Abstract
Poria cocos Wolf (PCW) is an edible, pharmaceutical mushroom with remarkable biological properties including anti-tumor, anti-inflammation, anti-oxidation, anti-ageing, and anti-diabetic effects. In the current study, we investigated the effects of PCW extract on hepatic steatosis under in vitro and in vivo conditions, and elucidated the underlying mechanisms. In this study, a mixture of HepG2 cells treated with free fatty acid (FFA)—palmitic and oleic acid—and high-fat diet (HFD)-fed obese mice were used; in this background, the triglyceride (TG) levels in HepG2 cells and mice liver were measured, and the expression levels of genes associated with lipogenesis, fatty acid oxidation, endoplasmic reticulum (ER) stress, and autophagy were determined. Treatment of HepG2 cells with FFA enhanced intracellular TG levels in HepG2 cells, but co-treatment with PCW significantly attenuated the TG levels. Notably, PCW significantly enhanced the phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), and sterol regulatory element-binding protein-1c (SREBP-1c) in FFA-treated HepG2 cells. PCW downregulated the expression of lipogenesis-related genes, but upregulated the expression of genes associated with fatty acid oxidation. Further, PCW inhibited FFA-induced expression of ER stress markers and induced autophagy proteins. However, inhibition of AMPK significantly attenuated the beneficial effects of PCW in HepG2 cells. Moreover, PCW efficiently decreased HFD-induced hepatic TG accumulation in vivo and increased the phosphorylation of hepatic AMPK. Three compounds present in PCW including poricoic acid, pachymic acid, and ergosterol, significantly decreased FFA-induced increase in intracellular TG levels, consistent with increased AMPK phosphorylation, suggesting that poricoic acid, pachymic acid, and ergosterol are responsible for PCW-mediated amelioration of hepatic steatosis. Taken together, these results demonstrated that PCW ameliorates hepatic steatosis through the regulation of lipid metabolism, inhibition of ER stress, and activation of autophagy in an AMPK-dependent manner. This suggested that PCW can be potentially used for the treatment of hepatic steatosis.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver problems, ranging from hepatic steatosis to more severe diseases, including non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatic carcinoma [1]
We evaluated the in vivo effects of Poria cocos Wolf (PCW) on hepatic steatosis in high-fat diet (HFD)-induced obese mice
Our findings indicated that PE stimulates the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) in HepG2 cells, and that PE inhibits lipogenesis and caused reduced accumulation of TG via AMPK-medicated phosphorylation of ACC
Summary
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver problems, ranging from hepatic steatosis to more severe diseases, including non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatic carcinoma [1]. The activation of AMPK inhibits fatty acid synthesis (lipogenesis), whereas it stimulates fatty acid oxidation. The anti-lipogenesis activity of AMPK, makes this enzyme a potential therapeutic target for the treatment of hepatic steatosis. Recent research has focused on the activation of autophagy and the development of AMPK activators as promising treatment strategies for hepatic steatosis. 2019, 20, 4801 focused on the activation of autophagy and the development of AMPK activators as promising treatment strategies for hepatic steatosis. HHoowweevveerr,, aa ccoommbbiinnaattoorriiaallttrreeaattmmeennttwwitihth 11mmmmool/lm/mLLFFFFAAaanndd8800μμmmool/lm/mLLPPCCWWeexxhhiibbiitteedd ccyyttoottooxxiicciittyy iinn HHeeppGG22 cceellllss((FFiigguurree11CC)),,aaltlthhoouugghh aaccoommbbininaattiioonn ooff 11 mmmmooll//mmLL FFFFAA aanndd 4400 μμmmooll//mmLL PPCCWW eexxhhiibbiitteedd lleessssccyyttoototoxxicicitiyty(F(Figiguurere1C1C).). .CCyyttoottooxxiicciittyyooff ffrreeee ffaattttyy aacciidd ((FFFFAA)) aanndd PPoorriiaa ccooccooss WWoollff ((PPCCWW)) oonn HHeeppGG22cceellllss..(A(A))HHeeppGG22 cceelllslswwereeretrteraetaetdedwwithithvavraioriuosucsocnocnecnetnratrtiaotniosnosfoFfFFAF(A0,(00.,205.,205.5, 0, 1.5.0, ,1o.0r,2o.0r 2m.0Mm) fMor) 2fo4rh. .HHepepGG22ceclelsllswwereere ttrreeaatteedd wwiitthh FFFFAA ((11 mmMM)) aanndd/oorr PPCCWW ((2200 oorr 4400 μμgg//mmLL)) ffoorr 2244 hh.. HToeptGhi2s end, we examined ER stress markers including GRP78, CHOP, XBP1c, and p-PERK in FFA-treated HepG2
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