1-Methylnicotinamide promotes hepatic steatosis in mice: A potential mechanism in chronic alcohol-induced fatty liver disease.
Biochim Biophys Acta Mol Cell Biol Lipids
; 1868(4): 159286, 2023 04.
Article
em En
| MEDLINE
| ID: mdl-36690322
ABSTRACT
Alcohol abuse and its related diseases are the major risk factors for human health. Alcohol-related liver disease (ALD) is a leading cause of morbidity and mortality worldwide. Although the mechanism of ALD has been widely investigated, liver metabolites associated with long-term alcohol intake-induced hepatic steatosis have not been well explored. In this study, we aimed to investigate the role and mechanisms of 1-methylnicotinamide (1-MNA), a metabolite during nicotinamide adenine dinucleotide (NAD+) metabolism, in the pathogenesis of ALD. C57BL/6 wild-type mice were subjected to chronic alcohol feeding with or without 1-MNA (50 mg/kg/day). Our data showed that 1-MNA administration significantly enhanced chronic alcohol consumption-induced hepatic steatosis. Mechanistic studies revealed that alcohol-increased hepatic protein levels of sterol regulatory element-binding transcription factor (SREBP-1c), a key enzyme that regulates lipid lipogenesis, were enhanced in mice administered with 1-MNA, regardless of alcohol feeding. Consistently, alcohol-increased mRNA and protein levels of hepatic diacylglycerol o-acyltransferase 2 (DGAT2) and very low-density lipoprotein receptor (VLDLR) were also exacerbated by 1-MNA administration. Alcohol-induced hepatic endoplasmic reticulum (ER) stress was enhanced by 1-MNA administration, which was evidenced by increased protein levels of binding immunoglobulin protein (BIP), phosphorylated- protein kinase r-like ER kinase (PERK), activating transcription factor 4 (ATF4), and C/EBP-homologous protein (CHOP) in the mouse liver. Overall, this study demonstrated that 1-MNA serves as a pathogenic factor in the development of ALD. Targeting liver 1-MNA levels may serve as a promising therapeutic approach for improving hepatic steatosis in ALD.
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01-internacional
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MEDLINE
Assunto principal:
Fígado Gorduroso
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Fígado Gorduroso Alcoólico
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Biochim Biophys Acta Mol Cell Biol Lipids
Ano de publicação:
2023
Tipo de documento:
Article