Liver MicroRNA-291b-3p Promotes Hepatic Lipogenesis through Negative Regulation of Adenosine 5′-Monophosphate (AMP)-activated Protein Kinase α1

Abstract

In a microarray study, we found that hepatic miR-291b-3p was significantly increased in leptin-receptor-deficient type 2 mice (db/db), a mouse model of diabetes. The function of miR291b-3p is unknown. The potential role of miR-291b-3p in regulating hepatic lipid metabolism was explored in this study. High-fat diet (HFD)-and chow-fed mice were injected with an adenovirus expressing a miR-291b-3p inhibitor and a miR291b-3p mimic through the tail vein. Hepatic lipids and lipogenic gene expression were analyzed. Additionally, gain-and loss-of-function studies were performed in vitro to identify direct targets of miR-291b-3p. MiR-291b-3p expression and the protein levels of sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FAS) were increased in the steatotic liver of db/db mice and HFD-fed mice versus their respective controls. Inhibition of hepatic miR-291b-3p expression prevented increases in hepatic lipogenesis and steatosis in HFD-fed mice. The opposite was observed when miR-291b-3p was overexpressed in the livers of chow-fed C57BL/6J wild-type mice. In vitro studies revealed that silencing of miR-291b-3p in NCTC1469 hepatic cells ameliorated oleic acid/palmitic acid mixture-induced elevation of cellular triglycerides. Importantly, we identified AMP-activated protein kinase (AMPK)-␣1 as a direct target of miR-291b-3p. Using metformin, an activator of AMPK, we showed that AMPK activation-induced inhibition of hepatic lipid accumulation was accompanied by reduced expression of miR-291b-3p in the liver. Liver miR-291b-3p promoted hepatic lipogenesis and lipid accumulation in mice. AMPK␣1 is a direct target of miR-291b-3p. In conclusion, our findings indicate that miR-291b-3p promotes hepatic lipogenesis by suppressing AMPK␣1 expression and activity, indicating the therapeutic potential of miR-291b-3p inhibitors in fatty liver disease.

Hepatic MiR-291b-3p Mediated Glucose Metabolism by Directly Targeting p65 to Upregulate PTEN Expression

“…In our previously study, we identified AMPK as a primary target of miR-291, and revealed that miR-291 inhibitors ameliorated hepatic TG accumulation, reduced FAS and SREBP-1 activity and this was attributed to the targeting of miR-291b-3p of AMPK24. In the present study, we found that short-term fasting led to increased level of miR-291b-3p (Fig.…”

“…We previously identified that the hepatic levels of miR-291b-3p were decreased by ~40%, accompanied by a significant reduction in the liver weight and the liver weight-to-body weight ratio, and a significant decrease in hepatic lipid deposition24. In the present study, compared with ad-GFP-treated mice (ad-NC), the HFD-fed mice injected with ad-miR-291i exhibited a significant reduction in fasting blood glucose levels.…”

“…Previously, we have shown that miR-291b-3p inhibitor ameliorated hepatic triglyceride (TG) accumulation, reduced fatty acid synthase (FAS) and Sterol-regulatory element binding protein (SREBP-1) activity, which was attributed to the targeting of AMPK by miR-291b-3p24. As an energy sensor, AMPK maintains the lipid and glucose homeostasis both at the cellular and the whole body level26.…”

Decreased MiR-155 Level in the Peripheral Blood of Non-Alcoholic Fatty Liver Disease Patients may Serve as a Biomarker and may Influence LXR Activity

“…Abnormal expression of miRNAs has been widely identified in different physiological and pathological circumstances [12][13][14]. For instance, miR-291b-3p was recently found to prompt hepatic lipogenesis mainly by targeting AMPKα1, and miR-125b enhances lipogenesis through binding the 3'UTR of SCD-1 [12,13]. In the current study, we mainly focus on miR-155, which has been widely explored in tumors [15,16].…”

“…Through a base-pairing mechanism, the mature miRNAs can bind to the 3′-untranslated region (UTR) of their target mRNAs, resulting in mRNA degradation [11]. Abnormal expression of miRNAs has been widely identified in different physiological and pathological circumstances [12][13][14]. For instance, miR-291b-3p was recently found to prompt hepatic lipogenesis mainly by targeting AMPKα1, and miR-125b enhances lipogenesis through binding the 3'UTR of SCD-1 [12,13].…”