Abstract
BackgroundCytochrome P4502E1 (CYP2E1) has been suggested to play critical roles in the pathogenesis of alcoholic fatty liver (AFL), but the underlying mechanisms remains unclear. The current study was designed to evaluate whether CYP2E1 suppression by chlormethiazole (CMZ) could suppress AFL in mice, and to explore the underlying mechanisms.MethodsMice were treated with or without CMZ (50 mg/kg bw, i.p.) and subjected to liquid diet with or without ethanol (5%, w/v) for 4 weeks. Biochemical parameters were measured using commercial kits. The protein and mRNA levels were detected by western blot and qPCR, respectively. Histopathology and immunohistochemical assay were performed with routine methods.ResultsCYP2E1 inhibition by CMZ completely blocked AFL in mice, shown as the decline of the hepatic and serum triglyceride levels, and the fewer fat droplets in the liver sections. Chronic ethanol exposure led to significant decrease of the mRNA and protein levels of peroxisome proliferator-activated receptor α (PPAR-α), which was blocked by CMZ co-treatment. CMZ co-treatment suppressed ethanol-induced oxidative stress, overproduction of tumor necrosis α (TNF-α), and decrease of protein levels of the PPAR-α co-activators including p300 and deacetylated PGC1-α. Furthermore, CMZ co-treatment led to the activation of AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), and PI3K/Akt/GSK3β pathway. However, chronic ethanol-induced decline of acyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) protein levels was partially restored by CMZ, while the activation of autophagy appeared to be suppressed by CMZ.ConclusionThese results suggested that CMZ suppressed chronic ethanol-induced oxidative stress, TNF-α overproduction, decline of p300 protein level and deacetylation of PGC1-α, and activated AMPK, MAPK, and PI3K/Akt/GSK3β pathway, which might contribute to the activation of PPAR-α and account for the protection of CMZ against AFL.
Highlights
Alcoholic liver disease (ALD) remains to be one of the most common etiologies of liver diseases and is a major cause of morbidity and mortality worldwide [1]
alcoholic fatty liver (AFL) was considered benign in the past, recent studies have demonstrated that fat accumulation renders the liver more vulnerable to toxins such as endotoxin, and AFL is progressed to hepatitis, fibrosis and even cirrhosis [3]
We aimed to address: 1) whether Cytochrome P4502E1 (CYP2E1) inhibition by CMZ could suppress chronic ethanol-induced fatty liver? 2) Whether the protective effects of CMZ were associated with peroxisome proliferator-activated receptor a (PPAR-a) pathway? And if so, which are the underlying mechanisms? And 3) whether the protective effects of CMZ were related with SREBP-1c pathway or autophagy
Summary
Alcoholic liver disease (ALD) remains to be one of the most common etiologies of liver diseases and is a major cause of morbidity and mortality worldwide [1]. ALD is a pathological process characterized by progressive liver damage from steatosis to steatohepatitis, fibrosis and cirrhosis [2]. Alcoholic fatty liver (AFL) is the earliest and most common pathological form of ALD. It was reported that AFL developed in about 90% of individuals who drank more than 60 g/day of alcohol, but might occur in individuals who drank less [4,5]. Other studies suggested that progression to fibrosis and cirrhosis occurred in 5%–15% of AFL patients despite abstinence [6,7]. Cytochrome P4502E1 (CYP2E1) has been suggested to play critical roles in the pathogenesis of alcoholic fatty liver (AFL), but the underlying mechanisms remains unclear. The current study was designed to evaluate whether CYP2E1 suppression by chlormethiazole (CMZ) could suppress AFL in mice, and to explore the underlying mechanisms
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