Newly identified peptide hormone inhibits intestinal fat absorption and improves NAFLD through its receptor GPRC6A.
J Hepatol
; 73(2): 383-393, 2020 08.
Article
em En
| MEDLINE
| ID: mdl-32147363
ABSTRACT
BACKGROUND & 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. LAYSUMMARY:
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Triglicerídeos
/
Hormônios Peptídicos
/
Receptores Acoplados a Proteínas G
/
Peptídeo 1 Semelhante ao Glucagon
/
Hepatopatia Gordurosa não Alcoólica
/
Absorção Intestinal
Limite:
Animals
Idioma:
En
Revista:
J Hepatol
Assunto da revista:
GASTROENTEROLOGIA
Ano de publicação:
2020
Tipo de documento:
Article