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JCI Insight. 2017 Jul 20;2(14). pii: 93735. doi: 10.1172/jci.insight.93735. eCollection 2017 Jul 20.

Hepatic JAK2 protects against atherosclerosis through circulating IGF-1.

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Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.
Institute of Medical Science.
Department of Immunology.
Department of Laboratory Medicine and Pathobiology.
Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.
Eppley Institute for Research in Cancer and Allied Diseases and the Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.


Atherosclerosis is considered both a metabolic and inflammatory disease; however, the specific tissue and signaling molecules that instigate and propagate this disease remain unclear. The liver is a central site of inflammation and lipid metabolism that is critical for atherosclerosis, and JAK2 is a key mediator of inflammation and, more recently, of hepatic lipid metabolism. However, precise effects of hepatic Jak2 on atherosclerosis remain unknown. We show here that hepatic Jak2 deficiency in atherosclerosis-prone mouse models exhibited accelerated atherosclerosis with increased plaque macrophages and decreased plaque smooth muscle cell content. JAK2's essential role in growth hormone signalling in liver that resulted in reduced IGF-1 with hepatic Jak2 deficiency played a causal role in exacerbating atherosclerosis. As such, restoring IGF-1 either pharmacologically or genetically attenuated atherosclerotic burden. Together, our data show hepatic Jak2 to play a protective role in atherogenesis through actions mediated by circulating IGF-1 and, to our knowledge, provide a novel liver-centric mechanism in atheroprotection.


Metabolism; Vascular Biology

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