Progression of Alcoholic and Non-alcoholic Steatohepatitis: Common Metabolic Aspects of Innate Immune System and Oxidative Stress

Abstract

Growing evidence indicates that the innate immune system and oxidative stress caused by gut-derived endotoxins play a key role in alcoholic liver disease (ALD). Intracellular mechanisms associated with endotoxin-induced signaling play a crucial role in the initiation and progression of ALD. It is now widely accepted that activation of the innate immune system and increased release of pro-inflammatory cytokines and other mediators play an important role in the development of ALD. Accumulating evidence suggests that alcohol-mediated upregulation of CYP2E1 expression may initiate lipid peroxidation via reactive oxygen species. Non-alcoholic steatohepatitis (NASH) is a liver disease characterized by histopathological features similar to those observed in ALD, but in the absence of significant alcohol consumption. Initial efforts to clarify the mechanisms that promote the progression from steatosis to steatohepatitis somewhat artificially divided disease mechanisms into "first and second hits." This model considered the development of steatosis to be the "first hit," increasing the sensitivity of the liver to the putative "second hit," leading to hepatocyte injury, inflammation, and oxidative stress. We have emphasized the important role of gut-derived bacterial toxins, the innate immune system, and oxidative stress in the common pathogenic mechanism in ALD and NASH progression.

Aloe veraGel Extract Attenuates Ethanol-Induced Hepatic Lipid Accumulation by Suppressing the Expression of Lipogenic Genes in Mice

“…Oxidative stress also seems to aggravate ethanol-induced fatty liver and elevates the GOT and GPT levels. 5,22,23,28) It has been reported that Aloe vera has an anti-oxidative effect 13) as well as an anti-inflammatory effect. 11,12) A previous study has shown that Aloe vera preserved such metabolizing enzymes as glutathione, glucose-6-phosphatase and microsomal aniline hydroxylase, and exhibited anti-oxidative activity through these enzymes.…”

Increase in Matrix Metalloproteinase-2 and 9 in the Liver of Nonalcoholic Steatohepatitis (NASH) Model Rats

“…In addition, oxidative stress plays an important role in the progression of NASH 13 . As we have shown in a previous study 11 , the diacron reactive oxidative metabolites d-ROMs test can be used as an indicator of oxidative stress.…”

Hfe-associated steatohepatitis: expression profiling and identifying the molecular basis of liver injury

“…TNFα activation via macrophages in response to gut-derived endotoxins plays a crucial role in the progression of ALD (190). In NASH as well, TNFα has been shown to be overexpressed in both adipose tissue and the liver, suggesting an important role for TNFα in the progression of NASH (183). In keeping with this, it is likely that endotoxins might also play a role in the pathogenesis of NASH (191,192).…”

“…ASH is characterized by steatosis as a result of excessive long-term alcohol intake, which results in disturbances of lipid metabolism such as inhibition of fatty acid oxidation and enhanced lipogenesis (183). Although the primary insult for the development of ASH and NASH is different, common mechanistic features in the development of liver injury exist which present clinically as similar serum and histological parameters.…”

“…Most patients with ASH have significant steatosis in more than 30 % of hepatocytes, and perivenular fibrosis and evidence from animal studies shows that 75 % of hepatocytes from alcohol fed animal's exhibit steatosis (183).…”