Ethanol-induced oxidant stress modulates hepatic autophagy and proteasome activity

Abstract

In this review, we describe research findings on the effects of alcohol exposure on two major catabolic systems in liver cells: the ubiquitin–proteasome system (UPS) and autophagy. These hydrolytic systems are not unique to liver cells; they exist in all eukaryotic tissues and cells. However, because the liver is the principal site of ethanol metabolism, it sustains the greatest damage from heavy drinking. Thus, the focus of this review is to specifically describe how ethanol oxidation modulates the activities of the UPS and autophagy and the mechanisms by which these changes contribute to the pathogenesis of alcohol-induced liver injury. Here, we describe the history and the importance of cellular hydrolytic systems, followed by a description of each catabolic pathway and the differential modulation of each by ethanol exposure. Overall, the evidence for an involvement of these catabolic systems in the pathogenesis of alcoholic liver disease is quite strong. It underscores their importance, not only as effective means of cellular recycling and eventual energy generation, but also as essential components of cellular defense.

Epigenetic Approaches in Neuroblastoma Disease Pathogenesis

“…Drugs of abuse have also been associated with proteasome inhibition which seems to be a key player in epigenetic mechanisms underlying the accumulation of oxidatively damaged histones [73]. In this frame, recent finding showed that ethanol exposure reduced intracellular 20S proteasome chymotrypsin-like activity in SH-SY5Y cells [74], in agreement with findings obtained in liver and brain demonstrating that ethanol decreased proteasome activity by interfering with 20S-CP (core particle) and 19S-RP (regulatory particle) assembly [75,76]. By contrast, cocaine has been reported to exert an opposite effect on the 20S proteasome, since the chymotrypsin-like activity [74] increases.…”

Diallyl Sulfide: Potential Use in Novel Therapeutic Interventions in Alcohol, Drugs, and Disease Mediated Cellular Toxicity by Targeting Cytochrome P450 2E1

“…CYP2E1 has been indicated to play a major role in all these conditions although the mechanism is complex and still remain unclear. For example, CYP2E1 regulates the liver triglyceride metabolism by influencing three independent pathways: peroxisome proliferator-activated receptor α (PPAR-α)-mediated fatty acid oxidation, sterol regulatory element-binding protein-1c (SREBP-1c)-regulated hepatic fatty acid synthesis and autophagymediated lipid decomposition [76–78]. PPAR-α and SREBP-1c are two important nuclear transcription factors that maintain fatty acid homeostasis in the liver.…”

Modulation of autophagy in human diseases strategies to foster strengths and circumvent weaknesses

“…On the basis pathomechanism above, in alcoholic cardiomyopathy, an increased level of autophagy is observed and some beneficial proteins such as myofibrillar proteins, mitochondrial proteins, fatty acid metabolism proteins, glycolytic proteins, and antioxidant proteins are reduced correspondingly . Further studies confirmed that the inhibition of mammalian target of rapamycin (mTOR) contributes to enhancement of autophagy and suppression of myocardial protein synthesis during alcohol intake . However, in heart failure, inhibition of autophagy during myocardial ischemia leads to activation of the cell death program, suggesting that autophagy plays a cardioprotective role during ischemia .…”