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.

P-Hydroxyacetophenone Ameliorates Alcohol-Induced Steatosis and Oxidative Stress via the NF-κB Signaling Pathway in Zebrafish and Hepatocytes

“…Alcohol abuse affects liver regulation of lipid metabolism and synthesis, leading to hepatocyte steatosis, which is the earliest histopathologic marker of ALD. In addition to lipid regulation abnormalities, ethanol-induced oxidative stress plays an important role in acute liver injury, as hepatocytes are the main cell types involved in ethanol metabolism (Garcia-Ruiz and Fernandez-Checa, 2018). When the concentration of ethanol is increased, ROS are generated by another alcohol-metabolizing enzyme, CYP2E1 (Leung and Nieto, 2013), which metabolizes ethanol to acetaldehyde, thus decreasing hepatic antioxidant defenses, especially GSH (Dai et al, 2003;Lu and Cederbaum, 2018).…”

Adaptation of Mitochondrial Substrate Flux in a Mouse Model of Nonalcoholic Fatty Liver Disease

“…Competition between substrates and excessive mixed nutrient entry into the ETS not matched by energy demand may overload the ETS, resulting in ROS production [32]. Oxidative stress is thought to play a significant role in NAFLD and NASH progression, although a cause-and-effect type of relationship has not yet been established [33,34]. Considering the level of GSH and malondialdehyde (MDA), we did not observe a difference in oxidative stress in the mice fed the WD in comparison with control animals.…”

Molecular links between non-alcoholic fatty liver disease and hepatocellular carcinoma

“…The excessive accumulation of these fatty acids increases β-oxidation and ROS production, which can limit mitochondrial function [62] . When these mitochondrial abnormalities are accompanied by diminished intracellular antioxidant protection in NASH, pathways of fatty acid metabolism are altered [63] , which, in turn, can cause metabolic stress [63] .…”