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6-Gingerol Ameliorates Hepatic Steatosis via HNF4α/miR-467b-3p/GPAT1 Cascade.
- Source :
-
Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2021; Vol. 12 (4), pp. 1201-1213. Date of Electronic Publication: 2021 Jun 15. - Publication Year :
- 2021
-
Abstract
- Background & Aims: The development of nonalcoholic fatty liver disease (NAFLD) can be modulated by microRNAs (miRNA). Dietary polyphenols modulate the expression of miRNA such as miR-467b-3p in the liver. In addition, 6-gingerol (6-G), the functional polyphenol of ginger, has been reported to ameliorate hepatic steatosis; however, the exact mechanism involved and the role of miRNA remain elusive. In this study, we assessed the role of miR-467b-3p in the pathogenesis of hepatic steatosis and the regulation of miR-467b-3p by 6-G through the hepatocyte nuclear factor 4α (HNF4α).<br />Methods: miR-467b-3p expression was measured in free fatty acid (FFA)-treated hepatocytes or liver from high-fat diet (HFD)-fed mice. Gain- or loss-of-function of miR-467b-3p was induced using miR-467b-3p-specific miRNA mimic or miRNA inhibitor, respectively. 6-G was exposed to FFA-treated cells and HFD-fed mice. The HNF4α/miR-467b-3p/GPAT1 axis was measured in mouse and human fatty liver tissues.<br />Results: We found that miR-467b-3p was down-regulated in liver tissues from HFD-fed mice and in FFA-treated Hepa1-6 cells. Overexpression of miR-467b-3p decreased intracellular lipid accumulation in FFA-treated hepatocytes and mitigated hepatic steatosis in HFD-fed mice via negative regulation of glycerol-3-phosphate acyltransferase-1 (GPAT1). In addition, miR-467b-3p up-regulation by 6-G was observed. 6-G inhibited FFA-induced lipid accumulation and mitigated hepatic steatosis. Moreover, it increased the transcriptional activity of HNF4α, resulting in the increase of miR-467b-3p and subsequent decrease of GPAT1. HNF4α/miR-467b-3p/GPAT1 signaling also was observed in human samples with hepatic steatosis.<br />Conclusions: Our findings establish a novel mechanism by which 6-G improves NAFLD. This suggests that targeting of the HNF4α/miR-467b-3p/GPAT1 cascade may be used as a potential therapeutic strategy to control NAFLD.<br /> (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Disease Models, Animal
Gene Expression
Genes, Reporter
Hepatocyte Nuclear Factor 4 chemistry
Humans
Lipid Metabolism
Male
Mice
Non-alcoholic Fatty Liver Disease etiology
Non-alcoholic Fatty Liver Disease metabolism
Non-alcoholic Fatty Liver Disease pathology
Structure-Activity Relationship
1-Acylglycerol-3-Phosphate O-Acyltransferase genetics
Catechols pharmacology
Fatty Alcohols pharmacology
Gene Expression Regulation genetics
Hepatocyte Nuclear Factor 4 genetics
MicroRNAs genetics
RNA Interference
Subjects
Details
- Language :
- English
- ISSN :
- 2352-345X
- Volume :
- 12
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cellular and molecular gastroenterology and hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 34139323
- Full Text :
- https://doi.org/10.1016/j.jcmgh.2021.06.007