The NERP-4-SNAT2 axis regulates pancreatic β-cell maintenance and function

被引：2

作者：

Zhang, Weidong ^{[1
,2
]}

Miura, Ayako ^{[2
,11
]}

Abu Saleh, Md Moin ^{[2
,12
]}

Shimizu, Koichiro ^{[2
,13
]}

Mita, Yuichiro ^{[2
,14
]}

Tanida, Ryota ^{[2
,15
]}

Hirako, Satoshi ^{[3
]}

Shioda, Seiji ^{[4
]}

Gmyr, Valery ^{[5
]}

Kerr-Conte, Julie ^{[5
]}

Pattou, Francois ^{[5
]}

Jin, Chunhuan ^{[6
]}

Kanai, Yoshikatsu ^{[6
]}

Sasaki, Kazuki ^{[7
]}

Minamino, Naoto ^{[8
]}

Sakoda, Hideyuki ^{[1
,2
]}

Nakazato, Masamitsu ^{[1
,2
,9
,10
]}

机构：

[1] Univ Miyazaki, Fac Med, Dept Bioregulatory Sci, Miyazaki, Japan

[2] Univ Miyazaki, Fac Med, Dept Internal Med, Div Neurol Respirol Endocrinol & Metab, Miyazaki, Japan

[3] Univ Human Arts & Sci, Dept Hlth & Nutr, Saitama, Japan

[4] Shonan Univ Med Sci, Fac Pharmaceut Sci, Dept Clin Pharm, Yokohama, 2440806, Japan

[5] Univ Lille, Inst Pasteur Lille, Inserm, U1190,EGID, Campus Hosp Univ Lille, F-59000 Lille, France

[6] Osaka Univ, Grad Sch Med, Dept Biosyst Pharmacol, Osaka, Japan

[7] Sasaki Fdn, Dept Peptid, Tokyo, Japan

[8] Natl Cerebral & Cardiovasc Ctr Res, Dept Mol Pharmacol, Suita, Japan

[9] Osaka Univ, Inst Prot Res, Osaka, Japan

[10] Japan Agcy Med Res & Dev, AMED CREST, Tokyo, Japan

[11] Univ Miyazaki, Fac Med, Dept Pharmacol, Miyazaki, Japan

[12] Royal Coll Surg Ireland Bahrain, Dept Postgrad Studies & Res, Busaiteen, Bahrain

[13] Univ Miyazaki, Fac Med, Dept Internal Med, Div Hematol Diabet & Endocrinol, Miyazaki, Japan

[14] Doshisha Univ, Fac Life & Med Sci, Dept Med Life Syst, Syst Life Sci Lab, Kyoto, Japan

[15] Kanazawa Univ, Grad Sch Med Sci, Dept Endocrinol & Metab, Kanazawa, Japan

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

基金：

日本学术振兴会;

关键词：

AMINO-ACID TRANSPORTER; ENDOPLASMIC-RETICULUM STRESS; INSULIN-SECRETION; GLUCOSE; PROTEIN; SYSTEM; IDENTIFICATION; GENE; DYSFUNCTION; RECEPTOR;

D O I：

10.1038/s41467-023-43976-8

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Insulin secretion from pancreatic beta cells is regulated by multiple stimuli, including nutrients, hormones, neuronal inputs, and local signalling. Amino acids modulate insulin secretion via amino acid transporters expressed on beta cells. The granin protein VGF has dual roles in beta cells: regulating secretory granule formation and functioning as a multiple peptide precursor. A VGF-derived peptide, neuroendocrine regulatory peptide-4 (NERP-4), increases Ca2+ influx in the pancreata of transgenic mice expressing apoaequorin, a Ca2+-induced bioluminescent protein complex. NERP-4 enhances glucose-stimulated insulin secretion from isolated human and mouse islets and beta-cell-derived MIN6-K8 cells. NERP-4 administration reverses the impairment of beta-cell maintenance and function in db/db mice by enhancing mitochondrial function and reducing metabolic stress. NERP-4 acts on sodium-coupled neutral amino acid transporter 2 (SNAT2), thereby increasing glutamine, alanine, and proline uptake into beta cells and stimulating insulin secretion. SNAT2 deletion and inhibition abolish the protective effects of NERP-4 on beta-cell maintenance. These findings demonstrate a novel autocrine mechanism of beta-cell maintenance and function that is mediated by the peptide-amino acid transporter axis. Amino acids modulate insulin secretion via amino acid transporters expressed on beta cells. Here, the authors show a VGF-derived peptide NERP-4 acts as a positive allosteric modulator on the amino acid transporter SNAT2/SLC38A2, thereby contributing to beta-cell maintenance and function.

引用

页数：21

共 77 条

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