Activation of LXRs Reduces Oxysterol Lipotoxicity in RPE Cells by Promoting Mitochondrial Function

Abstract

Effective treatments for age-related macular degeneration (AMD), the most prevalent neurodegenerative form of blindness in older adults, are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic changes. Liver X receptors (LXRs) play a critical role in intracellular homeostases, such as lipid metabolism, glucose homeostasis, inflammation, and mitochondrial function. However, its specific role in AMD and its underlying molecular mechanisms remain unknown. In this study, we investigated the effects of lipotoxicity in human retinal pigmental epithelial (ARPE-19) cells and evaluated how LXRs reduce 7-ketocholesterol (7KCh) lipotoxicity in RPE cells using models, both in vivo and in vitro. A decrease in oxidative lipid accumulation was observed in mouse retinas following the activation of the LXRs; this result was also confirmed in cell experiments. At the same time, LXRs activation reduced RPE cell apoptosis induced by oxysterols. We found that oxysterols decreased the mitochondrial membrane potential in ARPE-19 cells, while LXR agonists counteracted these effects. In cultured ARPE-19 cells, activating LXRs reduced p62, mTOR, and LC3I/II levels, and the knockdown of LXRs elevated the expression of these proteins, indicating that activating LXRs could boost mitophagy. The findings of this study suggest LXR-active pharmaceuticals as a potential therapeutic target for dry AMD.

Identification of 7-Ketocholesterol-Modulated Pathways and Sterculic Acid Protective Effect in Retinal Pigmented Epithelium Cells by Using Genome-Wide Transcriptomic Analysis

“…These genes are transcriptionally regulated by LXR (liver X receptor), which is activated by oxysterol-binding [45]. The role of LXR in the 7KCh response is controversial; whereas some authors showed that its activation counteracts 7KCh signaling [47][48][49], others demonstrated that LXR mediates cytokine release and cell death induced by this oxysterol [15,50]. A possible explanation of our results is that the cell mistakenly reacts to the presence of oxysterols as an excess of cholesterol and, in response, sterol biosynthesis is repressed, and cholesterol transport is favored.…”

Cholesterol metabolism: physiological regulation and diseases

“…Through further investigation, we found that the activation of LXR can reduce the apoptosis of RPE cells induced by oxysterol by maintaining mitochondrial membrane stasis, which jointly activates mitochondrial autophagy via the mTOR/p62 pathway to promote mitochondrial metabolism. 206 In addition to the above regulatory proteins, other molecular signals that increase the expression of ABCA1/ ABCG1 can also promote cholesterol efflux from cells and reduce the accumulation of ox-LDL, delaying disease progression.…”