6-Gingerol Ameliorates Hepatic Steatosis via HNF4α/miR-467b-3p/GPAT1 Cascade

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 4a (HNF4a).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 HNF4a/miR-467b-3p/GPAT1 axis was measured in mouse and human fatty liver tissues. 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 HNF4a, resulting in the increase of miR-467b-3p and subsequent decrease of GPAT1. HNF4a/miR-467b-3p/GPAT1 signaling also was observed in human samples with hepatic steatosis. CONCLUSIONS:Our findings establish a novel mechanism by which 6-G improves NAFLD. This suggests that targeting of the HNF4a/miR-467b-3p/GPAT1 cascade may be used as a potential therapeutic strategy to control NAFLD.

Gingerol ameliorates neuronal damage induced by hypoxia‐reoxygenation via the miR‐210/brain‐derived neurotrophic factor axis

“…Importantly, our investigation showed that gingerol inhibited the increase in miR‐210 expression observed in response to hypoxia/reoxygenation, indicating that miR‐210 might be the mediator of the protective effect of gingerol on hypoxia/reoxygenation‐stimulated neuronal cells. Two reports 35,36 indicate that the potential mechanism by which gingerol alters miR‐210 expression is mediated by upstream factors such as lncRNAs or transcription factors, which should be investigated in future studies. miR‐210 is upregulated in acute cerebral ischemia (ACI), indicating the potential role of this miRNA in ACI diagnosis, according to a previous investigation 37 .…”

Diterpenoid Alkaloids Isolated from Delphinium brunonianum and Their Inhibitory Effects on Hepatocytes Lipid Accumulation

“…We selected FFA-induced BRL cells (oleate and palmitate ratio was 2:1) to establish a cellular NAFLD model, which is a widely used method by researchers for studying diseases related to hepatocytes lipid accumulation [ 18 ]. The TG secretion was measured to preliminarily evaluate the inhibitory effect on lipid accumulation of 15 isolated alkaloid compounds.…”

6-Gingerol Ameliorates Hepatic Steatosis, Inflammation and Oxidative Stress in High-Fat Diet-Fed Mice through Activating LKB1/AMPK Signaling

“…Based on the results of the docking analysis, we found that the potential binding of 6-gingerol and LKB1 with favorable binding energies might account for the increasing stability of the LKB1/STRAD/MO25 complex, which, however, warrants future validation. What is more, it has been reported that 6-gingerol ameliorates hepatic steatosis via the HNF4α/miR-467b-3p/GPT1 pathway [ 24 ], which provides another research strategy. Moreover, our drug efficacy mainly concentrates in the amelioration of NAFLD.…”

“…6-Gingerol (6-G, PubChem CID: 442793), one of the major pharmacologically active ingredients extracted from ginger, has been found to have pleiotropic pharmacological functions, including anti-oxidative [ 17 ], anti-inflammatory [ 18 ], anti-obesity, anti-cancer [ 19 , 20 ], anti-hyperglycemic and immunomodulatory [ 21 , 22 ] effects. Previously, 6-gingerol was reported experimentally to alleviate hepatic steatosis in HFD-fed mice [ 23 , 24 ], as well as to mitigate intracellular lipid accumulation and to activate AMPK in free fatty acid (FFA)-induced Hepa1–6 cells [ 24 ]. It has been reported that 6-gingerol modulates the inflammatory status and the metabolic disorders in HFD-fed rats, which is associated with a 6-gingerol-induced activating effect on hepatic AMPK [ 25 ].…”