Journal
JOURNAL OF CELLULAR PHYSIOLOGY
Volume 233, Issue 8, Pages 6052-6066Publisher
WILEY
DOI: 10.1002/jcp.26442
Keywords
hepatocytes; insulin resistance; miR-125b; PIK3CD
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Funding
- National Key Research and Development Program [2016YFD0501206]
- National Natural Science Foundation of China [31402265, 31472247, 31572581, 31672621]
- National High Technology Research and Development Program 863 [2013AA102806]
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Insulin resistance is often characterized as the most critical factor contributing to the development of (T2D) type 2 diabetes. MicroRNAs (miRNAs) are endogenous non-coding short single-stranded RNAs that function as negative regulators in many physiological and pathological processes. The objective of this study was to evaluate the roles of miR-125b in the regulation of insulin sensitivity in hepatocytes. We found that hepatic miR-125b levels were significantly increased in the patients with type 2 diabetes, high fat diet (HFD) mice, ob/ob and db/db mice. In vitro, miR-125b was also significantly up-regulated in tumor necrosis factor-alpha- (TNF-) and glucosamine-induced insulin resistance conditions. Furthermore, miR-125b overexpression impaired the insulin signaling pathway in HepG2 cells, L02c cells, and primary hepatocytes. Inhibition of miR-125b improved insulin sensitivity, especially in insulin-resistant cells induced by either TNF- or glucosamine. We demonstrated that miR-125b targeted the 3-untranslated region (3-UTR) of phosphoinositide 3-kinase catalytic subunit delta (PIK3CD) mRNA. The hepatic PIK3CD protein levels were markedly decreased in patients with type 2 diabetes, HFD, ob/ob, and db/db mice. Inhibition of PIK3CD markedly attenuated the improvement of insulin sensitivity induced by miR-125b inhibitors. More importantly, overexpressing miR-125b in mice causes insulin resistance and impairs glucose homeostasis. Together, these findings indicate that miR-125b inhibits insulin sensitivity by targeting PIK3CD in hepatocytes, supporting hepatic miR-125b, or PIK3CD are potential therapeutic target of insulin resistance.
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