Mitochondrial Oxidative Stress and Antioxidants Balance in Fatty Liver Disease

Abstract

Fatty liver disease is one of the most prevalent forms of chronic liver disease that encompasses both alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are intermediate stages of ALD and NAFLD, which can progress to more advanced forms, including cirrhosis and hepatocellular carcinoma. Oxidative stress and particularly alterations in mitochondrial function are thought to play a significant role in both ASH and NASH and recognized to contribute to the generation of reactive oxygen species (ROS), as documented in experimental models. Despite the evidence of ROS generation, the therapeutic efficacy of treatment with antioxidants in patients with fatty liver disease has yielded poor results. Although oxidative stress is considered to be the disequilibrium between ROS and antioxidants, there is evidence that a subtle balance among antioxidants, particularly in mitochondria, is necessary to avoid the generation of ROS and hence oxidative stress. Conclusion: As mitochondria are a major source of ROS, the present review summarizes the role of mitochondrial oxidative stress in ASH and NASH and presents emerging data indicating the need to preserve mitochondrial antioxidant balance as a potential approach for the treatment of human fatty liver disease, which may pave the way for the design of future trials to test the therapeutic role of antioxidants in fatty liver disease.

Figure 1

Mitochondrial ROS generation and antioxidant strategies. Oxygen consumption is a major driving force for ATP generation in the MRC. However, a collateral consequence of the OXPHOS is the transfer of electrons to molecular oxygen, resulting in the formation of superoxide anion. Because a superoxide anion is a highly reactive free radical, its down‐regulation is ensured by the presence of SOD2, which dismutates superoxide anion into hydrogen peroxide. The elimination of this oxidant is essential to prevent the generation of more reactive species by the Haber–Weiss/Fenton reactions. Hydrogen peroxide can be eliminated by the presence of several strategies, the mGSH/Gpx and the PrxIII/Trx2 couples, thus denoting the relevance of its catabolism (see “Oxidative Stress: Concept, Sources, and Defenses” section). Essential for appropriate GSH redox function is the availability of mGSH, determined from its import from cytosol by a specific process mediated by the 2‐oxoglutarate carrier. Abbreviation: 2‐OG, 2‐oxoglutarate carrier.

Figure 2

Critical antioxidant balance to prevent ROS generation and oxidative stress in fatty liver disease. (A) ROS generation and antioxidant defense status in fatty liver disease. Increased generation of superoxide anion within the MRC, which can be exacerbated by decreased levels/activity of SOD2. The increased generation of superoxide anion facilitates the formation of peroxynitrite from NO. In addition to impaired SOD2 defense, mGSH depletion contributes to limit defense against hydrogen peroxide detoxification. (B) The decreased status of SOD2 provides a rationale for the use of SOD mimetics, which decreases superoxide anion formation as well as the generation of peroxynitrite. However, because of the limitation of mGSH, the SOD mimetics results in the accumulation of hydrogen peroxide. (C) The use of both SOD mimetics with the replenishment of mGSH by the GSHEE, a permeable form of GSH prodrugs, results in the net decrease of superoxide anion, peroxynitrite, and hydrogen peroxide.