MGAT2 inhibitor decreases liver fibrosis and inflammation in murine NASH models and reduces body weight in human adults with obesity.
Cell Metab
; 34(11): 1732-1748.e5, 2022 11 01.
Article
em En
| MEDLINE
| ID: mdl-36323235
ABSTRACT
Monoacylglycerol acyltransferase 2 (MGAT2) is an important enzyme highly expressed in the human small intestine and liver for the regulation of triglyceride absorption and homeostasis. We report that treatment with BMS-963272, a potent and selective MGAT2 inhibitor, decreased inflammation and fibrosis in CDAHFD and STAM, two murine nonalcoholic steatohepatitis (NASH) models. In high-fat-diet-treated cynomolgus monkeys, in contrast to a selective diacylglycerol acyltransferase 1 (DGAT1) inhibitor, BMS-963272 did not cause diarrhea. In a Phase 1 multiple-dose trial of healthy human adults with obesity (NCT04116632), BMS-963272 was safe and well tolerated with no treatment discontinuations due to adverse events. Consistent with the findings in rodent models, BMS-963272 elevated plasma long-chain dicarboxylic acid, indicating robust pharmacodynamic biomarker modulation; increased gut hormones GLP-1 and PYY; and decreased body weight in human subjects. These data suggest MGAT2 inhibition is a promising therapeutic opportunity for NASH, a disease with high unmet medical needs.
Palavras-chave
DCA; DGAT; GLP-1; MGAT2; NAFLD; NASH; PYY; dicarboxylic acid; liver fibrosis; steatosis; weight loss
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
3_ND
Base de dados:
MEDLINE
Assunto principal:
Hepatopatia Gordurosa não Alcoólica
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Obesidade
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Animals
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Humans
Idioma:
En
Revista:
Cell Metab
Ano de publicação:
2022
Tipo de documento:
Article