Age-related TFEB downregulation in proximal tubules causes systemic metabolic disorders and occasional apolipoprotein A4–related amyloidosis

Nakamura, Jun; Yamamoto, Takeshi; Takabatake, Yoshitsugu; Namba-Hamano, Tomoko; Takahashi, Atsushi; Matsuda, Jun; Minami, Satoshi; Sakai, Shinsuke; Yonishi, Hiroaki; Maeda, Shihomi; Matsui, Sho; Kawai, Hideaki; Matsui, Isao; Yamamuro, Tadashi; Edahiro, Ryuya; Takashima, Seiji; Takasawa, Akira; Okada, Yukinori; Yoshimori, Tamotsu; Ballabio, Andrea; Isaka, Yoshitaka

doi:https://doi.org/10.1172/jci.insight.184451

Age-related TFEB downregulation in proximal tubules causes systemic metabolic disorders and occasional apolipoprotein A4–related amyloidosis

Nakamura, Jun; Yamamoto, Takeshi; Takabatake, Yoshitsugu et al.

JCI Insight, 2025, 10(3), e184451

Number of Access:3,976（2025-07-23 08:39 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/100437

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Title	Age-related TFEB downregulation in proximal tubules causes systemic metabolic disorders and occasional apolipoprotein A4–related amyloidosis
Creator	NRID 1000010846679 1000010846679 CreatorName Nakamura, Jun
	NRID 1000020756994 1000020756994 ORCID 0009-0007-3817-0557 0009-0007-3817-0557 researchmap permalink tyamamoto-handai3857 tyamamoto-handai3857 Scopus Author ID 55628566248 55628566248 CreatorName Yamamoto, Takeshi
	NRID 1000030403075 1000030403075 CreatorName Takabatake, Yoshitsugu
	NRID 1000030734420 1000030734420 researchmap permalink namba-handai3857 namba-handai3857 Scopus Author ID 8577526800 8577526800 CreatorName Namba-Hamano, Tomoko
	NRID 1000010704786 1000010704786 researchmap permalink takahashi-handai3857 takahashi-handai3857 Scopus Author ID 55728349700 55728349700 CreatorName Takahashi, Atsushi
	NRID 1000010778260 1000010778260 researchmap permalink jun_matsuda jun_matsuda ORCID 0000-0003-1492-6157 0000-0003-1492-6157 CreatorName Matsuda, Jun
	NRID 1000000791592 1000000791592 ORCID 0000-0001-5043-3435 0000-0001-5043-3435 researchmap permalink minami415 minami415 Scopus Author ID 57188809277 57188809277 CreatorName Minami, Satoshi
	NRID 1000060817360 1000060817360 CreatorName Sakai, Shinsuke
	NRID 1000040822143 1000040822143 CreatorName Yonishi, Hiroaki
	CreatorName Maeda, Shihomi
	NRID 1000070974286 1000070974286 CreatorName Matsui, Sho
	CreatorName Kawai, Hideaki
	NRID 1000060456986 1000060456986 ORCID 0000-0001-8378-6130 0000-0001-8378-6130 researchmap permalink matsui-handai3857 matsui-handai3857 Scopus Author ID 24488796300 24488796300 CreatorName Matsui, Isao
	CreatorName Yamamuro, Tadashi
	researchmap permalink ryuya_edahiro_88 ryuya_edahiro_88 CreatorName Edahiro, Ryuya
	NRID 1000090379272 1000090379272 researchmap permalink read0118567 read0118567 Scopus Author ID 7402272558 7402272558 CreatorName Takashima, Seiji
	NRID 1000000593021 1000000593021 CreatorName Takasawa, Akira
	NRID 1000070727411 1000070727411 ORCID 0000-0002-0311-8472 0000-0002-0311-8472 researchmap permalink yokada yokada Scopus Author ID 7005443464 7005443464 CreatorName Okada, Yukinori
	NRID 1000060191649 1000060191649 researchmap permalink read0085516 read0085516 CreatorName Yoshimori, Tamotsu
	CreatorName Ballabio, Andrea
	NRID 1000000379166 1000000379166 researchmap permalink isaka-handai3857 isaka-handai3857 Scopus Author ID 16207611100 16207611100 ORCID 0000-0002-0820-7167 0000-0002-0820-7167 CreatorName Isaka, Yoshitaka
Description	Nakamura J., Yamamoto T., Takabatake Y., et al. Age-related TFEB downregulation in proximal tubules causes systemic metabolic disorders and occasional apolipoprotein A4–related amyloidosis. JCI Insight 10, e184451 (2025); https://doi.org/10.1172/jci.insight.184451.
Abstract	With the aging of society, the incidence of chronic kidney disease (CKD), a common cause of death, has been increasing. Transcription factor EB (TFEB), the master transcriptional regulator of the autophagy/lysosomal pathway, is regarded as a promising candidate for preventing various age-related diseases. However, whether TFEB in the proximal tubules plays a significant role in elderly patients with CKD remains unknown. First, we found that nuclear TFEB localization in proximal tubular epithelial cells (PTECs) declined with age in both mice and humans. Next, we generated PTEC-specific Tfeb-deficient mice and bred them for up to 24 months. We found that TFEB deficiency in the proximal tubules caused metabolic disorders and occasionally led to apolipoprotein A4 (APOA4) amyloidosis. Supporting this result, we identified markedly decreased nuclear TFEB localization in the proximal tubules of elderly patients with APOA4 amyloidosis. The metabolic disturbances were accompanied by mitochondrial dysfunction due to transcriptional changes involved in fatty acid oxidation and oxidative phosphorylation pathways, as well as decreased mitochondrial clearance. This decreased clearance was reflected by the accumulation of mitochondria–lysosome-related organelles, which depended on lysosomal function. These results shed light on the presumptive mechanisms of APOA4 amyloidosis pathogenesis and provide a therapeutic strategy for CKD-related metabolic disorders and APOA4 amyloidosis.
Publisher	American Society for Clinical Investigation
Source Title	JCI Insight
Volume (Issue)	10(3)
Page	e184451
Date of Issued	2025-02-10
Language	English
Handle URL	https://hdl.handle.net/11094/100437
eISSN	23793708
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1172/jci.insight.184451
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCTERMS.bibliographicCitation	JCI Insight. 2025, 10(3), p. e184451
DC.title	Age-related TFEB downregulation in proximal tubules causes systemic metabolic disorders and occasional apolipoprotein A4–related amyloidosis
DC.creator	Nakamura, Jun
	Yamamoto, Takeshi
	Takabatake, Yoshitsugu
	Namba-Hamano, Tomoko
	Takahashi, Atsushi
	Matsuda, Jun
	Minami, Satoshi
	Sakai, Shinsuke
	Yonishi, Hiroaki
	Maeda, Shihomi
	Matsui, Sho
	Kawai, Hideaki
	Matsui, Isao
	Yamamuro, Tadashi
	Edahiro, Ryuya
	Takashima, Seiji
	Takasawa, Akira
	Okada, Yukinori
	Yoshimori, Tamotsu
	Ballabio, Andrea
	Isaka, Yoshitaka
DC.publisher	American Society for Clinical Investigation
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-02-10
DC.identifier	https://doi.org/10.1172/jci.insight.184451
DC.description	Nakamura J., Yamamoto T., Takabatake Y., et al. Age-related TFEB downregulation in proximal tubules causes systemic metabolic disorders and occasional apolipoprotein A4–related amyloidosis. JCI Insight 10, e184451 (2025); https://doi.org/10.1172/jci.insight.184451.
DCTERMS.abstract	With the aging of society, the incidence of chronic kidney disease (CKD), a common cause of death, has been increasing. Transcription factor EB (TFEB), the master transcriptional regulator of the autophagy/lysosomal pathway, is regarded as a promising candidate for preventing various age-related diseases. However, whether TFEB in the proximal tubules plays a significant role in elderly patients with CKD remains unknown. First, we found that nuclear TFEB localization in proximal tubular epithelial cells (PTECs) declined with age in both mice and humans. Next, we generated PTEC-specific Tfeb-deficient mice and bred them for up to 24 months. We found that TFEB deficiency in the proximal tubules caused metabolic disorders and occasionally led to apolipoprotein A4 (APOA4) amyloidosis. Supporting this result, we identified markedly decreased nuclear TFEB localization in the proximal tubules of elderly patients with APOA4 amyloidosis. The metabolic disturbances were accompanied by mitochondrial dysfunction due to transcriptional changes involved in fatty acid oxidation and oxidative phosphorylation pathways, as well as decreased mitochondrial clearance. This decreased clearance was reflected by the accumulation of mitochondria–lysosome-related organelles, which depended on lysosomal function. These results shed light on the presumptive mechanisms of APOA4 amyloidosis pathogenesis and provide a therapeutic strategy for CKD-related metabolic disorders and APOA4 amyloidosis.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	100437
citation_title	Age-related TFEB downregulation in proximal tubules causes systemic metabolic disorders and occasional apolipoprotein A4–related amyloidosis
citation_author	Nakamura, Jun
	Yamamoto, Takeshi
	Takabatake, Yoshitsugu
	Namba-Hamano, Tomoko
	Takahashi, Atsushi
	Matsuda, Jun
	Minami, Satoshi
	Sakai, Shinsuke
	Yonishi, Hiroaki
	Maeda, Shihomi
	Matsui, Sho
	Kawai, Hideaki
	Matsui, Isao
	Yamamuro, Tadashi
	Edahiro, Ryuya
	Takashima, Seiji
	Takasawa, Akira
	Okada, Yukinori
	Yoshimori, Tamotsu
	Ballabio, Andrea
	Isaka, Yoshitaka
citation_publisher	American Society for Clinical Investigation
citation_language	English
citation_date	2025-02-10
citation_journal_title	JCI Insight
citation_volume	10
citation_issue	3
citation_firstpage	e184451
citation_doi	https://doi.org/10.1172/jci.insight.184451
citation_public_url	https://hdl.handle.net/11094/100437

Age-related TFEB downregulation in proximal tubules causes systemic metabolic disorders and occasional apolipoprotein A4–related amyloidosis

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