NK cells induce hepatic ER stress to promote insulin resistance in obesity through osteopontin production

Abstract

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.

Hepatic deficiency of selenoprotein S exacerbates hepatic steatosis and insulin resistance

“…Chronic ER stress affects major pathways of lipid metabolism by the alteration of fatty acid uptake, DNL, very low density lipoprotein secretion and fatty acid oxidation, which contributes to hepatic steatosis [ 17 , 18 , 38 ]. In the liver, ER stress causes hyperactivation of JNK, leading to decreased tyrosine phosphorylation of IRS-1 and subsequent IR, which is also a risk factor for the progression of NAFLD [ 20 , 39 ]. Consistent with previous studies identifying that SelS silencing increased ER stress markers expression [ 24 , 27 ], while SelS overexpression protected several cell lines from ER stress injury [ 26 – 28 ], we further confirmed ER stress was increased in SelS H-KO mice and SelS-KD hepatocytes, but suppressed in SelS-OE hepatocytes.…”

“…The disruption of endoplasmic reticulum (ER) homeostasis known as ER stress is essential for the initiation and progression of NAFLD and IR [ 16 – 20 ]. In response to unfolded or misfolded ER proteins, an adaptive unfolded protein response (UPR) is triggered via glucose-regulated protein 78 (GRP78) dissociating from three ER stress sensors, including inositol-requiring enzyme 1α (IRE1α), protein kinase RNA-like ER kinase (PERK) and activating transcription factor 6 (ATF6), thereby activating all signaling cascades to restore ER homeostasis.…”

Integrative Multiomic Analyses of Diabetic Neuropathic Pain in Dorsal Root Ganglia: Proteomics, Phospho-proteomics, and Metabolomics

“…SPP1 is marker for proprioceptors in the DRG and is linked to nerve injury and mechanical pain [54,55]. SPP1 has also been reported to be linked to ER stress [56,57], in ammation in diabetes and neurodegeneration [58,59], and adhesion in the extracellular matrix [60] (Supplementary Figure S6b). However, these reports looked at total SPP1, less is known about the function of phosphorylated SPP1.…”

Integrative Multiomic Analyses of Diabetic Neuropathic Pain in Dorsal Root Ganglia: Proteomics, Phospho-proteomics, and Metabolomics

“…SPP1 is marker for proprioceptors in the DRG and is linked to nerve injury and mechanical pain [54, 55]. SPP1 has also been reported to be linked to ER stress [56, 57], inflammation in diabetes and neurodegeneration [58, 59], and adhesion in the extracellular matrix [60] (Supplementary Figure S6b). However, these reports looked at total SPP1, less is known about the function of phosphorylated SPP1.…”