ABSTRACT
OBJECTIVE Dihydroquercetin(TAX)is the most abundant dihydroflavone found in on-ions,milk thistle and Douglas fir bark.We investigated whether TAX could inhibit the lipid accumulation in alcoholic liver steatosis in vivo and in vitro.METHODS An in vivo model was established by intragas-trically treating mice with ethanol,and an in vitro model was created by treating HepG2 cells with etha-nol.RESULTS TAX regulated Sterol Regulatory Element-binding Protein-1(SREBP1)and Acetyl CoA Carboxylase (ACC) expression via elevating Liver Kinase B1 (LKB1)/ AMP-activated Kinase (AMPK) phosphorylation. Also, TAX upregulated SIRT1 expression, which suppressed by ethanal intake. Suppression of Purinergic 2X7 receptor (P2x7R), nucleotide-binding oligomerization domain-like re-ceptor protein 3(NLRP3)and Cysteine protease-1(caspase-1)cleavage by TAX resulted in the inhibi-tion of Interleukin-1β(IL-1β) production and release. Additionally, TAX reduced lipogenesis and pro-moted lipid oxidation via the regulation of AMPK and ACC in ethanol-treated steatotic HepG2 cell.TAX downregulated IL-1β cleavage response to Lipopolysaccharides (LPS) plus adenosine triphosphate(ATP) stimulation in HepG2 cells. P2x7R deficiency attenuated lipid accumulation with increasing AMPK activity and decreasing SREBP1 expression in ethanol-treated HepG2 cells.CONCLUSION Our data showed that TAX exhibited the inhibitory properties on lipogenesis and hepatoprotective ca-pacity,indicating that TAX has therapeutic potential for preventing alcoholic liver steatosis.
ABSTRACT
OBJECTIVE The current study was designed to investigate the anti-steatosis effect of Pleurotus citrinopileatus extract (PC) and the underlying mechanism in vivo and in vitro. METHODS Acute and chronic alcoholic hepatosteatosis murine models and ethanol-treated HepG2 cells were applied. RESULTS In vitro,the anti-steatosis effect of PC was further confirmed via Nile red staining in HepG2 cells treated with ethanol.Both of acute and chronic alcohol-induced mice hepatosteatosis model,PC decreased serum aminotransferase and triglyceride accumulation. Upregulated sterol-regulatory element binding protein1(Srebp1),purinergic ligand-gated ion channel 7receptor(P2X7R)and downregulated sirtuin1 (SIRT1), adenosine 5′-monophosphate (AMP)-activated protein kinase α (AMPKα) caused by acute and chronic alcohol intake were modulated by PC.In ethanol-exposed HepG2 cells,PC reduced lipid accumulation in a concentration-dependent manner and exhibited superior ability in controlling lipid accumulation compared with metformin. CONCLUSION PC could abolish hepatic lipid accumulation through regulating SIRT1-AMPKα signaling in acute and chronic alcohol-induced hepatic steatosis.
ABSTRACT
OBJECTIVE Regulating P2x7R- NLRP3 inflammasome activation might be a potentialtherapeutic strategy to treat alcoholic hepatosteatosis. We investigated whether this process would be modulated by gentiopicroside (GPS), which is attributed to the bitterness of gentian root extract. METHODSAn in vivo model was established by intragastrically treating mice with ethanol, and an in vitro modelwas created by treating HepG2 cells with ethanol or treating RAW 264.7 macrophages and murinebone marrow- derived macrophages (BMDMs) with lipopolysaccharides (LPS) plus adenosine triphos-phate (ATP). RESULTS In alcoholic hepatosteatotic mice model, GPS decreased serum aminotrans-ferase and triglyceride accumulation. GPS regulated sterol regulatory element-binding protein-1 (Srebp1),peroxisome proliferators- actived receptors α (PPARα) and acetyl CoA carboxylase (ACC) expressionvia elevating liver kinase B1 (LKB1)/AMP-activated Kinase (AMPK). Suppression of nucleotide-bindingoligomerization domain-like receptor protein 3 (NLRP3), caspase-1 and expression by GPS resulted inthe inhibition of interleukin-1β (IL-1β) production. In ethanol-exposed HepG2 cells, GPS reduced lipo-genesis and promoted lipid oxidation via P2x7R- NLRP3 inflammasome activation. P2x7R silencingenhanced AMPK activity, and reduced Srebp1 expression in ethanol-treated hepatocytes. GPS down-regulated P2x7R-mediated inflammatory response to extracellular ATP in LPS-primed RAW 264.7 macro-phages and BMDMs. Additionally, P2x7R deficiency attenuated IL- 1β cleavage in RAW 264.7 macro-phages, and GPS further suppressed IL-1β cleavage. CONCLUSION Activation of LKB1/AMPK signalingby GPS might be mediated by P2x7R-NLRP3 inflammasome, suggesting a therapeutic utility of P2x7Rblockade in alcoholic hepatosteatosis treatment.