RGD Reference Report - Adipocyte JAK2 mediates spontaneous metabolic liver disease and hepatocellular carcinoma. - Rat Genome Database

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Adipocyte JAK2 mediates spontaneous metabolic liver disease and hepatocellular carcinoma.

Authors: Corbit, Kevin C  Wilson, Camella G  Lowe, Dylan  Tran, Jennifer L  Vera, Nicholas B  Clasquin, Michelle  Mattis, Aras N  Weiss, Ethan J 
Citation: Corbit KC, etal., JCI Insight. 2019 Aug 8;5. pii: 131310. doi: 10.1172/jci.insight.131310.
RGD ID: 127285655
Pubmed: PMID:31393852   (View Abstract at PubMed)
PMCID: PMC6777921   (View Article at PubMed Central)
DOI: DOI:10.1172/jci.insight.131310   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
JAK2Humanhepatocellular carcinoma  ISOJak2 (Mus musculus)associated with Diseases of the Aged and non-alcoholic fatty liver diseaseRGD 
Jak2Rathepatocellular carcinoma  ISOJak2 (Mus musculus)associated with Diseases of the Aged and non-alcoholic fatty liver diseaseRGD 
Jak2Mousehepatocellular carcinoma  IMP associated with Diseases of the Aged and non-alcoholic fatty liver diseaseRGD 

Objects Annotated

Genes (Rattus norvegicus)
Jak2  (Janus kinase 2)

Genes (Mus musculus)
Jak2  (Janus kinase 2)

Genes (Homo sapiens)
JAK2  (Janus kinase 2)


Additional Information