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

Growth 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.

Abbreviations

NASH

non-alcoholic steato-hepatitis

NAFLD

non-alcoholic fatty liver disease

GH

growth hormone

JAK2

Janus kinase 2

CON

CON mice

JAK2L

hepatocyte-specific deletion of JAK2

JAK2A

adipocyte-specific deletion of JAK2

JAK2LA

hepatocyte and adipocyte JAK2 knockout

TG

triglyceride

AST

aspartate aminotransferase

ALT

alanine transaminase

Stat5

signal transducer and activator of transcription 5

qRT-PCR

quantitative reverse-transcription polymerase chain reaction

Mcp1

monocyte chemoattractant protein-1

Cd11b

cluster of differentiation molecule 11b

F4/80

EGF-like module-containing mucin-like hormone receptor-like 1

FcgR1

high affinity immunoglobulin gamma Fc receptor I

L-Fabp

liver fatty acid binding protein

PPARγ

peroxisome proliferator-activated receptor gamma

FATP

fatty acid transport protein

CD36/FAT

Fatty Acid Translocase

ITT

insulin tolerance test.

Lpl

lipoprotein lipase

IL-

interleukin-

FcgR1

Fc receptor IgG

Tnfα

tumor necrosis factor alpha

Tgfβ1

transforming growth factor beta 1

αSMA, alpha 2

smooth muscle actin

IGF-1

insulin-like growth factor 1.