Hepatocyte-specific deletion of Janus kinase 2 (JAK2) protects against diet-induced steatohepatitis and glucose intolerance

Sally Yu Shi, Rubén García Martin, Robin E. Duncan, Diana Choi, Shun Yan Lu, Stephanie A. Schroer, Erica P. Cai, Cynthia T. Luk, Kathryn E. Hopperton, Anthony F. Domenichiello, Christine Tang, Mark Naples, Mark J. Dekker, Adria Giacca, Khosrow Adeli, Kay Uwe Wagner, Richard P. Bazinet, Minna Woo

Research output: Contribution to journalArticle

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is becoming the leading cause of chronic liver disease and is now considered to be the hepatic manifestation of the metabolic syndrome. However, the role of steatosis per se and the precise factors required in the progression to steatohepatitis or insulin resistance remain elusive. The JAK-STAT pathway is critical in mediating signaling of a wide variety of cytokines and growth factors. Mice with hepatocyte-specific deletion of Janus kinase 2 (L-JAK2 KO mice) develop spontaneous steatosis as early as 2 weeks of age. In this study, we investigated the metabolic consequences of jak2 deletion in response to diet-induced metabolic stress. To our surprise, despite the profound hepatosteatosis, deletion of hepatic jak2 did not sensitize the liver to accelerated inflammatory injury on a prolonged high fat diet (HFD). This was accompanied by complete protection against HFD-induced wholebody insulin resistance and glucose intolerance. Improved glucose-stimulated insulin secretion and an increase in β-cell mass were also present in these mice. Moreover, L-JAK2 KO mice had progressively reduced adiposity in association with blunted hepatic growth hormone signaling. These mice also exhibited increased resting energy expenditure on both chow and high fat diet. In conclusion, our findings indicate a key role of hepatic JAK2 in metabolism such that its absence completely arrests steatohepatitis development and confers protection against diet-induced systemic insulin resistance and glucose intolerance.

Original languageEnglish (US)
Pages (from-to)10277-10288
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number13
DOIs
StatePublished - Mar 23 2012

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Janus Kinase 2
Glucose Intolerance
Fatty Liver
Nutrition
Hepatocytes
Diet
High Fat Diet
Glucose
Liver
Insulin
Insulin Resistance
Fats
Physiological Stress
Critical Pathways
Adiposity
Metabolism
Energy Metabolism
Growth Hormone
Liver Diseases
Intercellular Signaling Peptides and Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Shi, S. Y., García Martin, R., Duncan, R. E., Choi, D., Lu, S. Y., Schroer, S. A., ... Woo, M. (2012). Hepatocyte-specific deletion of Janus kinase 2 (JAK2) protects against diet-induced steatohepatitis and glucose intolerance. Journal of Biological Chemistry, 287(13), 10277-10288. https://doi.org/10.1074/jbc.M111.317453

Hepatocyte-specific deletion of Janus kinase 2 (JAK2) protects against diet-induced steatohepatitis and glucose intolerance. / Shi, Sally Yu; García Martin, Rubén; Duncan, Robin E.; Choi, Diana; Lu, Shun Yan; Schroer, Stephanie A.; Cai, Erica P.; Luk, Cynthia T.; Hopperton, Kathryn E.; Domenichiello, Anthony F.; Tang, Christine; Naples, Mark; Dekker, Mark J.; Giacca, Adria; Adeli, Khosrow; Wagner, Kay Uwe; Bazinet, Richard P.; Woo, Minna.

In: Journal of Biological Chemistry, Vol. 287, No. 13, 23.03.2012, p. 10277-10288.

Research output: Contribution to journalArticle

Shi, SY, García Martin, R, Duncan, RE, Choi, D, Lu, SY, Schroer, SA, Cai, EP, Luk, CT, Hopperton, KE, Domenichiello, AF, Tang, C, Naples, M, Dekker, MJ, Giacca, A, Adeli, K, Wagner, KU, Bazinet, RP & Woo, M 2012, 'Hepatocyte-specific deletion of Janus kinase 2 (JAK2) protects against diet-induced steatohepatitis and glucose intolerance', Journal of Biological Chemistry, vol. 287, no. 13, pp. 10277-10288. https://doi.org/10.1074/jbc.M111.317453
Shi, Sally Yu ; García Martin, Rubén ; Duncan, Robin E. ; Choi, Diana ; Lu, Shun Yan ; Schroer, Stephanie A. ; Cai, Erica P. ; Luk, Cynthia T. ; Hopperton, Kathryn E. ; Domenichiello, Anthony F. ; Tang, Christine ; Naples, Mark ; Dekker, Mark J. ; Giacca, Adria ; Adeli, Khosrow ; Wagner, Kay Uwe ; Bazinet, Richard P. ; Woo, Minna. / Hepatocyte-specific deletion of Janus kinase 2 (JAK2) protects against diet-induced steatohepatitis and glucose intolerance. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 13. pp. 10277-10288.
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AU - Shi, Sally Yu

AU - García Martin, Rubén

AU - Duncan, Robin E.

AU - Choi, Diana

AU - Lu, Shun Yan

AU - Schroer, Stephanie A.

AU - Cai, Erica P.

AU - Luk, Cynthia T.

AU - Hopperton, Kathryn E.

AU - Domenichiello, Anthony F.

AU - Tang, Christine

AU - Naples, Mark

AU - Dekker, Mark J.

AU - Giacca, Adria

AU - Adeli, Khosrow

AU - Wagner, Kay Uwe

AU - Bazinet, Richard P.

AU - Woo, Minna

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N2 - Non-alcoholic fatty liver disease (NAFLD) is becoming the leading cause of chronic liver disease and is now considered to be the hepatic manifestation of the metabolic syndrome. However, the role of steatosis per se and the precise factors required in the progression to steatohepatitis or insulin resistance remain elusive. The JAK-STAT pathway is critical in mediating signaling of a wide variety of cytokines and growth factors. Mice with hepatocyte-specific deletion of Janus kinase 2 (L-JAK2 KO mice) develop spontaneous steatosis as early as 2 weeks of age. In this study, we investigated the metabolic consequences of jak2 deletion in response to diet-induced metabolic stress. To our surprise, despite the profound hepatosteatosis, deletion of hepatic jak2 did not sensitize the liver to accelerated inflammatory injury on a prolonged high fat diet (HFD). This was accompanied by complete protection against HFD-induced wholebody insulin resistance and glucose intolerance. Improved glucose-stimulated insulin secretion and an increase in β-cell mass were also present in these mice. Moreover, L-JAK2 KO mice had progressively reduced adiposity in association with blunted hepatic growth hormone signaling. These mice also exhibited increased resting energy expenditure on both chow and high fat diet. In conclusion, our findings indicate a key role of hepatic JAK2 in metabolism such that its absence completely arrests steatohepatitis development and confers protection against diet-induced systemic insulin resistance and glucose intolerance.

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