Monday, July 9, 2018

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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