Oxidative stress and glutamate excretion in alcoholic steatosis: Metabolic synapse between hepatocyte and stellate cell

Abstract

Chronic alcohol consumption induces the development of alcoholic steatosis in the liver, which is one of the most widespread liver diseases worldwide. During general alcohol metabolism, hepatocytes generate mitochondria- and cytochrome P450 2E1 (CYP2E1)-mediated reactive oxygen species (ROS) whose accumulation elicits activation of the hepatic anti-oxidant system, including glutathione (GSH). However, chronic alcohol consumption decreases GSH generation through cysteine deficiency by suppressing the methionine cycle and trans-sulfuration system, whereas it turns on an alternative defense pathway, such as the xCT transporter, to compensate for GSH shortage. The xCT transporter mediates the uptake of cystine coupled to the efflux of glutamate, leading to an increase in blood glutamate. In response to the elevated glutamate in the liver, the expression of metabotropic glutamate receptor 5 (mGluR5) is up-regulated in hepatic stellate cells (HSCs) along with enhanced production of 2-arachidonoylglycerol, which in turn stimulates cannabinoid receptor 1 (CB1R) on neighboring hepatocytes to increase de novo lipogenesis. On the other hand, blockade of mGluR5 and CB1R attenuates alcoholic steatosis. Interestingly, although the increased expression of CYP2E1-mediated xCT and ROS generation are mainly observed at the perivenous area (zone 3), fat accumulation is mostly detected at hepatic zone 2. To resolve this discrepancy, this review summarizes recent advances on glutamate/mGluR5-derived alcoholic steatosis and zone-dependently different responses to alcohol intake. In addition, the bidirectional loop pathway and its unique metabolic synapse between hepatocytes and HSCs are discussed.

The Protective Effects of Ganoderic Acids from Ganoderma lucidum Fruiting Body on Alcoholic Liver Injury and Intestinal Microflora Disturbance in Mice with Excessive Alcohol Intake

“…Human health is strongly related to the homeostasis of gut microflora and the permeability of the intestinal barrier. Over the past few years, many studies have suggested that excessive drinking might cause the disorder of gut microbial homeostasis and the destruction of intestinal barrier permeability, resulting in the proliferation of harmful bacteria in the intestinal tract, the absorption of harmful metabolites, and the damage of liver metabolism function [ 10 , 11 ]. The “gut–liver–metabolite” axis plays an influential role in the pathological development of ALD.…”

Galacto-Oligosaccharide Alleviates Alcohol-Induced Liver Injury by Inhibiting Oxidative Stress and Inflammation

“…Notably, an increasing number of studies have shown that ALD is inextricably linked to the intestinal flora. Alcohol metabolism in the body causes intestinal damage, disrupts intestinal barrier permeability, and produces oxidative-stress-induced damage and inflammation in the intestine [39][40][41][42]. Meanwhile, GOS, a prebiotic, exerts a good effect on regulating and improving the intestinal flora, which has been confirmed in many studies [43][44][45].…”

Exosome-Based Delivery of Super-Repressor IκBα Alleviates Alcohol-Associated Liver Injury in Mice

“…Although there have been many efforts to abate these processes, there is still no approved drug for ALD. Since liver damage could not be reversed in the late stage of ALD such as ALC or HCC [ 2 ], there is an urgent need for a new therapeutic agent, especially targeting early-stage ALD. In the present study, we provide several lines of evidence for the efficient preventive effect of Exo-srIκB against ALI, AFL, and ALF in mice.…”

“…Alcohol-associated liver disease (ALD) caused by chronic and excessive alcohol consumption is one of the most prevalent chronic liver diseases worldwide [ 1 ]. Usually, ALD follows a well-defined disease spectrum starting with the alcohol-associated fatty liver (AFL) that develops into alcohol-associated steatohepatitis, fibrosis (ALF), cirrhosis (ALC), and hepatocellular carcinoma (HCC) [ 2 ]. Chronic alcohol consumption induces gut dysbiosis and increases intestinal permeability, resulting in the hepatic influx of abnormally high amounts of pathogen-associated molecular patterns, including lipopolysaccharide (LPS), through the portal circulation [ 1 ].…”