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Article: Newly identified peptide hormone inhibits intestinal fat absorption and improves NAFLD through its receptor GPRC6A

TitleNewly identified peptide hormone inhibits intestinal fat absorption and improves NAFLD through its receptor GPRC6A
Authors
KeywordsDiabetes
Hormone
Insulin
Metabolism
NAFLD
Obesity
Oral peptide
Issue Date2020
Citation
Journal of Hepatology, 2020, v. 73, n. 2, p. 383-393 How to Cite?
AbstractBackground & Aims: Circulating peptides and G protein-coupled receptors (GPCRs) have gained much attention because of their biofunctions in metabolic disorders including obesity and non-alcoholic fatty liver disease (NAFLD). Herein, we aimed to characterize the role and therapeutic potential of a newly identified peptide hormone in NAFLD. Methods: Using bioinformatics, we identified a murine circulating pentadecapeptide flanked by potential convertase cleavage sites of osteocalcin (OCN), which we named ‘metabolitin (MTL)’. We used ligand-receptor binding, receptor internalization, bioluminescence resonance energy transfer and Nano isothermal titration calorimetry assays to study the binding relationship between MTL and GPRC6A. For in vivo biological studies, wild-type mice kept on a high-fat diet (HFD) were injected or gavaged with MTL to study its function in NAFLD. Results: We confirmed that MTL binds to GPRC6A and OCN interacts with GPRC6A using in vitro biological studies. Both intraperitoneal and oral administration of MTL greatly improved NAFLD and insulin resistance in a mouse model. Interacting with GPRC6A expressed in intestines, MTL can significantly inhibit intestinal neurotensin secretion, which in turn inhibits triglyceride but not cholesterol gut absorption, mediated by the 5′AMP-activated protein kinase pathway. In addition, glucagon like peptide–1 secretion was induced by MTL treatment. Conclusions: Oral or intraperitoneal MTL significantly improves the symptoms of NAFLD by inhibiting lipid absorption and insulin resistance. MTL could be a potential therapeutic candidate for the treatment of NAFLD. Lay summary: A novel murine peptide hormone, herein named ‘metabolitin’, inhibits fatty acid absorption and improves systemic insulin resistance in a murine model of obesity and non-alcoholic fatty liver disease. Thus, metabolitin has therapeutic potential for the treatment of patients with non-alcoholic fatty liver disease.
Persistent Identifierhttp://hdl.handle.net/10722/336786
ISSN
2023 Impact Factor: 26.8
2023 SCImago Journal Rankings: 9.857
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorTeng, Bin-
dc.contributor.authorHuang, Chen-
dc.contributor.authorCheng, Chuan Li-
dc.contributor.authorUdduttula, Anjaneyulu-
dc.contributor.authorYu, Xiang Fang-
dc.contributor.authorLiu, Chang-
dc.contributor.authorLi, Jian-
dc.contributor.authorYao, Zhen Yu-
dc.contributor.authorLong, Jing-
dc.contributor.authorMiao, Li Fu-
dc.contributor.authorZou, Chao-
dc.contributor.authorChu, Jun-
dc.contributor.authorZhang, Jian V.-
dc.contributor.authorRen, Pei Gen-
dc.date.accessioned2024-02-29T06:56:32Z-
dc.date.available2024-02-29T06:56:32Z-
dc.date.issued2020-
dc.identifier.citationJournal of Hepatology, 2020, v. 73, n. 2, p. 383-393-
dc.identifier.issn0168-8278-
dc.identifier.urihttp://hdl.handle.net/10722/336786-
dc.description.abstractBackground & Aims: Circulating peptides and G protein-coupled receptors (GPCRs) have gained much attention because of their biofunctions in metabolic disorders including obesity and non-alcoholic fatty liver disease (NAFLD). Herein, we aimed to characterize the role and therapeutic potential of a newly identified peptide hormone in NAFLD. Methods: Using bioinformatics, we identified a murine circulating pentadecapeptide flanked by potential convertase cleavage sites of osteocalcin (OCN), which we named ‘metabolitin (MTL)’. We used ligand-receptor binding, receptor internalization, bioluminescence resonance energy transfer and Nano isothermal titration calorimetry assays to study the binding relationship between MTL and GPRC6A. For in vivo biological studies, wild-type mice kept on a high-fat diet (HFD) were injected or gavaged with MTL to study its function in NAFLD. Results: We confirmed that MTL binds to GPRC6A and OCN interacts with GPRC6A using in vitro biological studies. Both intraperitoneal and oral administration of MTL greatly improved NAFLD and insulin resistance in a mouse model. Interacting with GPRC6A expressed in intestines, MTL can significantly inhibit intestinal neurotensin secretion, which in turn inhibits triglyceride but not cholesterol gut absorption, mediated by the 5′AMP-activated protein kinase pathway. In addition, glucagon like peptide–1 secretion was induced by MTL treatment. Conclusions: Oral or intraperitoneal MTL significantly improves the symptoms of NAFLD by inhibiting lipid absorption and insulin resistance. MTL could be a potential therapeutic candidate for the treatment of NAFLD. Lay summary: A novel murine peptide hormone, herein named ‘metabolitin’, inhibits fatty acid absorption and improves systemic insulin resistance in a murine model of obesity and non-alcoholic fatty liver disease. Thus, metabolitin has therapeutic potential for the treatment of patients with non-alcoholic fatty liver disease.-
dc.languageeng-
dc.relation.ispartofJournal of Hepatology-
dc.subjectDiabetes-
dc.subjectHormone-
dc.subjectInsulin-
dc.subjectMetabolism-
dc.subjectNAFLD-
dc.subjectObesity-
dc.subjectOral peptide-
dc.titleNewly identified peptide hormone inhibits intestinal fat absorption and improves NAFLD through its receptor GPRC6A-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.jhep.2020.02.026-
dc.identifier.pmid32147363-
dc.identifier.scopuseid_2-s2.0-85085303074-
dc.identifier.volume73-
dc.identifier.issue2-
dc.identifier.spage383-
dc.identifier.epage393-
dc.identifier.eissn1600-0641-
dc.identifier.isiWOS:000548853900028-

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