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NK cells induce hepatic ER stress to promote insulin resistance in obesity through osteopontin production
Author(s) -
Wu Junhua,
Wu Danyang,
Zhang Longyao,
Lin Chuxuan,
Liao Jiahao,
Xie Ruyin,
Li Zhulin,
Wu Siyang,
Liu Aimin,
Hu Weining,
Xi Yang,
Bu Shizhong,
Wang Fuyan
Publication year - 2020
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.3ma1119-173r
Subject(s) - osteopontin , insulin resistance , endocrinology , medicine , unfolded protein response , biology , adipose tissue , steatosis , proinflammatory cytokine , hepatic stellate cell , fatty liver , endoplasmic reticulum , insulin , inflammation , microbiology and biotechnology , disease
High‐fat diet (HFD) induced hepatic endoplasmic reticulum (ER) stress drives insulin resistance (IR) and steatosis. NK cells in adipose tissue play an important role in the pathogenesis of IR in obesity. Whether NK cells in the liver can induce hepatic ER stress and thus promote IR in obesity is still unknown. We demonstrate that HFD‐fed mice display elevated production of proinflammatory cytokine osteopontin (OPN) in hepatic NK cells, especially in CD49a + DX5 – tissue‐resident NK (trNK) cells. Obesity‐induced ER stress, IR, and steatosis in the liver are ameliorated by ablating NK cells with neutralizing antibody in HFD‐fed mice. OPN treatment enhances the expression of ER stress markers, including p‐PERK, p‐eIF2, ATF4, and CHOP in both murine liver tissues and HL‐7702, a human liver cell line. Pretreatment of HL‐7702 cells with OPN promotes hyperactivation of JNK and subsequent decrease of tyrosine phosphorylation of insulin receptor substrate‐1 (IRS‐1), resulting in impaired insulin signaling, which can be reversed by inhibiting ER stress. Collectively, we demonstrate that hepatic NK cells induce obesity‐induced hepatic ER stress, and IR through OPN production.