Metabolic dysfunction-associated steatotic liver disease-induced changes in the antioxidant system: a review

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous condition characterized by liver steatosis, inflammation, consequent fibrosis, and cirrhosis. Chronic impairment of lipid metabolism is closely related to oxidative stress, leading to cellular lipotoxicity, mitochondrial dysfunction, and endoplasmic reticulum stress. The detrimental effect of oxidative stress is usually accompanied by changes in antioxidant defense mechanisms, with the alterations in antioxidant enzymes expression/activities during MASLD development and progression reported in many clinical and experimental studies. This review will provide a comprehensive overview of the present research on MASLD-induced changes in the catalytic activity and expression of the main antioxidant enzymes (superoxide dismutases, catalase, glutathione peroxidases, glutathione S-transferases, glutathione reductase, NAD(P)H:quinone oxidoreductase) and in the level of non-enzymatic antioxidant glutathione. Furthermore, an overview of the therapeutic effects of vitamin E on antioxidant enzymes during the progression of MASLD will be presented. Generally, at the beginning of MASLD development, the expression/activity of antioxidant enzymes usually increases to protect organisms against the increased production of reactive oxygen species. However, in advanced stage of MASLD, the expression/activity of several antioxidants generally decreases due to damage to hepatic and extrahepatic cells, which further exacerbates the damage. Although the results obtained in patients, in various experimental animal or cell models have been inconsistent, taken together the importance of antioxidant enzymes in MASLD development and progression has been clearly shown.

Keywords: Antioxidant enzyme; Catalytic activity; Expression; Glutathione; Metabolic dysfunction-associated steatotic liver disease.

Fig. 1

Progression of the metabolic dysfunction-associated steatotic liver disease. MASLD encompasses a broad clinical spectrum of liver damage. First, when exposed to some risk factors (e.g. insulin resistance, type 2 diabetes mellitus, obesity, hypertension, dyslipidemia) simple macrovesicular steatosis (MASL) develops in the liver of predisposed individuals. This form may progress to a more severe form of metabolic dysfunction-associated steatohepatitis (MASH), with combined inflammation, fibrosis, hepatocyte damage, and liver steatosis. Eventually, the disease may further advance to liver fibrosis, which carries the potential to escalate into life-threatening conditions such as liver cirrhosis and hepatocellular carcinoma

Fig. 2

Oxidative and nitrosative stress in MASLD. Oxidative and nitrosative stress are recognized as the significant contributors to hepatocellular injury in MASLD and the critical drivers of the transition from MASL to MASH. In the cell, reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated by several mechanisms comprising catalytic activity of various enzymes (e.g. cyclooxygenase, lipoxygenase, nitric oxide synthase, NADPH oxidase), oxidative protein folding in endoplasmic reticulum, ω-oxidation of free fatty acids catalyzed by cytochrome P450 (CYP) 2E1 and CYP4A11 in peroxisomes and microsomes, the effect of pro-inflammatory cytokines, and mitochondrial respiratory chain. Oxidative and nitrosative stress are associated with widespread protein oxidation and carbonylation, lipid peroxidation, and DNA oxidation, which reduces the antioxidative capacity and shifts the intracellular redox status toward an oxidized state. Expression and/or activity of antioxidant enzymes as well as intracellular levels of glutathione can be altered. Abbreviations: CAT catalase; COX cyclooxygenase; GPx glutathione peroxidase; GR glutathione reductase; GSH glutathione; GST glutathione S-transferase; LOX lipoxygenase; NOS nitric oxide synthase; NOX NADPH oxidase; NQO1 NAD(P)H quinone oxidoreductase; SOD superoxide dismutase