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TFEB-mediated lysosomal exocytosis alleviates high-fat diet-induced lipotoxicity in the kidney
Jun Nakamura1, Takeshi Yamamoto1, Yoshitsugu Takabatake1
1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
Abstract:
Obesity is a major risk factor for end-stage kidney disease. We previously found that lysosomal dysfunction and impaired autophagic flux contribute to lipotoxicity in obesity-related kidney disease, in both humans and experimental animal models. However, the regulatory factors involved in countering renal lipotoxicity are largely unknown. Here, we found that palmitic acid strongly promoted dephosphorylation and nuclear translocation of transcription factor EB (TFEB) by inhibiting the mechanistic target of rapamycin kinase complex 1 pathway in a Rag GTPase-dependent manner, though 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-specific (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 helped 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 patients with chronic kidney disease. These results indicate a critical role of TFEB-mediated lysosomal exocytosis in counteracting renal lipotoxicity.
Insights
Transcription factor EB (TFEB) counters kidney lipotoxicity by promoting lysosomal exocytosis of phospholipids. TFEB deficiency worsens kidney injury in obesity, highlighting its protective role in kidney disease.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Obesity is a primary risk factor for end-stage kidney disease.
- Lysosomal dysfunction and impaired autophagic flux contribute to lipotoxicity in obesity-related kidney disease.
- Regulatory factors mitigating renal lipotoxicity remain largely unknown.
Purpose of the Study:
- To investigate the role of transcription factor EB (TFEB) in counteracting renal lipotoxicity.
- To elucidate the mechanisms by which TFEB influences kidney health in obesity-related disease.
Main Methods:
- Utilized palmitic acid to study TFEB regulation in vitro.
- Generated proximal tubular epithelial cell-specific Tfeb-deficient mice fed a high-fat diet (HFD).
- Assessed lysosomal function, autophagic flux, and kidney injury markers.
Main Results:
- Palmitic acid induced TFEB dephosphorylation and nuclear translocation via mTORC1/Rag GTPase pathway.
- PTEC-specific Tfeb-deficient mice on HFD showed increased phospholipid accumulation (MLBs) and autophagic stagnation.
- TFEB activation mediated lysosomal exocytosis, reducing MLB accumulation.
- Tfeb deficiency exacerbated kidney injury following ischemia/reperfusion.
- Human CKD patients with higher BMI had decreased nuclear TFEB and increased proximal tubule vacuolation.
Conclusions:
- TFEB plays a critical role in mitigating renal lipotoxicity through lysosomal exocytosis.
- TFEB deficiency exacerbates kidney injury in obesity-related kidney disease.
- TFEB represents a potential therapeutic target for obesity-related kidney disease.
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