hobbs
Nov 16, 2012·Cell Death & Disease·C De PalmaE Clementi
Jan 22, 2013·Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver·Luca ValentiStefano Romeo
Feb 13, 2013·Biology of the Cell·Zeina ChamounJean Gruenberg
Apr 3, 2013·Biochimica Et Biophysica Acta·Anne Schreiber, Matthias Peter
Feb 11, 2014·Journal of Lipid Research·Hanna RuhanenVesa M Olkkonen
Jun 12, 2014·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Eriks SmagrisHelen H Hobbs
Apr 17, 2015·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Phillip M MarvynRobin E Duncan
May 12, 2015·Nature Cell Biology·Susmita Kaushik, Ana Maria Cuervo

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Citations

Jul 18, 2017·International Journal of Molecular Sciences·Paola Dongiovanni, Luca Valenti
Mar 2, 2018·Clinical Journal of Gastroenterology·Yuya SekoYoshito Itoh
Apr 13, 2018·Human Molecular Genetics·Eeva SlizJohannes Kettunen
Sep 2, 2018·Journal of Cellular Biochemistry·Florentina NegoitaHelena A Jones
Jul 24, 2018·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·David A Brenner
Nov 18, 2018·Liver International : Official Journal of the International Association for the Study of the Liver·Christian A HudertSusanna Wiegand
Dec 15, 2018·Current Opinion in Lipidology·Maria Camila Perez-MatosZhenghui Gordon Jiang
Feb 28, 2018·Journal of Human Genetics·Marcin KrawczykUNKNOWN NAFLD Clinical Study Group (NAFLD CSG)
Feb 26, 2019·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Yang WangHelen H Hobbs
Apr 27, 2019·Nature Reviews. Gastroenterology & Hepatology·Arun J Sanyal
Oct 23, 2019·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Hans Dieter NischalkeUlrich Spengler
Aug 6, 2019·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Linshan Shang, Douglas G Mashek
Mar 14, 2020·The Biochemical Journal·Alexander Yang, Emilio P Mottillo
Apr 29, 2020·Liver International : Official Journal of the International Association for the Study of the Liver·Yuya SekoYoshito Itoh
Jul 7, 2019·Nature Reviews. Gastroenterology & Hepatology·Valerio NobiliNaim Alkhouri
Jul 7, 2020·Middle East Journal of Digestive Diseases·Sara SakiReza Malekzadeh
Mar 15, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Silvia SookoianNicholas O Davidson
Aug 26, 2020·PloS One·Marina SerperUNKNOWN VA Million Veteran Program
Aug 20, 2020·American Journal of Physiology. Gastrointestinal and Liver Physiology·Simone CarottiUmberto Vespasiani-Gentilucci
Apr 3, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Matteo TardelliMichael Trauner
Oct 3, 2018·The Journal of Clinical Investigation·Helen H Hobbs
May 24, 2020·Cancers·Yetirajam Rajesh, Devanand Sarkar
May 21, 2020·Diabetes & Metabolism Journal·Byung Wan LeeUNKNOWN Korean Diabetes Association (KDA) Fatty Liver Research Group
Jun 7, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Luca Valenti, Paola Dongiovanni
Aug 18, 2018·Nature Reviews. Disease Primers·Helmut K SeitzHidekazu Tsukamoto
Mar 23, 2019·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Scott McHenry, Nicholas O Davidson
Mar 6, 2019·JGH Open : an Open Access Journal of Gastroenterology and Hepatology·Kuniko YamamotoKatsutoshi Tokushige
Apr 26, 2019·Proceedings of the National Academy of Sciences of the United States of America·Soumik BasuRayHelen H Hobbs
Apr 29, 2020·International Journal of Molecular Sciences·Marica MeroniPaola Dongiovanni
May 10, 2020·Gastroenterology Research and Practice·Carla De BenedittisMario Pirisi
May 10, 2018·Nature Reviews. Gastroenterology & Hepatology·Susanne SchusterAriel E Feldstein
Aug 6, 2019·Current Hepatology Reports·Mazen Noureddin, Arun J Sanyal
Jan 24, 2020·Frontiers in Pharmacology·Karthik Chandrasekharan, William Alazawi
Aug 4, 2019·International Journal of Environmental Research and Public Health·Alice Emma TalientoLuca Valenti
Jul 4, 2020·Endocrinology and Metabolism·Dae Ho Lee
Jul 4, 2018·Nature Medicine·Scott L FriedmanArun J Sanyal
Dec 6, 2018·International Journal of Molecular Sciences·Marica MeroniPaola Dongiovanni
May 10, 2020·Alimentary Pharmacology & Therapeutics·Björn CarlssonRohit Loomba
Apr 28, 2019·Nature Reviews. Gastroenterology & Hepatology·Quentin M AnsteeMathias Heikenwalder

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Methods Mentioned

BETA
electrophoresis
immunoprecipitation
transgenic

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