Disruption of HepatocyteJak2leads to Spontaneous NASH in Aged Mice and Uncouples Metabolic Liver Disease from Insulin Resistance
Authors: Wilson Camella G. , Mattis Aras N. , Tran Jennifer L. , Corbit Kevin , Weiss Ethan J. 
Published: October 2016

ABSTRACTGrowth Hormone (GH) is a master regulator of metabolic homeostasis and longevity. Whole body GH insensitivity (GHI) augments insulin sensitivity, age-related disease resistance, adiposity, and occurrence of NAFLD. Conversely, acromegalic patients are prone to diabetes and increased mortality due to constitutive high levels of circulating GH. However, which tissues control the various metabolic aspects of GH physiology are unknown. Therefore, we determined the role of GH in age-related metabolic dysfunction by inducing hepatocyte- (JAK2L) or adipocyte-specific (JAK2A) GHI individually or combinatorially (JAK2LA) via deletion ofJak2, an obligate transducer of GH signaling. Aged JAK2L mice were insulin resistant but lean and had significant NASH, hepatic inflammation, and fibrosis. In contrast, JAK2A animals had increased adiposity and were completely resistant to age-associated hepatic steatosis, NASH, and insulin resistance. Interestingly, while JAK2LA mice retained enhanced whole-body insulin sensitivity, they still developed NASH to an almost identical degree as JAK2L mice but with a substantial reduction in the degree of microvesicular steatosis. Collectively, loss of adipocyteJak2conferred whole body insulin sensitivity even in the face of obesity and NASH. Deletion of hepatocyteJak2promoted NASH in aged mice without any dietary or drugs perturbations. The effect appears to be liver autonomous and cannot be overcome by the insulin sensitizing effect of adipocyteJak2deletion. Here, we describe the first model of spontaneous NASH that is coupled to augmented insulin sensitivity. Further, there was an inverse correlation between insulin sensitivity and the degree of microvesicular steatosis. Therefore, GH signaling independently mediates insulin/glucose and lipid homeostasis and directly regulates the development of NASH in aged mice.Financial Support:This study was supported by National Institutes of Health (NIH) Grants 1R01DK091276 (to E.J.W.). We also acknowledge the support of the University of California, San Francisco (UCSF) Cardiovascular Research Institute, the UCSF Diabetes Center (P30 DK063720), the UCSF Liver Center (P30 DK026743, and the James Peter Read Foundation.AbbreviationsNASHnon-alcoholic steato-hepatitisNAFLDnon-alcoholic fatty liver diseaseGHgrowth hormoneJAK2Janus kinase 2CONCON miceJAK2Lhepatocyte-specific deletion of JAK2JAK2Aadipocyte-specific deletion of JAK2JAK2LAhepatocyte and adipocyte JAK2 knockoutTGtriglycerideASTaspartate aminotransferaseALTalanine transaminaseStat5signal transducer and activator of transcription 5qRT-PCRquantitative reverse-transcription polymerase chain reactionMcp1monocyte chemoattractant protein-1Cd11bcluster of differentiation molecule 11bF4/80EGF-like module-containing mucin-like hormone receptor-like 1FcgR1high affinity immunoglobulin gamma Fc receptor IL-Fabpliver fatty acid binding proteinPPARγperoxisome proliferator-activated receptor gammaFATPfatty acid transport proteinCD36/FATFatty Acid TranslocaseITTinsulin tolerance test.Lpllipoprotein lipaseIL-interleukin-FcgR1Fc receptor IgGTnfαtumor necrosis factor alphaTgfβ1transforming growth factor beta 1αSMA, alpha 2smooth muscle actinIGF-1insulin-like growth factor 1.