KLF15 Is a Molecular Link between Endoplasmic Reticulum Stress and Insulin Resistance

Dae Young Jung, Uma Devi Chalasani, Ning Pan, Randall H. Friedline, Domenick A. Prosdocimo, Minwoo Nam, Yoshihiro Azuma, Rajanikanth Maganti, Kristine Yu, Ashish Velagapudi, Bryan O'Sullivan-Murphy, Juliano L. Sartoretto, Mukesh K. Jain, Marcus P. Cooper, Fumihiko Urano, Jason K. Kim, Susan Gray

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish
Article numbere77851
JournalPloS one
Volume8
Issue number10
DOIs
StatePublished - Oct 22 2013

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