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Publication
KLF15 is a molecular link between endoplasmic reticulum stress and insulin
resistance.
Authors Jung DY, Chalasani U, Pan N, Friedline RH, Prosdocimo DA, Nam M, Azuma Y,
Maganti R, Yu K, Velagapudi A, O'Sullivan-Murphy B, Sartoretto JL, Jain MK,
Cooper MP, Urano F, Kim JK, Gray S
Submitted By Susan Gray on 3/19/2014
Status Published
Journal PLoS ONE
Year 2013
Date Published
Volume : Pages 8 : e77851
PubMed Reference 24167585
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-1a 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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