Reactive Oxygen Species and Oxidative Stress in the Pathogenesis of MAFLD

Abstract

The pathogenesis of metabolic-associated fatty liver disease (MAFLD) is complex and thought to be dependent on multiple parallel hits on a background of genetic susceptibility. The evidence suggests that MAFLD progression is a dynamic two-way process relating to repetitive bouts of metabolic stress and inflammation interspersed with endogenous anti-inflammatory reparative responses. In MAFLD, excessive hepatic lipid accumulation causes the production of lipotoxins that induce mitochondrial dysfunction, endoplasmic reticular stress, and over production of reactive oxygen species (ROS). Models of MAFLD show marked disruption of mitochondrial function and reduced oxidative capacitance with impact on cellular processes including mitophagy, oxidative phosphorylation, and mitochondrial biogenesis. In excess, ROS modify insulin and innate immune signaling and alter the expression and activity of essential enzymes involved in lipid homeostasis. ROS can also cause direct damage to intracellular structures causing hepatocyte injury and death. In select cases, the use of anti-oxidants and ROS scavengers have been shown to diminish the proapoptopic effects of fatty acids. Given this link, endogenous anti-oxidant pathways have been a target of interest, with

IPMK modulates FFA-induced insulin resistance in primary mouse hepatocytes

“…The elevated influx of FFA exceeding the metabolic capacity of hepatocytes causes incomplete beta-oxidation and mitochondrial dysfunction (Clare, Dillon, & Brennan, 2022), which leads to ROS and oxidative stress, ultimately resulting in insulin resistance (Hurrle & Hsu, 2017). ROS are associated with metabolic processes, and oxidized proteins are more efficiently degraded (Forrester, Kikuchi, Hernandes, Xu, & Griendling, 2018;Raynes, Pomatto, & Davies, 2016).…”

Nobiletin Ameliorates Hepatic Lipid Deposition, Oxidative Stress, and Inflammation by Mechanisms That Involve the Nrf2/NF-κB Axis in Nonalcoholic Fatty Liver Disease

“…As a result, unrestricted ROS attack mitochondrial membrane phospholipids and then, together with its end products such as malondialdehyde (MDA), exacerbate mitochondrial dysfunction, which further promotes the production of ROS . Furthermore, ROS can directly or indirectly promote the phosphorylation and nuclear translocation of NF-κB through multiple pathways, leading to the production of a large amount of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β. − On the other hand, high concentrations of glucose, insulin, and fatty acids within the liver can activate nuclear transcription factors including ChREBP, LXRα, and SREBP-1c. They will upregulate the mRNA expression levels of de novo lipogenesis (DNL)-related genes, including acyl-CoA carboxylase ( Acc1 ) and fatty acid synthase ( Fasn ), eventually facilitating liver DNL. , Accompanying the hyperfunction of liver DNL is the accumulation of saturated fatty acids, such as palmitic acid .…”

“…Furthermore, ROS can directly or indirectly promote the phosphorylation and nuclear translocation of NF-κB through multiple pathways, leading to the production of a large amount of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β. − On the other hand, high concentrations of glucose, insulin, and fatty acids within the liver can activate nuclear transcription factors including ChREBP, LXRα, and SREBP-1c. They will upregulate the mRNA expression levels of de novo lipogenesis (DNL)-related genes, including acyl-CoA carboxylase ( Acc1 ) and fatty acid synthase ( Fasn ), eventually facilitating liver DNL. , Accompanying the hyperfunction of liver DNL is the accumulation of saturated fatty acids, such as palmitic acid . As a major source of lipotoxicity, palmitic acid and its lipotoxic metabolites, including diacylglycerol and ceramides, can activate the NF-κB pathway through toll-like receptor 4 (TLR4) and induce an inflammatory response by releasing inflammatory factors, ultimately driving the transition from NAFL to NASH. , …”

“…They will upregulate the mRNA expression levels of de novo lipogenesis (DNL)-related genes, including acyl-CoA carboxylase (Acc1) and fatty acid synthase (Fasn), eventually facilitating liver DNL. 14,16 Accompanying the hyperfunction of liver DNL is the accumulation of saturated fatty acids, such as palmitic acid. 17 As a major source of lipotoxicity, palmitic acid and its lipotoxic metabolites, including diacylglycerol and ceramides, can activate the NF-κB pathway through toll-like receptor 4 (TLR4) and induce an inflammatory response by releasing inflammatory factors, ultimately driving the transition from NAFL to NASH.…”

LBP resists hepatic oxidative stress by regulating LD homeostasis

“…Oxidative stress is de ned as the excessive production of reactive oxygen species (ROS) relative to antioxidant defense, which is the main cause of hepatic steatosis and leads to obesity 3,4,5 . The neutral lipids of hepatocytes mainly accumulate in lipid droplets (LDs), which is considered a depot for rapid access to provide cells with fatty acids for energy production, membrane biosynthesis, and lipid signaling 6 .…”