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MiR?146a improves hepatic lipid and glucose metabolism by targeting MED1.

ABSTRACT: Non?alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. Increasing evidence has shown that microRNAs (miRNAs) play a vital role in the progression of NAFLD. The aim of the present study was to examine the expression level and roles of miR?146a in fatty liver of high?fat diet (HFD) and ob/ob mice and fatty acid?treated hepatic cells using RT?qPCR and western blot analysis. The results showed that the expression of miR?146a was significantly decreased in the livers of high?fat diet (HFD) and ob/ob mice and free fatty acid?stimulated cells by RT?qPCR. Overexpression of hepatic miR?146a improved glucose and insulin tolerance as well as lipid accumulation in the liver by promoting the oxidative metabolism of fatty acids. In addition, the overexpression of miR?146a increased the amount of mitochondria and promoted mitochondrial respiration in hepatocytes. Similarly, inhibition of miR?146a expression levels significantly reduced mitochondrial numbers in AML12 cells as well as the expression of mitochondrial respiration related genes. Additionally, MED1 was a direct target of miR?146a and restoring MED1 abolished the metabolic effects of miR?146a on lipid metabolism and mitochondrial function. Therefore, results of the present study identified a novel function of miR?146a in glucose and lipid metabolism in targeting MED1, suggesting that miR?146a serves as a potential therapeutic target for metabolic syndrome disease.

SUBMITTER: Li K

PROVIDER: S-EPMC6984781 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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miR‑146a improves hepatic lipid and glucose metabolism by targeting MED1.

Li Kun K Zhao Bao B Wei Diandian D Wang Wenrui W Cui Yixuan Y Qian Lisheng L Liu Guodong G

International journal of molecular medicine 20191227 2

Non‑alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. Increasing evidence has shown that microRNAs (miRNAs) play a vital role in the progression of NAFLD. The aim of the present study was to examine the expression level and roles of miR‑146a in fatty liver of high‑fat diet (HFD) and ob/ob mice and fatty acid‑treated hepatic cells using RT‑qPCR and western blot analysis. The results showed that the expression of miR‑146a was significantly decreased ...[more]

PMID: 31894315

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Project description:Hepatic macroautophagy/autophagy and fatty acid metabolism are transcriptionally regulated by nuclear receptors (NRs); however, it is not known whether their transcriptional co-activators are involved in autophagy. We thus examined MED1 (mediator complex subunit 1), a key component of the Mediator Complex that directly interacts with NRs, on these processes. We found that MED1 knockdown (KD) in cultured hepatic cells decreased autophagy and mitochondrial activity that was accompanied by decreased transcription of genes involved in these processes. Lipophagy and fatty acid β-oxidation also were impaired. These effects also occurred after thyroid hormone stimulation, nutrient-replete or -deplete conditions, and in liver-specific Med1 KD (Med1 LKD) mice under fed and fasting conditions. Together, these findings showed that Med1 played a key role in hepatic autophagy, mitochondria function, and lipid metabolism under these conditions. Additionally, we identified downregulated hepatic genes in Med1 LKD mice, and subjected them to ChIP Enrichment Analysis. Our findings showed that the transcriptional activity of several NRs and transcription factors (TFs), including PPARA and FOXO1, likely were affected by Med1 LKD. Finally, Med1 expression and autophagy also were decreased in two mouse models of nonalcoholic fatty liver disease (NAFLD) suggesting that decreased Med1 may contribute to hepatosteatosis. In summary, MED1 plays an essential role in regulating hepatic autophagy and lipid oxidation during different hormonal and nutrient conditions. Thus, MED1 may serve as an integrator of multiple transcriptional pathways involved in these metabolic processes.Abbreviations: BAF: bafilomycin A1; db/db mice; Leprdb/db mice; ECAR: extracellular acidification rate; KD: knockdown; MED1: mediator complex subunit 1; NAFLD: nonalcoholic fatty liver disease; OCR: oxygen consumption rate; PPARA/PPARα: peroxisomal proliferator activated receptor alpha; TF: transcription factor; TFEB: transcription factor EB; tf-LC3: tandem fluorescence RFP-GFP-LC3; TG: triglyceride; TH: Thyroid hormone; TR: thyroid hormone receptors; V-ATPase: vacuolar-type H+-ATPase; WDF: Western diet with 15% fructose in drinking water.

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MiR?146a improves hepatic lipid and glucose metabolism by targeting MED1.

Publications

miR‑146a improves hepatic lipid and glucose metabolism by targeting MED1.

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