title: Hepatocyte-specific deletion of Janus kinase 2 (JAK2) protects against diet-induced steatohepatitis and glucose intolerance.
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 whole-body 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.
authors.affiliation: Toronto General Research Institute, Toronto, Ontario M5G 2C4, Canada,; Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Sally Yu
authors.initials: SY
authors.lastname: Shi
authors.affiliation: Toronto General Research Institute, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Rubén García
authors.initials: RG
authors.lastname: Martin
authors.affiliation: Department of Nutritional Sciences, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: Robin E
authors.initials: RE
authors.lastname: Duncan
authors.affiliation: Toronto General Research Institute, Toronto, Ontario M5G 2C4, Canada,; Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Diana
authors.initials: D
authors.lastname: Choi
authors.affiliation: Toronto General Research Institute, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Shun-Yan
authors.initials: SY
authors.lastname: Lu
authors.affiliation: Toronto General Research Institute, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Schroer
authors.affiliation: Toronto General Research Institute, Toronto, Ontario M5G 2C4, Canada,; Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Erica P
authors.initials: EP
authors.lastname: Cai
authors.affiliation: Toronto General Research Institute, Toronto, Ontario M5G 2C4, Canada,; Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: Luk
authors.affiliation: Department of Nutritional Sciences, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Hopperton
authors.affiliation: Department of Nutritional Sciences, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Domenichiello
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Tang
authors.affiliation: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Naples
authors.affiliation: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dekker
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
authors.affiliation: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Khosrow
authors.initials: K
authors.lastname: Adeli
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases and the Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, and.
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Wagner
authors.affiliation: Department of Nutritional Sciences, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Bazinet
authors.affiliation: Toronto General Research Institute, Toronto, Ontario M5G 2C4, Canada,; Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 2M9, Canada.,; Department of Medicine and Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario M3B 1W5, Canada. Electronic address: mwoo@uhnres.utoronto.ca.
authors.forename: Minna
authors.initials: M
authors.lastname: Woo
mesh_terms: D050154:Adiposity / Q000187:drug effects / Q000235:genetics; D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D005234:Fatty Liver / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017353:Gene Deletion; D018149:Glucose Intolerance / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D007333:Insulin Resistance / Q000235:genetics; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D004041:Dietary Fats; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2