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Publication
Adipocyte JAK2 mediates spontaneous metabolic liver disease and hepatocellular
carcinoma.
Authors Corbit KC, Wilson CG, Lowe D, Tran JL, Vera NB, Clasquin M, Mattis AN, Weiss EJ
Submitted By Submitted Externally on 11/24/2019
Status Published
Journal JCI insight
Year 2019
Date Published 8/1/2019
Volume : Pages 5 : Not Specified
PubMed Reference 31393852
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 suggests a attention be paid towards inhibition of adipocyte GH
signaling as a therapeutic target of metabolic liver disease.




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