Carbonic anhydrase 8 (CAR8) negatively regulates GLP-1 secretion from enteroendocrine cells in response to long-chain fatty acids

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 320; no. 4; pp. G617 - G626
• Main Authors: Fujiwara, Yuta, Yamane, Shunsuke, Harada, Norio, Ikeguchi-Ogura, Eri, Usui, Ryota, Nakamura, Toshihiro, Iwasaki, Kanako, Suzuki, Kazuyo, Yabe, Daisuke, Hayashi, Yoshitaka, Inagaki, Nobuya
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.04.2021
• Subjects: Animals; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Calcium (intracellular); Calcium (reticular); Calcium efflux; Calcium Signaling; Carbonic anhydrases; Cell Line; Corn Oil - pharmacology; Diabetes mellitus; Drug development; Endoplasmic reticulum; Enteroendocrine Cells - drug effects; Enteroendocrine Cells - enzymology; Fatty acids; Fatty Acids - pharmacology; Glucagon; Glucagon - genetics; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - metabolism; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Inositol 1,4,5-Trisphosphate - metabolism; Inositol 1,4,5-trisphosphate receptors; Insulin; Insulin secretion; Intestine; L cells; Linolenic acid; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nutrients; Phospholipase C; Secretion; Secretory Pathway; Therapeutic targets; Type C Phospholipases - metabolism; carbonic anhydrase 8 (CAR8); incretin; glucagon-like peptide-1 (GLP-1)
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00312.2020

Glucagon-like peptide-1 (GLP-1) is an incretin secreted from enteroendocrine preproglucagon (PPG)-expressing cells (traditionally known as L cells) in response to luminal nutrients that potentiates insulin secretion. Augmentation of endogenous GLP-1 secretion might well represent a novel therapeutic target for diabetes treatment in addition to the incretin-associated drugs currently in use. In this study, we found that PPG cells substantially express carbonic anhydrase 8 (CAR8), which has been reported to inhibit inositol 1,4,5-trisphosphate (IP3) binding to the IP3 receptor and subsequent Ca efflux from the endoplasmic reticulum in neuronal cells. In vitro experiments using STC-1 cells demonstrated that knockdown increases long-chain fatty acid (LCFA)-stimulated GLP-1 secretion. This effect was reduced in the presence of phospholipase C (PLC) inhibitor; in addition, knockdown increased the intracellular Ca elevation caused by α-linolenic acid, indicating that CAR8 exerts its effect on GLP-1 secretion via the PLC/IP3/Ca pathway. null mutant mice showed significant increase in GLP-1 response to oral corn oil administration compared with that in wild-type littermates, with no significant change in intestinal GLP-1 content. These results demonstrate that CAR8 negatively regulates GLP-1 secretion from PPG cells in response to LCFAs, suggesting the possibility of augmentation of postprandial GLP-1 secretion by CAR8 inhibition. This study focused on the physiological significance of carbonic anhydrase 8 (CAR8) in GLP-1 secretion from enteroendocrine preproglucagon (PPG)-expressing cells. We found an inhibitory role of CAR8 in LCFA-induced GLP-1 secretion in vitro and in vivo, suggesting a novel therapeutic approach to diabetes and obesity through augmentation of postprandial GLP-1 secretion by CAR8 inhibition.