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Review
. 2008 Apr 1;44(7):1259-72.
doi: 10.1016/j.freeradbiomed.2007.12.029. Epub 2008 Jan 3.

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Sudheer K Mantena  1 , Adrienne L King, Kelly K Andringa, Heather B Eccleston, Shannon M Bailey
Affiliations
Review

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Sudheer K Mantena et al. Free Radic Biol Med. .

Abstract

Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits." Genetic risk factors can also influence the susceptibility to and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunction are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: (1) the "two-hit" or "multi-hit" hypothesis, (2) the role of mitochondrial bioenergetic defects and oxidant stress, (3) the interplay between NO and mitochondria in fatty liver disease, (4) genetic risk factors and oxidative stress-responsive genes, and (5) the feasibility of antioxidants for treatment.

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Figures

Figure 1
Figure 1. Pathophysiology of alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH)
Figure 2
Figure 2. Alcohol and obesity induced mitochondrial dysfunction and oxidative stress
Alcohol and obesity disrupt the functioning of the oxidative phosphorylation (OxPhos) system which results in the generation of superoxide (O2• − ) within Complexes I and III. The O2• − is dismutated to hydrogen peroxide (H2O2) by manganese superoxide dismutase (MnSOD) that can then diffuse from the mitochondrion into the cytoplasm to affect cellular redox signaling pathways. Alcohol and obesity also cause an increase in iNOS expression that leads to diffusion of nitric oxide (NO) into mitochondria where it inhibits cytochrome c oxidase; reacts with O2• − to form highly reactive peroxynitrite (ONOO− ). Hydrogen peroxide, O2• − , and ONOO− can initiate reactions that lead to increased generation of reactive lipid species (RLS), induce post-translational modification of proteins, and damage mitochondrial DNA (mtDNA).
Figure 3
Figure 3. Proposed therapeutic agents for the treatment of fatty liver diseases
See this image and copyright information in PMC

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