Fig. 8: The proposed model of lipid metabolism dysregulation caused by PGC1A deficiency in the RPE. | Cell Death & Disease

Fig. 8: The proposed model of lipid metabolism dysregulation caused by PGC1A deficiency in the RPE.

From: PGC-1α repression dysregulates lipid metabolism and induces lipid droplet accumulation in the retinal pigment epithelium

Fig. 8

PGC1A deficiency downregulated lipid metabolism-related transcription factors such as PPARs and LXRs, reduced fatty acid β-oxidation (FAO), affected active fatty acid (FA) transportation and low-density lipoprotein (LDL) uptake, and decreased cholesterol efflux. Furthermore, PGC1A repression may reduce triglyceride biosynthesis by downregulating the expression of DGAT1/2 while promoting cholesterol esterification by increasing SOAT1/2 protein levels. Inhibition of PGC1A decreased the inhibitory phosphorylation of HMGCR by AMPK, increasing HMGCR activity and promoting cholesterol synthesis. These changes ultimately contributed to the accumulation of lipid droplets. In addition, the repression of PGC1A led to reduced mitochondrial mass, lower mitochondrial membrane potential, and decreased cardiolipin content, further hindering FAO. Moreover, accumulation of lipids or fatty acids in the cytoplasm increased lipid peroxidation, especially under elevated levels of reactive oxygen species (ROS), resulting from deficiencies in antioxidant enzymes. As a result, dysregulated lipid metabolism and mitochondrial dysfunction caused by PGC1A inhibition can lead to RPE cell death and degeneration.

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