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ResearchIn-Press PreviewMetabolismNephrology Open Access | 10.1172/jci.insight.162498

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

Jun Nakamura,1 Takeshi Yamamoto,1 Yoshitsugu Takabatake,1 Tomoko Namba-Hamano,1 Satoshi Minami,1 Atsushi Takahashi,1 Jun Matsuda,1 Shinsuke Sakai,1 Hiroaki Yonishi,1 Shihomi Maeda,1 Sho Matsui,1 Isao Matsui,1 Takayuki Hamano,2 Masatomo Takahashi,3 Maiko Goto,3 Yoshihiro Izumi,3 Takeshi Bamba,3 Miwa Sasai,4 Masahiro Yamamoto,4 Taiji Matsusaka,5 Fumio Niimura,6 Motoko Yanagita,7 Shuhei Nakamura,8 Tamotsu Yoshimori,8 Andrea Ballabio,9 and Yoshitaka Isaka1

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Nakamura, J. in: JCI | PubMed | Google Scholar

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Yamamoto, T. in: JCI | PubMed | Google Scholar

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Takabatake, Y. in: JCI | PubMed | Google Scholar |

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Namba-Hamano, T. in: JCI | PubMed | Google Scholar |

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Minami, S. in: JCI | PubMed | Google Scholar |

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Takahashi, A. in: JCI | PubMed | Google Scholar

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Matsuda, J. in: JCI | PubMed | Google Scholar

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Sakai, S. in: JCI | PubMed | Google Scholar

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Yonishi, H. in: JCI | PubMed | Google Scholar |

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Maeda, S. in: JCI | PubMed | Google Scholar

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Matsui, S. in: JCI | PubMed | Google Scholar

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Matsui, I. in: JCI | PubMed | Google Scholar |

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Hamano, T. in: JCI | PubMed | Google Scholar |

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Takahashi, M. in: JCI | PubMed | Google Scholar |

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Goto, M. in: JCI | PubMed | Google Scholar

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Izumi, Y. in: JCI | PubMed | Google Scholar |

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Bamba, T. in: JCI | PubMed | Google Scholar |

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Sasai, M. in: JCI | PubMed | Google Scholar |

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Yamamoto, M. in: JCI | PubMed | Google Scholar |

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Matsusaka, T. in: JCI | PubMed | Google Scholar

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Niimura, F. in: JCI | PubMed | Google Scholar

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Yanagita, M. in: JCI | PubMed | Google Scholar |

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Nakamura, S. in: JCI | PubMed | Google Scholar

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Yoshimori, T. in: JCI | PubMed | Google Scholar

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Ballabio, A. in: JCI | PubMed | Google Scholar

1Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

2Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

3Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

5Institute of Medical Sciences and Department of Basic Sciences, Tokai University School of Medicine, Kanagawa, Japan

6Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

7Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan

8Department of Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

9Via Campi Flegrei 34, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

Find articles by Isaka, Y. in: JCI | PubMed | Google Scholar

Published January 17, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.162498.
Copyright © 2023, Nakamura et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 17, 2023 - Version history
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Abstract

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.

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