Upregulation of LXRβ/ABCA1 pathway alleviates cochlear hair cell senescence of C57BL/6 J mice via reducing lipid droplet accumulation.

Abstract

Senescence and loss of cochlear hair cells is an important pathologic basis of age-related hearing loss. Lipid droplet accumulation has previously been shown to play an important role in neurodegeneration; however, its role in age-related hearing loss has not yet been investigated. LXRβ/ABCA1 is a key pathway that regulates lipid metabolism, while its dysfunction can cause abnormal accumulation of lipid droplets in neurons, leading to neurodegeneration. In this study, we found that decreased expression of LXRβ/ABCA1, elevated levels of lipid droplet accumulation, and increased activation of the NLRP3 inflammasome were demonstrated in senescent cochlear hair cells in both animal and cellular models of age-related hearing loss. We then manipulated the LXRβ/ABCA1 pathway transduction of cochlear hair cells. Upregulation of LXRβ/ABCA1 in senescent hair cells was found to reduce the accumulation of lipid droplets, inhibit NLRP3 inflammasome activation, and ultimately alleviate cochlear hair cell senescence. In our study, we also found that NLRP3 inflammasome activation can abrogate the alleviated effect of LXRβ/ABCA1 pathway on the senescence of cochlear hair cells but did not affect the expression of LXRβ/ABCA1.Our study are the first to demonstrate that abnormal lipid droplet accumulation and decreased LXRβ/ABCA1 pathway are observed in cochlear hair cells following the occurrence of age-related hearing loss. Upregulation of LXRβ/ABCA1 in senescent cochlear hair cells can reduce lipid droplet accumulation in cochlear hair cells and alleviate their senescence, which may be related to the inhibition of NLRP3 inflammasome activation. These findings provide potential targets for the treatment of age-related hearing loss.