Mechanisms
of lipid-induced cellular injury in NAFLD. ROS are formed through oxidative
processes within the cell. In the mitochondria, impaired MRC activity leads to
the formation of superoxide anions and hydrogen peroxide. The accumulation of
fatty acids in the cytosol increases fatty acid oxidation in peroxisomes and
the ER. The initial reaction in peroxisomal β oxidation is catalyzed by
acyl-CoA oxidase (AOX) that forms hydrogen peroxide through the donation of
electrons to molecular oxygen. Microsomal w oxidation is catalyzed by
cytochrome P450 (CYP) enzymes 2E1, 4A10, and 4A14, which form ROS through
flavoprotein-mediated donation of electrons to molecular oxygen. PUFAs are
extremely susceptible to lipid peroxidation by ROS. By-products of PUFA
peroxidation are aldehydes, such as HNE and MDA. These aldehydes are themselves
cytotoxic and can freely diffuse into the extracellular space to affect distant
cells. ROS and aldehydes induce oxidative stress and cell death via ATP and NAD
depletion, DNA and protein damage, and glutathione depletion. Additionally,
they induce inflammation through the production of proinflammatory cytokines,
leading to neutrophil chemotaxis. Within the extracellular space, HNE and MDA
are themselves potent chemoattractants for neutrophils. Finally, ROS and
products of lipid peroxidation can lead to fibrosis by activating hepatic
stellate cells, which synthesize collagen and perpetuate the inflammatory
response.
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