title: KLF15 is a molecular link between endoplasmic reticulum stress and insulin resistance.
abstract: Obesity places major demands on the protein folding capacity of the endoplasmic reticulum (ER), resulting in ER stress, a condition that promotes hepatic insulin resistance and steatosis. Here we identify the transcription factor, Kruppel-like factor 15 (KLF15), as an essential mediator of ER stress-induced insulin resistance in the liver. Mice with a targeted deletion of KLF15 exhibit increased hepatic ER stress, inflammation, and JNK activation compared to WT mice; however, KLF15 (-/-) mice are protected against hepatic insulin resistance and fatty liver under high-fat feeding conditions and in response to pharmacological induction of ER stress. The mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cellular energy homeostasis, has been shown to cooperate with ER stress signaling pathways to promote hepatic insulin resistance and lipid accumulation. We find that the uncoupling of ER stress and insulin resistance in KLF15 (-/-) liver is associated with the maintenance of a low energy state characterized by decreased mTORC1 activity, increased AMPK phosphorylation and PGC-1α expression and activation of autophagy, an intracellular degradation process that enhances hepatic insulin sensitivity. Furthermore, in primary hepatocytes, KLF15 deficiency markedly inhibits activation of mTORC1 by amino acids and insulin, suggesting a mechanism by which KLF15 controls mTORC1-mediated insulin resistance. This study establishes KLF15 as an important molecular link between ER stress and insulin action.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Jung
authors.forename: Umadevi
authors.initials: U
authors.lastname: Chalasani
authors.forename: Ning
authors.initials: N
authors.lastname: Pan
authors.forename: Randall H
authors.initials: RH
authors.lastname: Friedline
authors.forename: Domenick A
authors.initials: DA
authors.lastname: Prosdocimo
authors.forename: Minwoo
authors.initials: M
authors.lastname: Nam
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Azuma
authors.forename: Rajanikanth
authors.initials: R
authors.lastname: Maganti
authors.forename: Kristine
authors.initials: K
authors.lastname: Yu
authors.forename: Ashish
authors.initials: A
authors.lastname: Velagapudi
authors.forename: Bryan
authors.initials: B
authors.lastname: O'Sullivan-Murphy
authors.forename: Juliano L
authors.initials: JL
authors.lastname: Sartoretto
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
authors.forename: Marcus P
authors.initials: MP
authors.lastname: Cooper
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Urano
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Susan
authors.initials: S
authors.lastname: Gray
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007333:Insulin Resistance; D051741:Kruppel-Like Transcription Factors; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D004041:Dietary Fats; C467418:Klf15 protein, mouse; D051741:Kruppel-Like Transcription Factors; D046912:Multiprotein Complexes; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases