Adipocyte JAK2 mediates spontaneous metabolic liver disease and hepatocellular carcinoma

JCI Insight
Kevin C CorbitEthan J Weiss

Abstract

Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are liver manifestations of the metabolic syndrome and can progress to hepatocellular carcinoma (HCC). Loss of Growth Hormone (GH) signaling is reported to predispose to NAFLD and NASH through direct actions on the liver. Here, we report that aged mice lacking hepatocyte Jak2 (JAK2L), an obligate transducer of Growth Hormone (GH) signaling, spontaneously develop the full spectrum of phenotypes found in patients with metabolic liver disease, beginning with insulin resistance and lipodystrophy and manifesting as NAFLD, NASH and even HCC, independent of dietary intervention. Remarkably, insulin resistance, metabolic liver disease, and carcinogenesis are prevented in JAK2L mice via concomitant deletion of adipocyte Jak2 (JAK2LA). Further, we demonstrate that GH increases hepatic lipid burden but does so indirectly via signaling through adipocyte JAK2. Collectively, these data establish adipocytes as the mediator of GH-induced metabolic liver disease and carcinogenesis. In addition, we report a new spontaneous model of NAFLD, NASH, and HCC that recapitulates the natural sequelae of human insulin resistance-associated disease progression. The work presented here sug...Continue Reading

References

May 1, 1973·Diabetes·M TzagournisJ Herrold
Nov 24, 1999·The American Journal of Medicine·G MarchesiniN Melchionda
Jul 27, 2001·Diabetes·G MarchesiniN Melchionda
Feb 12, 2002·The Journal of Clinical Endocrinology and Metabolism·Jean-Marc SchwarzMorris Schambelan
Mar 27, 2002·The Journal of Biological Chemistry·Masao SaitohGeorge Thomas
Sep 9, 2004·Genesis : the Journal of Genetics and Development·Andrea KremplerKay-Uwe Wagner
May 3, 2005·The Journal of Clinical Investigation·Kerry L DonnellyElizabeth J Parks
Feb 6, 2008·Cell Metabolism·Michael S Brown, Joseph L Goldstein
Apr 17, 2008·The Journal of Clinical Endocrinology and Metabolism·Alla A SakharovaAriel Barkan
Aug 5, 2008·JAMA : the Journal of the American Medical Association·Janet LoSteven Grinspoon
Aug 7, 2008·Journal of Lipid Research·Michaela ArtwohlSabina M Baumgartner-Parzer
Jul 30, 2010·The Journal of Clinical Endocrinology and Metabolism·Pouneh K FazeliAnne Klibanski
Jan 22, 2011·The British Journal of Nutrition·Kyriakoula MarinouBarbara A Fielding
Mar 3, 2011·The Journal of Clinical Investigation·Brandon C SosEthan J Weiss
Mar 16, 2012·Seminars in Liver Disease·David E Kleiner, Elizabeth M Brunt
Apr 17, 2012·Cell·Mathieu Laplante, David M Sabatini
Jun 20, 2012·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Ji Hoon YuLothar Hennighausen
Jun 21, 2013·Molecular Endocrinology·Sarah M NordstromEthan J Weiss
Dec 24, 2013·The Journal of Endocrinology·Pouneh K Fazeli, Anne Klibanski
Jan 8, 2015·Proceedings of the National Academy of Sciences of the United States of America·Daniel F VatnerGerald I Shulman
Mar 13, 2015·The Journal of Clinical Endocrinology and Metabolism·Rosellina M MancinaJan Borén
May 28, 2015·Diabetes·Jose Cordoba-ChaconRhonda D Kineman
Jun 25, 2015·Asian Pacific Journal of Cancer Prevention : APJCP·Rania Elsayed Wasfy, Aliaa Atef Shams Eldeen
Aug 12, 2015·Growth Hormone & IGF Research : Official Journal of the Growth Hormone Research Society and the International IGF Research Society·Jaime Guevara-AguirreEnrique Teran
Aug 27, 2015·Growth Hormone & IGF Research : Official Journal of the Growth Hormone Research Society and the International IGF Research Society·Zvi Laron, Rivka Kauli
Mar 8, 2016·Trends in Endocrinology and Metabolism : TEM·Nicoleta Cristina Olarescu, Jens Bollerslev
Jun 4, 2016·Molecular Metabolism·Peter L LeeDavid A Guertin
Oct 8, 2016·Scientific Reports·Madeleine ThemannsRichard Moriggl
Nov 23, 2016·Handbook of Experimental Pharmacology·Arthur T Suckow, Celia P Briscoe
Jan 20, 2017·The Journal of Biological Chemistry·Sally Yu ShiMinna Woo
Feb 15, 2017·JCI Insight·Kevin C CorbitEthan J Weiss
Apr 22, 2017·The Journal of Endocrinology·Caroline E Geisler, Benjamin J Renquist
Apr 27, 2017·Frontiers in Cell and Developmental Biology·Roman CamardaAndrei Goga
Jul 6, 2017·International Journal of Molecular Sciences·Yutaka Takahashi
Jul 9, 2017·Drug Discovery Today·Henrik H HansenKeld Fosgerau

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