Intestinal Nogo-B reduces GLP1 levels by binding to proglucagon on the endoplasmic reticulum to inhibit PCSK1 cleavage

Ke Gong^#^{1 2 3}, Chao Xue^#⁴, Zian Feng¹, Ruru Pan¹, Mengyao Wang³, Shasha Chen³, Yuanli Chen³, Yudong Guan⁵, Lingyun Dai⁵, Shuang Zhang³, Liwei Jiang⁶, Ling Li⁶, Bei Wang⁷, Zequn Yin¹, Likun Ma¹, Yasuko Iwakiri⁸, Junming Tang², Chenzhong Liao³, Houzao Chen⁹, Yajun Duan¹⁰

Affiliations

¹ Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
² Department of Physiology, Faculty of Basic Medical Sciences, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, Hubei, China.
³ Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, Anhui, China.
⁴ College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China.
⁵ Department of Geriatrics, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People’s Hospital, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China.
⁶ Laboratory of Immunoengineering, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, China.
⁷ Department of Pathology, China-Japan Friendship Hospital, Beijing, China.
⁸ Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA.
⁹ Department of Biochemistry & Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
¹⁰ Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. yajunduan@ustc.edu.cn.

^# Contributed equally.

PMID: 39122737
PMCID: PMC11315690
DOI: 10.1038/s41467-024-51352-3

Abstract

Glucagon-like peptide 1 (GLP1), which is mainly processed and cleaved from proglucagon in enteroendocrine cells (EECs) of the intestinal tract, acts on the GLP1 receptor in pancreatic cells to stimulate insulin secretion and to inhibit glucagon secretion. However, GLP1 processing is not fully understood. Here, we show that reticulon 4B (Nogo-B), an endoplasmic reticulum (ER)-resident protein, interacts with the major proglucagon fragment of proglucagon to retain proglucagon on the ER, thereby inhibiting PCSK1-mediated cleavage of proglucagon in the Golgi. Intestinal Nogo-B knockout in male type 2 diabetes mellitus (T2DM) mice increases GLP1 and insulin levels and decreases glucagon levels, thereby alleviating pancreatic injury and insulin resistance. Finally, we identify aberrantly elevated Nogo-B expression and inhibited proglucagon cleavage in EECs from diabetic patients. Our study reveals the subcellular regulatory processes involving Nogo-B during GLP1 production and suggests intestinal Nogo-B as a potential therapeutic target for T2DM.

Nat Commun. 2024 Aug 10;15(1):6845.doi: 10.1038/s41467-024-51352-3. (IF:14.700).

Intestinal Nogo-B reduces GLP1 levels by binding to proglucagon on the endoplasmic reticulum to inhibit PCSK1 cleavage

Affiliations

Abstract

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