Protein kinase B (PKB/Akt) plays important roles in the regulation of
lipid homeostasis, and impairment of Akt activity has been demonstrated to be involved in the development of
non-alcoholic fatty liver disease (
NAFLD). Previous studies suggest that
cytochrome P4502E1 (
CYP2E1) plays causal roles in the pathogenesis of
alcoholic fatty liver (AFL). We hypothesized that Akt activity might be impaired due to CYP2E1-induced oxidative stress in chronic
ethanol-induced hepatic steatosis. In this study, we found that chronic
ethanol-induced hepatic steatosis was accompanied with reduced phosphorylation of Akt at Thr308 in mice liver. Chronic
ethanol exposure had no effects on the
protein levels of
phosphatidylinositol 3 kinase (PI3K) and
phosphatase and
tensin homologue deleted on chromosome ten (PTEN), and led to a slight decrease of
phosphoinositide-dependent
protein kinase 1 (PDK-1)
protein level.
Ethanol exposure resulted in increased levels of
malondialdehyde (MDA) and
4-hydroxynonenal (4-HNE)-Akt adducts, which was significantly inhibited by
chlormethiazole (CMZ), an efficient
CYP2E1 inhibitor. Interestingly,
N-acetyl-L-cysteine (NAC) significantly attenuated chronic
ethanol-induced hepatic fat accumulation and the decline of Akt phosphorylation at Thr308. In the in vitro studies, Akt phosphorylation was suppressed in CYP2E1-expressing HepG2 (CYP2E1-HepG2) cells compared with the negative control HepG2 (NC-HepG2) cells, and 4-HNE treatment led to significant decrease of Akt phosphorylation at Thr308 in wild type HepG2 cells. Lastly, pharmacological activation of Akt by
insulin-like growth factor-1 (IGF-1) significantly alleviated chronic
ethanol-induced
fatty liver in mice. Collectively, these results indicate that CYP2E1-induced oxidative stress may be responsible for
ethanol-induced suppression of Akt phosphorylation and pharmacological modulation of Akt in liver may be an effective strategy for the treatment of
ethanol-induced
fatty liver.