The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.
Hepatology
; 78(3): 878-895, 2023 09 01.
Article
em En
| MEDLINE
| ID: mdl-36745935
ABSTRACT
BACKGROUND AND AIMS:
Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage. APPROACH ANDRESULTS:
C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD + /NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation.CONCLUSIONS:
Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Hepatopatias Alcoólicas
Tipo de estudo:
Guideline
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article