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AMPK activator-mediated inhibition of endoplasmic reticulum stress ameliorates carrageenan-induced insulin resistance through the suppression of selenoprotein P in HepG2 hepatocytes

Jung, Tae Woo, Lee, So Young, Hong, Ho Cheol, Choi, Hae Yoon, Yoo, Hye Jin, Baik, Sei Hyun, Choi, Kyung Mook
Molecular and Cellular Endocrinology 2014 v.382 pp. 66-73
AMP-activated protein kinase, Toll-like receptor 4, binding proteins, carrageenan, endoplasmic reticulum, hepatocytes, human cell lines, inflammation, insulin resistance, mitogen-activated protein kinase, noninsulin-dependent diabetes mellitus, selenoproteins
Carrageenan (CGN) has been shown to cause inflammation through toll-like receptor 4, which may play an important role in insulin resistance and type 2 diabetes mellitus. Selenoprotein P (SeP) has recently been identified as a novel hepatokine that causes insulin resistance. Here, we report that treatment of HepG2 cells with CGN increased both CCAAT enhancer binding protein homologous protein (CHOP) and SeP expression. Pretreatment with 4-phenylbutyrate (4-PBA), an endoplasmic reticulum stress inhibitor, and PD98059, a c-Jun N-terminal kinase (JNK) inhibitor, reversed CGN-induced SeP expression. Moreover, both 4-PBA and knock-down of SeP improved CGN-induced insulin resistance. In addition, we found that adenosine monophosphate-activated protein kinase (AMPK) activators ameliorated CGN-induced insulin resistance in addition to suppressing CHOP and SeP expression. In conclusion, CGN-induced ER stress increased the expression of SeP through the JNK pathway, while AMPK activators ameliorated CGN-induced insulin resistance via SeP inhibition through the AMPK-mediated alleviation of ER stress in hepatocytes.