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BackgroundAlcoholic steatosis is the earliest and most common liver disease, and may precede the onset of more severe forms of liver injury.MethodsThe effect of Korean Red Ginseng extract (RGE) was tested in two murine models of ethanol (EtOH)-feeding and EtOH-treated hepatocytes.ResultsBlood biochemistry analysis demonstrated that RGE treatment improved liver function. Histopathology and measurement of hepatic triglyceride content verified the ability of RGE to inhibit fat accumulation. Consistent with this, RGE administration downregulated hepatic lipogenic gene induction and restored hepatic lipolytic gene repression by EtOH. The role of oxidative stress in the pathogenesis of alcoholic liver diseases is well established. Treatment with RGE attenuated EtOH-induced cytochrome P450 2E1, 4-hydroxynonenal, and nitrotyrosine levels. Alcohol consumption also decreased phosphorylation of adenosine monophosphate-activated protein kinase, which was restored by RGE. Moreover, RGE markedly inhibited fat accumulation in EtOH-treated hepatocytes, which correlated with a decrease in sterol regulatory element-binding protein-1 and a commensurate increase in sirtuin 1 and peroxisome proliferator-activated receptor-α expression. Interestingly, the ginsenosides Rb2 and Rd, but not Rb1, significantly inhibited fat accumulation in hepatocytes.ConclusionThese results demonstrate that RGE and its ginsenoside components inhibit alcoholic steatosis and liver injury by adenosine monophosphate-activated protein kinase/sirtuin 1 activation both in vivo and in vitro, suggesting that RGE may have a potential to treat alcoholic liver disease.

The Sestrin2 (Sesn2) is an evolutionary conserved enzyme that scavenges reactive oxygen species and regulates autophagy through the AMPK-mTOR pathway. The present study was aimed at determining whether Toll-like receptor (TLR) signaling regulates Sesn2 expression and identifying the underlying molecular mechanism. Lipopolysaccharide (LPS), a representative TLR4 ligand, significantly increased the levels of Sesn2 protein in macrophages. LPS also increased Sesn2 mRNA levels and luciferase reporter activity; however, the mRNA levels of Sesn1 were not affected by LPS. Moreover, treatment of macrophages with other TLR ligands (eg, polyI:C or peptidoglycan) also induced Sesn2 expression. We found that LPS-mediated Sesn2 induction was transcriptionally regulated by AP-1 and Nrf2, and that overexpression of c-Jun or Nrf2 increased Sesn2 protein levels and Sesn2 promoter-driven luciferase reporter activity. Moreover, deletion of the antioxidant response element (ARE) in the Sesn2 promoter or Nrf2 knockout abolished LPS-mediated induction of Sesn2. LPS induced Sesn2 gene expression through p38 and PI3K activation. Surprisingly, treatment with the proteasome inhibitor MG132, but not the lysosomal inhibitor chloroquine, caused Sesn2 to accumulate in the cells. In the presence of MG132, we observed that Sesn2 was ubiquitinated. However, LPS treatment attenuated Sesn2 ubiquitination induced by MG132, which resulted in Sesn2 accumulation. Mice treated with D-galactosamine (Gal)/LPS exhibited enhanced Sesn2 expression in the liver. Moreover, infection with a recombinant adenovirus encoding Sens2 markedly reduced the number of Gal/LPS-induced TUNEL-positive cells. Our results suggest that TLR-mediated Sesn2 induction is dependent on AP-1, Nrf2, and the inhibition of ubiquitin-mediated degradation of Sesn2 and might protect cells against endotoxin toxicity.