TFEB-Mediated Lysosomal Exocytosis Alleviates High-Fat Diet-Induced Lipotoxicity in the Kidney

Authors

Jun Nakamura
Takeshi Yamamoto
Yoshitsugu Takabatake
Tomoko Namba-Hamano
Satoshi Minami
Atsushi Takahashi
Jun Matsuda
Shinsuke Sakai
Hiroaki Yonishi
Shihomi Maeda
Sho Matsui
Isao Matsui
Takayuki Hamano
Masatomo Takahashi
Maiko Goto
Yoshihiro Izumi
Takeshi Bamba
Miwa Sasai
Masahiro Yamamoto
Taiji Matsusaka
Fumio Niimura
Motoko Yanagita
Shuhei Nakamura
Tamotsu Yoshimori
Andrea Ballabio
Yoshitaka Isaka

Publication Date

2-22-2023

Journal

JCI Insight

DOI

10.1172/jci.insight.162498

PMID

36649084

PMCID

PMC9977505

PubMedCentral® Posted Date

2-22-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Humans, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Diet, High-Fat, Exocytosis, Kidney, Lipids, Lysosomes, Obesity, Renal Insufficiency, Chronic, Metabolism, Nephrology, Chronic kidney disease, Lysosomes, Obesity

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.