title: Proteasome dysfunction mediates obesity-induced endoplasmic reticulum stress and insulin resistance in the liver.
abstract: Chronic endoplasmic reticulum (ER) stress is a major contributor to obesity-induced insulin resistance in the liver. However, the molecular link between obesity and ER stress remains to be identified. Proteasomes are important multicatalytic enzyme complexes that degrade misfolded and oxidized proteins. Here, we report that both mouse models of obesity and diabetes and proteasome activator (PA)28-null mice showed 30-40% reduction in proteasome activity and accumulation of polyubiquitinated proteins in the liver. PA28-null mice also showed hepatic steatosis, decreased hepatic insulin signaling, and increased hepatic glucose production. The link between proteasome dysfunction and hepatic insulin resistance involves ER stress leading to hyperactivation of c-Jun NH₂-terminal kinase in the liver. Administration of a chemical chaperone, phenylbutyric acid (PBA), partially rescued the phenotypes of PA28-null mice. To confirm part of the results obtained from in vivo experiments, we pretreated rat hepatoma-derived H4IIEC3 cells with bortezomib, a selective inhibitor of the 26S proteasome. Bortezomib causes ER stress and insulin resistance in vitro--responses that are partly blocked by PBA. Taken together, our data suggest that proteasome dysfunction mediates obesity-induced ER stress, leading to insulin resistance in the liver.
authors.affiliation: Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Sciences, Ishikawa, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Otoda
authors.forename: Toshinari
authors.initials: T
authors.lastname: Takamura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Misu
authors.forename: Tsuguhito
authors.initials: T
authors.lastname: Ota
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murata
authors.forename: Hiroto
authors.initials: H
authors.lastname: Hayashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takayama
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kikuchi
authors.forename: Takehiro
authors.initials: T
authors.lastname: Kanamori
authors.forename: Kosuke R
authors.initials: KR
authors.lastname: Shima
authors.forename: Fei
authors.initials: F
authors.lastname: Lan
authors.forename: Takashi
authors.initials: T
authors.lastname: Takeda
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Kurita
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Ishikura
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kita
authors.forename: Kaito
authors.initials: K
authors.lastname: Iwayama
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Kato
authors.forename: Masafumi
authors.initials: M
authors.lastname: Uno
authors.forename: Yumie
authors.initials: Y
authors.lastname: Takeshita
authors.forename: Miyuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Kunpei
authors.initials: K
authors.lastname: Tokuyama
authors.forename: Shoichi
authors.initials: S
authors.lastname: Iseki
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D019440:Anti-Obesity Agents; D007004:Hypoglycemic Agents; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex