title: Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver.
abstract: Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of human type 2 diabetes (T2DM). Although SIRT1 has a therapeutic effect on metabolic deterioration in T2DM, the precise mechanisms by which SIRT1 improves insulin resistance remain unclear. Here, we demonstrate that adenovirus-mediated overexpression of SIRT1 in the liver of diet-induced insulin-resistant low-density lipoprotein receptor-deficient mice and of genetically obese ob/ob mice attenuates hepatic steatosis and ameliorates systemic insulin resistance. These beneficial effects were associated with decreased mammalian target of rapamycin complex 1 (mTORC1) activity, inhibited the unfolded protein response (UPR), and enhanced insulin receptor signaling in the liver, leading to decreased hepatic gluconeogenesis and improved glucose tolerance. The tunicamycin-induced splicing of X-box binding protein-1 and expression of GRP78 and CHOP were reduced by resveratrol in cultured cells in a SIRT1-dependent manner. Conversely, SIRT1-deficient mouse embryonic fibroblasts challenged with tunicamycin exhibited markedly increased mTORC1 activity and impaired ER homeostasi and insulin signaling. These effects were abolished by mTORC1 inhibition by rapamycin in human HepG2 cells. These studies indicate that SIRT1 serves as a negative regulator of UPR signaling in T2DM and that SIRT1 attenuates hepatic steatosis, ameliorates insulin resistance, and restores glucose homeostasis, largely through the inhibition of mTORC1 and ER stress.
authors.affiliation: Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, 02118, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.forename: Shanqin
authors.initials: S
authors.lastname: Xu
authors.forename: Amber
authors.initials: A
authors.lastname: Giles
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nakamura
authors.forename: Jong Woo
authors.initials: JW
authors.lastname: Lee
authors.forename: Xiuyun
authors.initials: X
authors.lastname: Hou
authors.forename: Gizem
authors.initials: G
authors.lastname: Donmez
authors.forename: Ji
authors.initials: J
authors.lastname: Li
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Luo
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
authors.forename: Mengwei
authors.initials: M
authors.lastname: Zang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005951:Glucose Tolerance Test; D056945:Hep G2 Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D011973:Receptors, LDL; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1