Mitochondria, oxidative stress and nonalcoholic fatty liver disease: A complex relationship

Abstract

According to the ‘multiple‐hit’ hypothesis, several factors can act simultaneously in nonalcoholic fatty liver disease (NAFLD) progression. Increased nitro‐oxidative (nitroso‐oxidative) stress may be considered one of the main contributors involved in the development and risk of NAFLD progression to nonalcoholic steatohepatitis (NASH) characterized by inflammation and fibrosis. Moreover, it has been repeatedly postulated that mitochondrial abnormalities are closely related to the development and progression of liver steatosis and NAFLD pathogenesis. However, it is difficult to determine with certainty whether mitochondrial dysfunction or oxidative stress are primary events or a simple consequence of NAFLD development. On the one hand, increasing lipid accumulation in hepatocytes could cause a wide range of effects from mild to severe mitochondrial damage with a negative impact on cell fate. This can start the cascade of events, including an increase of cellular reactive nitrogen species (RNS) and reactive oxygen species (ROS) production that promotes disease progression from simple steatosis to more severe NAFLD stages. On the other hand, progressing mitochondrial bioenergetic catastrophe and oxidative stress manifestation could be considered accompanying events in the vast spectrum of abnormalities observed during the transition from NAFL to NASH and cirrhosis. This review updates our current understanding of NAFLD pathogenesis and clarifies whether mitochondrial dysfunction and ROS/RNS are culprits or bystanders of NAFLD progression.

Oxidative Stress in Non-Alcoholic Fatty Liver Disease

“…Systemic OS and inflammation are also key factors in the pathogenesis of other diseases more or less closely related to fat accumulation and/or obesity, including atherosclerosis, insulin resistance, type 2 diabetes, and cancer [69,70]. It has recently been hypothesized that the increased OS and inflammation in NAFLD also promote the processes of aging [71,72]. On the contrary, it is known that caloric restriction and the consequent weight reduction have the effect of reduction of oxidation markers, increase of antioxidant defenses, and improvement of cardiovascular risk associated with obesity [73,74] (Figure 1).…”

“…Furthermore, along with the increased mitochondrial ROS production, decreased expression and activity of ROS detoxification mechanisms (e.g., SOD2, catalase, or GSH) have also been reported in in vitro and in vivo experiments. Thus, levels of ROS, lipid peroxidation, and apoptosis are increased in fatty liver disease and are even more so in NASH, suggesting that these processes drive the progression of NAFLD to NASH [72,153,159].…”

Impact of Genetic Polymorphism on Response to Therapy in Non-Alcoholic Fatty Liver Disease

“…Finally, other reported genetic determinants associated with NAFLD include SH2B Adaptor Protein 1 (SH2B1), superoxide dismutase 2 (SOD2), signal transducer and activator of transcription 3 (STAT3), phosphatidylethanolamine-N-methyltransferase (PEMT), apolipoprotein B (APOB) or uncoupling protein 2 (UCP2) [21]. Of note, there are some mitochondria-related SNPs among the NAFLD-associated genetic determinants, since mitochondria dysfunction increases oxidative stress which is closely related to NAFLD pathogenesis [22]. Thus, C47T variant in the mitochondrial enzyme SOD2 is linked to advanced fibrosis in NASH [23], whereas mitochondrial UCP2-866 G > A polymorphism reduces risk of NASH progression [24].…”

“…determinants, since mitochondria dysfunction increases oxidative stress which is closely related to NAFLD pathogenesis [22]. Thus, C47T variant in the mitochondrial enzyme SOD2 is linked to advanced fibrosis in NASH [23], whereas mitochondrial UCP2-866 G > A polymorphism reduces risk of NASH progression [24].…”

TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species

“…Many acute and chronic liver diseases are recognised. For almost all of these, oxidative stress and reactive oxygen species (ROS) play a significant role in the initiation and progression of the disease [1,[3][4][5][6][7][8][9]. Those liver diseases, or liver injuries, especially important when considering the role of oxidative stress, are acute liver injury caused by drug toxicity or ischemia-reperfusion injury, and the chronic liver diseases hepatitis B and C, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).…”