期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms10353
关键词
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资金
- l'Association Francaise contre l'Amylose
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- French National Reference Center for AL amyloidosis
- UK NHS Research and Development funds
- University College London Amyloidosis Research Fund
- UK Medical Research Council [MR/K000187/1]
- Rosetrees Trust/Royal Free Charity PhD programme [M427]
- British Heart Foundation [PG08/008]
- Wellcome Trust Investigator Award [097806/Z/11/Z]
- Cariplo Foundation Projects [2014-0700, 2013-0964]
- Telethon Grant [GG14127]
- INBB (National Institute of Biostructures and Biosystems)
- Italian Ministry of Health
- Italian Ministry of University and Research [FIRB RBFR109EOS]
- Medical Research Council [MC_U117533887, MR/K000187/1] Funding Source: researchfish
- Rosetrees Trust [M427] Funding Source: researchfish
- The Francis Crick Institute [10029] Funding Source: researchfish
- MRC [MR/K000187/1, MC_U117533887] Funding Source: UKRI
- NATIONAL CANCER INSTITUTE [P30CA008748] Funding Source: NIH RePORTER
Apolipoprotein C-III deficiency provides cardiovascular protection, but apolipoprotein C-III is not known to be associated with human amyloidosis. Here we report a form of amyloidosis characterized by renal insufficiency caused by a new apolipoprotein C-III variant, D25V. Despite their uremic state, the D25V-carriers exhibit low triglyceride (TG) and apolipoprotein C-III levels, and low very-low-density lipoprotein (VLDL)/high high-density lipoprotein (HDL) profile. Amyloid fibrils comprise the D25V-variant only, showing that wild-type apolipoprotein C-III does not contribute to amyloid deposition in vivo. The mutation profoundly impacts helical structure stability of D25V-variant, which is remarkably fibrillogenic under physiological conditions in vitro producing typical amyloid fibrils in its lipid-free form. D25V apolipoprotein C-III is a new human amyloidogenic protein and the first conferring cardioprotection even in the unfavourable context of renal failure, extending the evidence for an important cardiovascular protective role of apolipoprotein C-III deficiency. Thus, fibrate therapy, which reduces hepatic APOC3 transcription, may delay amyloid deposition in affected patients.
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