Hepatic miR‐125b inhibits insulin signaling pathway by targeting PIK3CD

Abstract

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-α) 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-α 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.

Circulating miR-143-3p inhibition protects against insulin resistance in Metabolic Syndrome via targeting of the insulin-like growth factor 2 receptor

“…Here, we revealed circulating miRNA profiles of MetS patients via microarray analysis and confirmed that circulating miR-143-3p was increased significantly in MetS patients compared with controls, both in serum and urine samples. Recently, Rui Wang et al reported that elevated circulating miRNA-122 is associated with obesity and insulin resistance in young adults, 19 Xiliang Du et al revealed that miR-125b overexpression impaired the insulin signaling pathway in HepG2 cells, L02c cells, and primary hepatocytes, 20 while, He Qing Fang et al showed that circulating miRNA-21 is downregulated in patients with MetS. 21 However, neither of these 2 miRNAs was detected in our present study.…”

Amelioration of hepatic steatosis is associated with modulation of gut microbiota and suppression of hepatic miR-34a in Gynostemma pentaphylla (Thunb.) Makino treated mice

“…Thus, miRNAs is very likely to be the link between gut microbiota and NAFLD. The miRNAs we scanned were stably expressed in the liver and involved in the course of NAFLD such as hepatic steatosis (miR10b [ 60 ], miR-24 [ 61 ], miR-29a [ 62 ], miR-155 [ 63 ], miR-34a [ 64 ], miR-125b [ 65 ], miR-486 [ 66 ], miR-199a [ 67 ], miR-30b [ 68 ], miR-30c [ 69 ], miR467b [ 70 ], miR-148a [ 71 ]), insulin resistance (miR-125b [ 72 ], miR-206 [ 73 ], miR-130a [ 74 ], miR-291b [ 75 ]), inflammatory and hepatic fibrosis (miR-21a [ 76 , 77 ], miR-199a [ 78 ], miR-370 [ 79 ], miR-130a [ 80 ], miR-34a [ 81 ], miR-24 [ 82 ]), as well as cirrhosis and HCC (miR-210 [ 83 ], miR-10b [ 84 ]). We further analyzed the correlation between the alteration of gut microbiota and miRNAs.…”

miR-378b Regulates Insulin Sensitivity by Targeting Insulin Receptor and p110α in Alcohol-Induced Hepatic Steatosis

“…The levels of glucose and insulin were measured using biochemical (U83730050, Guilin Unitech Medical Electronics Co., Ltd., Guilin, China) and ultra-sensitive mouse insulin immunoassay kit (Li Ka Shing Faculty of Medicine, The University of Hong Kong) according to the supplier's protocol, respectively. Homeostasis model assessment of insulin resistance (HOMA-IR) index was calculated according to the formula: [fasting glucose level (mM)] × [fasting serum insulin (mU/L)]/ 22.5 (Du et al, 2018).…”