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MicroRNA-124 promotes hepatic triglyceride accumulation through targeting tribbles homolog 3.

ABSTRACT: An increase in hepatic triglyceride (TG) contents usually results in non-alcoholic fatty liver disease (NAFLD) and related metabolic diseases. However, the mechanisms underlying perturbations of hepatic TG homeostasis remain largely unknown. Here, we showed that MicroRNA-124 was up-regulated in the livers of C57BL/6 mice fed a short-term high-fat-diet (HFD). Adenoviral overexpression of miR-124 in C57BL/6 mice led to accumulation of excessive triglycerides and up-regulation of lipogenic genes in the liver. We further identified tribbles homolog 3 (TRB3) as a direct target of miR-124. AKT signaling, which is negatively regulated by TRB3, was enhanced by miR-124 overexpression. Moreover, restoration of TRB3 expression markedly abolished the effect of miR-124 on hepatic TG metabolism. Therefore, our findings revealed that miR-124 played a role in mediating high-fat-diet induced TG accumulation in the liver.

SUBMITTER: Liu X

PROVIDER: S-EPMC5109039 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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MicroRNA-124 promotes hepatic triglyceride accumulation through targeting tribbles homolog 3.

Liu Xing X Zhao Jiejie J Liu Qi Q Xiong Xuelian X Zhang Zhijian Z Jiao Yang Y Li Xiaoying X Liu Bin B Li Yao Y Lu Yan Y

Scientific reports 20161115

An increase in hepatic triglyceride (TG) contents usually results in non-alcoholic fatty liver disease (NAFLD) and related metabolic diseases. However, the mechanisms underlying perturbations of hepatic TG homeostasis remain largely unknown. Here, we showed that MicroRNA-124 was up-regulated in the livers of C57BL/6 mice fed a short-term high-fat-diet (HFD). Adenoviral overexpression of miR-124 in C57BL/6 mice led to accumulation of excessive triglycerides and up-regulation of lipogenic genes in ...[more]

PMID: 27845424

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Project description:Dickkopf-1 (DKK1) is a powerful antagonist of canonical WNT signaling pathway, and is regarded as a biomarker for osteoporosis. Its expression is highly correlated with bone mass and osteoblasts maturation. In this study, mouse primary bone marrow cells and osteoblast cell lines were used. Luciferase reporter assay and western blotting methods were employed to validate if miRNA-433-3p epigenetically regulated DKK1 translation. Rat bone marrow derived osteoblasts were infected with lentivirus vector in which miR-433-3p was constructed. The authors constructed lentivirus mediated miRNA-433-3p stable expression and examined the alkaline phosphatase (ALP) activity and mineral deposition level in vitro. In situ hybridization method was used to observe miR-433-3p in primary osteoblasts. We built up an OVX rat model to mimic postmenopausal osteoporosis, and found aberrant circulating miR-433-3p and miR-106b, which were not reported previously. Results showed that miR-433-3p potentially regulated DKK1 mRNA, Furthermore, the correlation of serum DKK1 with circulating miR-433-3p level was significant (r = 0.7520, p = 0.046). In the luciferase reporter assay, we found that miR-433-3p siRNA decreased luminescence signal, indicating direct regulation of miR-433-3p on DKK1 mRNA. When the miR-433-3p binding site in DKK1 3'UTR was mutant, such reduction was prohibited. Western blotting result validated that miR-433-3p inhibited over 90% of DKK1 protein expression. Similarly, the change of protein expression was not observed in mutant group. The stable expression of lentivirus mediated miR-433-3p increased ALP activity and mineralization both in human and rat derived immortalized cells. We found that primary osteoblasts had higher miR-433-3p level compared with immortal cells through real-time PCR, as well as in situ hybridization experiment. Conclusively, our findings further emphasized the vital role of miR-433-3p in DKK1/WNT/?-catenin pathway through decreasing DKK1 expression and inducing osteoblasts differentiation.

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MicroRNA-124 promotes hepatic triglyceride accumulation through targeting tribbles homolog 3.

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MicroRNA-124 promotes hepatic triglyceride accumulation through targeting tribbles homolog 3.

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