Impairment of Akt activity by CYP2E1 mediated oxidative stress is involved in chronic ethanol-induced fatty liver

Abstract

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.

Liver X Receptor α–Induced Cannabinoid Receptor 2 Inhibits Ubiquitin‐Specific Peptidase 4 Through miR‐27b, Protecting Hepatocytes From TGF‐β

“…E). Akt is used to indicate hepatocyte viability, as it is suppressed in oxidative stress‐induced liver injury; thus, Akt activator protects hepatocytes from apoptosis and alleviates endotoxin‐induced liver injury . As expected, GW3965 treatment prevented decrease of p‐Akt (Fig.…”

Magnolol Prevents Acute Alcoholic Liver Damage by Activating PI3K/Nrf2/PPARγ and Inhibiting NLRP3 Signaling Pathway

“…CYP2E1 is one of the main enzymes in MEOS and plays a vital role in ethanol metabolism (Doody et al, 2017;Yuan et al, 2018). After excessive drinking or drinking a high concentration of alcohol, the activity of CYP2E1 is promoted and resulting in excessive reactive oxygen species (ROS) (Chen., 2014;Zeng et al, 2018). Then large amounts of reducing substances in the tissue including SOD and GSH-Px are consumed; alcohol-induced GSH-Px and SOD consumption are thought to aggravate oxidative damage in ALD mice model (Cederbaum, 2013;Zeng et al, 2018).…”

“…After excessive drinking or drinking a high concentration of alcohol, the activity of CYP2E1 is promoted and resulting in excessive reactive oxygen species (ROS) (Chen., 2014;Zeng et al, 2018). Then large amounts of reducing substances in the tissue including SOD and GSH-Px are consumed; alcohol-induced GSH-Px and SOD consumption are thought to aggravate oxidative damage in ALD mice model (Cederbaum, 2013;Zeng et al, 2018). The remaining lots of ROS cannot be inactivated, which also promotes the production of toxic lipid intermediates FIGURE 10 | Effects of magnolol on NLRP3 inflammasome, caspase-1 and caspase-3 signaling pathway in ALD mice.…”

“…by fatty acids through abnormal decomposition reactions, causing oxidative stress and damage to the liver (Chen et al, 2014;Zeng et al, 2018). Besides, several reports indicated that iNOS and Cox-2, which are key mediators, play roles in the development of liver damage .…”

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“…Accumulating evidence has suggested that oxidative stress plays a central role in the development of alcoholic liver injury (Dey & Cederbaum, ). During alcohol metabolism, alcohol can induce a hypermetabolic state in the liver and be selectively metabolized by the activated cytochrome P4502 E1 whose overexpression, from which much H 2 O 2 is generated producing cell damage (Zeng et al., ). The generation and accumulation of reactive oxygen species (ROS), together with the inhibition of antioxidant system by alcohol, result in oxidative stress and subsequently promote cell apoptosis or death by overwhelming the intrinsic antioxidants, depleting glutathione, and enhancing oxidative damage (Foadoddini et al., ; Ji et al., ).…”