title: Toll-like receptor 4-induced endoplasmic reticulum stress contributes to impairment of vasodilator action of insulin.
abstract: Impairment of vasodilator action of insulin is associated with endothelial dysfunction and insulin resistance. Activation of Toll-like receptor 4 (TLR4) induces proinflammatory response and endoplasmic reticulum (ER) stress. Saturated fatty acids (SFA) activate TLR4, which induces ER stress and endothelial dysfunction. Therefore, we determined whether TLR4-mediated ER stress is an obligatory step mediating SFA-induced endothelial dysfunction. Palmitate stimulated proinflammatory responses and ER stress, and this was suppressed by knockdown of TLR4 in primary human aortic endothelial cells (HAEC). Next, we examined the role of TLR4 in vasodilatory responses in intact vessels isolated from wild-type (WT, C57BL/6) and TLR4-KO mice after feeding high-fat (HFD) or normal chow diet (NCD) for 12 wk. Arterioles isolated from HFD WT mice exhibited impaired insulin-stimulated vasodilation compared with arterioles isolated from NCD WT mice. Deficiency of TLR4 was protective from HFD-induced impairment of insulin-stimulated vasodilation. There were no differences in acetylcholine (Ach)- or sodium nitroprusside (SNP)-stimulated vasodilation between the two groups. Furthermore, we examined whether ER stress is involved in SFA-induced impairment of vasodilator actions of insulin. Infusion of palmitate showed the impairment of vasodilatory response to insulin, which was ameliorated by coinfusion with tauroursodeoxycholic acid (TUDCA), an ER stress suppressor. Taken together, the results suggest that TLR4-induced ER stress may be an obligatory step mediating the SFA-mediated endothelial dysfunction.
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama; University of Alabama at Birmingham Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, Alabama; and jakim@uab.edu.
authors.forename: Jeong-A
authors.initials: JA
authors.lastname: Kim
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Jang
authors.affiliation: Western Human Nutrition Research Center, United States Department of Agriculture, and Department of Nutrition, University of California, Davis, Davis, California.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Hwang
mesh_terms: D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010168:Palmitates / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D007328:Insulin; D010168:Palmitates; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014665:Vasodilator Agents
keywords: ER stress; TLR4; endothelial dysfunction; insulin; nitric oxide