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 pro-apoptopic effects of fatty acids. Given this link, endogenous anti-oxidant pathways have been a target of interest, with Nrf2 activation showing a reduction in oxidative stress and inflammation in models of MAFLD. Thyroid hormone receptor β (THRβ) agonists and nuclear peroxisome proliferation-activated receptor (PPAR) family have also gained interest in reducing hepatic lipotoxicity and restoring hepatic function in models of MAFLD. Unfortunately, the true interplay between the clinical and molecular components of MAFLD progression remain only partly understood. Most recently, multiomics-based strategies are being adopted for hypothesis-free analysis of the molecular changes in MAFLD. Transcriptome profiling maps the unique genotype-phenotype associations in MAFLD and with various single-cell transcriptome-based projects underway, there is hope of novel physiological insights to MAFLD progression and uncover therapeutic targets.

Keywords: Fatty liver disease; Metabolic-associated fatty liver disease; Non-alcoholic steatohepatitis; Oxidative stress; Reactive oxidation species.

Fig. 1. General overview of MAFLD pathogenesis. Schematic adapted from Akshintala et al and Cusi.,

Fig. 2. General overview of some aspects of mitochondrial dysfunction in metabolic associated liver disease as described in the text, diagram adapted from Wu et al.

Aerobic respiration with ATP synthase highlighted as essential co-factor in oxidative phosphorylation in making ATP. Fis1 is an outer mitochondrial membrane protein that interacts with DRP1 to initiate fission and damaged mitochondria purged by mitophagy. Healthy mitochondria fuse to continue network facilitated by MFN1/2.

Fig. 3. General overview of the potential pathophysiological mechanisms linking reactive oxygen species (ROS) to MAFLD development.,,,