Clarification of routes and molecular mechanisms underlying fatty acid uptake by tubular epithelial cells
| Project/Area Number |
20K08878
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 54040:Metabolism and endocrinology-related
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| Research Institution | Gunma University |
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Principal Investigator |
Iso Tatsuya 群馬大学, 大学院医学系研究科, 非常勤講師 (10400756)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 腎臓 / 脂肪酸 / 近位尿細管上皮細胞 / ネフロン / CD36 / 脂肪酸代謝 / 尿細管上皮細胞 |
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| Outline of Research at the Start |
腎臓は体液の恒常性を保つために機能するが、糸球体を通過する時点では、原尿中には糖やタンパクを含む多くの体液成分が含まれている。尿細管での再吸収過程において、生命維持に必要な成分（糖やタンパク）は再吸収され、老廃物は排出される。しかしながら、腎臓の最も重要なエネルギー基質である脂肪酸が、恒常的に原尿中に濾過されるか、それが再吸収されるか不明である。本研究では、腎臓における脂肪酸の取り込み機構（再吸収機構）を明らかにし、慢性腎臓病の病態生理の解明を目指す。
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| Outline of Final Research Achievements |
We investigated how fatty acids (FAs) are taken up by tubular epithelial cells (TECs) in mice by using in vivo FA tracing and histological methods. CD36, a well-known FA transporter, was abundantly expressed on the basolateral side of proximal TECs (PTECs). The uptake of 125I-BMIPP (a radiolabeled FA tracer) was significantly reduced in CD36-knockout kidneys shortly after injection. In vivo imaging with multiphoton microscopy revealed that BODIPY-C12 (a fluorescence-labeled FA tracer) accumulated on both the basolateral and apical sides of PTECs. Numerous lipid droplets accumulated in PTECs after accelerated lipolysis. Furthermore, PTEC-specific injury resulted in a compensatory increase in lipid accumulation in downstream TECs. Importantly, urinary FAs were undetectable, even in mice and humans with remarkable albuminuria. Our data demonstrate that renal TECs take up FAs from blood (CD36-dependent) and primary urine (CD36-independent) and can store excess FAs as neutral lipids.
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| Academic Significance and Societal Importance of the Research Achievements |
腎臓の脂肪酸取り込み機構が不明だったのには、大きく3つの要因があると思われる。一つ目は、原尿（管腔側）からの恒常的な脂肪酸取り込みの可能性について想定されてこなかったためである。2つ目は、アルブミンが恒常的に糸球体を一定程度通過するにも関わらず、それに伴う脂肪酸の原尿中への濾過の可能性について十分認知されてこなかったためである。3つ目は、二方向からの脂肪酸取り込みがあるため、一方の脂肪酸取り込み障害があっても、もう一方の取り込み増加によってマスクされてしまうからである。本申請課題は、これまでほとんど不明であった、腎臓の脂肪酸取り込み機構の全容解明に大きく貢献する独創性の高い重要な研究である。
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Report
(4 results)
Research Products
(34 results)
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[Journal Article] Urinary <scp>FABP1</scp> is a biomarker for impaired proximal tubular protein reabsorption and is synergistically enhanced by concurrent liver injury2021
Author(s)
Kawakami Ryo, Matsui Miki, Konno Ayumu, Kaneko Ryosuke, Shrestha Suman, Sunaga Hiroaki, Hanaoka Hirofumi, Goto Sawako, Hosojima Michihiro, Kabasawa Hideyuki, Obokata Masaru, Koitabashi Norimichi, Matsui Hiroki, Sasaki Tsutomu, Saito Akihiko, Yanagita Motoko, Hirai Hirokazu, Kurabayashi Masahiko, Iso Tatsuya
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Journal Title
The Journal of Pathology
Volume: 255
Issue: 4
Pages: 362-373
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Fatty acids are taken up from both basolateral and apical side in the kidney: Unappreciated mechanisms of fatty acid uptake by the kidney2023
Author(s)
Iso T, Kawakami R, Hanaoka H, Kanai A, Obinata H, Nakano D, Ikeuchi H, Hiromura K, Nishiyama A, Yanagita M, Ishii H, Kurabayashi M
Organizer
日本生理学会第100回記念大会
Related Report
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[Presentation] Unappreciated Mechanisms of Fatty Acid Uptake in the Kidney: Fatty Acids are Taken Up from Both Basolateral and Apical Side2022
Author(s)
Ryo Kawakami, Hirofumi Hanaoka, Ayaka Kanai, Hideru Obinata, Miki Matsui, Hiroki Matsui, Norimichi Koitabashi, Tomoyuki Yokoyama, Hideki Ishii, Masahiko Kurabayashi, Tatsuya Iso
Organizer
第86回日本循環器学会学術集会
Related Report
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[Presentation] Unappreciated Mechanisms of Fatty Acid Uptake in the Kidney: Fatty Acids are Taken Up from Both Basolateral and Apical Side2022
Author(s)
Ryo Kawakami, Hirofumi Hanaoka, Ayaka Kanai, Hideru Obinata, Miki Matsui, Hiroki Matsui, Norimichi Koitabashi, Tomoyuki Yokoyama, Hideki Ishii, Masahiko Kurabayashi, Tatsuya Iso.
Organizer
第86回日本循環器学会学術集会
Related Report
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[Presentation] Unappreciated mechanisms of fatty acid uptake in the kidney: Fatty acids are taken up from both basolateral and apical side2021
Author(s)
Kawakami R, Hanaoka H, Kanai A, Obinata H, Matsui M, Sunaga H, Matsui H, Koitabashi N, Yokoyama T, Kurabayashi M, Iso T.
Organizer
The 94th annual meeting of American Heart Association
Related Report
Int'l Joint Research
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[Presentation] Urinary fatty acid binding protein 1 is a biomarker for impaired proximal tubular protein reabsorption and is synergistically enhanced by concurrent liver injury2021
Author(s)
Kawakami R, Matsui M, Konno A, Kaneko R, Sunaga H, Hanaoka H, Obokata M, Matsui H, Koitabashi N, Hirai H, Kurabayashi M, Iso T.
Organizer
The 94th annual meeting of American Heart Association
Related Report
Int'l Joint Research
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[Presentation] Unappreciated mechanisms of fatty acid uptake in the kidney: Fatty acids are taken up from both basolateral and apical side2021
Author(s)
Kawakami R, Hanoka H, Kanai A, Obinata H, Nakano D, Matsui M, Matsui H, Koitabashi N, Yokoyama T, Nishiyama A, Saito A, Yanagita M, Kurabayashi M, Iso T.
Organizer
The 5th JCS Council Forum on Basic Cardio Vascular Research
Related Report
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[Presentation] Urinary FABP1 is a biomarker for impaired proximal tubular protein reabsorption and is synergistically enhanced by concurrent liver injury2021
Author(s)
Kawakami R, Matsui M, Konno A, Kaneko R, Hanaoka H, Matsui H, Koitabashi N, Saito A, Yanagita M, Hirai H, Kurabayashi M, Iso T
Organizer
The 5th JCS Council Forum on Basic Cardio Vascular Research
Related Report
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[Presentation] Unappreciated mechanisms of fatty acids handling in the kidney: Remarkable capability for fatty acid reabsorption2020
Author(s)
Kawakami R, Hanaoka H, Kanai A, Nakano D, Goto S, Sunaga H, Matsui H, Koitabashi N, Saito A, Nishiyama A, Yanagita M, Kurabayashi M, Iso T
Organizer
第24回日本心血管内分泌代謝学会学術集会
Related Report
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