TFEB-mediated lysosomal exocytosis alleviates high fat diet-induced lipotoxicity in the kidney

: Obesity is a major risk factor for end-stage kidney disease. We previously found that lysosomal dysfunction and impaired autophagic flux contributed to lipotoxicity in obesity-related kidney disease, both in humans and experimental animal models. However, the regulatory factors involved in countering renal lipotoxicity are largely unknown. Here we found that palmitic acid (PA) strongly promoted dephosphorylation and nuclear translocation of transcription factor EB (TFEB) by inhibiting the mechanistic target of rapamycin kinase complex 1 (MTORC1) pathway in a Rag GTPase-dependent manner, although these effects gradually diminished after extended treatment. We then investigated the role of TFEB in the pathogenesis of obesity-related kidney disease. Proximal tubular epithelial cell (PTEC)-specific Tfeb-deficient mice fed a high-fat diet (HFD) exhibited greater phospholipid accumulation in enlarged lysosomes, which manifested as multilamellar bodies (MLBs). Activated TFEB mediated lysosomal exocytosis of phospholipids, which help reduce MLB accumulation in PTECs. Furthermore, HFD-fed PTEC-specific Tfeb-deficient mice showed autophagic stagnation and exacerbated injury upon renal ischemia-reperfusion. Finally, higher body mass index was associated with increased vacuolation and decreased nuclear TFEB in the proximal tubules of chronic kidney disease patients. These results indicate a critical role of TFEB-mediated lysosomal exocytosis in counteracting renal lipotoxicity.