Program in Molecular Medicine; Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes; Department of Medicine, Division of Cardiovascular Medicine
Cellular and Molecular Physiology | Endocrinology | Nutritional and Metabolic Diseases
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-1alpha 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.
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Copyright 2013 Jung et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
Jung DY, Chalasani U, Pan N, Friedline RH, Prosdocimo DA, et al. (2013) KLF15 Is a Molecular Link between Endoplasmic Reticulum Stress and Insulin Resistance. PLoS ONE 8(10): e77851. doi:10.1371/journal.pone.0077851 Link to article on publisher's site
Jung, Dae Young; Chalasani, UmaDevi; Pan, Ning; Friedline, Randall H.; Prosdocimo, Domenick A.; Nam, Minwoo; Azuma, Yoshihiro; Maganti, Rajanikanth; Yu, Kristine; Velagapudi, Ashish; O'Sullivan-Murphy, Bryan; Sartoretto, Juliano L.; Jain, Mukesh K.; Cooper, Marcus P.; Urano, Fumihiko; Kim, Jason K.; and Gray, Susan, "KLF15 is a molecular link between endoplasmic reticulum stress and insulin resistance" (2013). Open Access Articles. 2404.