Mitochondrial pyruvate carrier 1 regulates fatty acid synthase lactylation and mediates treatment of nonalcoholic fatty liver disease.
Hepatology
; 78(6): 1800-1815, 2023 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-36651176
ABSTRACT
BACKGROUND AND AIMS:
NAFLD has become a major metabolic disease worldwide. A few studies have reported the potential relationship between mitochondrial pyruvate carrier 1 (MPC1) and inflammation, fibrosis, and insulin sensitivity in obese or NASH mouse models. However, the impact of MPC1 on NAFLD-related liver lipid metabolism and its role in the NAFLD progression require further investigation. APPROACH ANDRESULTS:
MPC1 expression was measured in liver tissues from normal controls and patients with NAFLD. We characterized the metabolic phenotypes and expression of genes involved in hepatic lipid accumulation in MPC1 systemic heterozygous knockout (MPC1 +/- ) mice. Hepatic protein lactylation was detected using Tandem Mass Tags proteomics and verified by the overexpression of lactylation mutants in cells. Finally, the effect of MPC1 inhibition on liver inflammation was examined in mice and AML-12 cells. Here, we found that MPC1 expression was positively correlated to liver lipid deposition in patients with NAFLD. MPC1 +/- mice fed with high-fat diet had reduced hepatic lipid accumulation but no change in the expression of lipid synthesis-related genes. MPC1 knockout affected the lactylation of several proteins, especially fatty acid synthase, through the regulation of lactate levels in hepatocytes. Lactylation at the K673 site of fatty acid synthase inhibited fatty acid synthase activity, which mediated the downregulation of liver lipid accumulation by MPC1. Moreover, although MPC1 knockout caused lactate accumulation, inflammation level was controlled because of mitochondrial protection and macrophage polarization.CONCLUSIONS:
In NAFLD, MPC1 levels are positively correlated with hepatic lipid deposition; the enhanced lactylation at fatty acid synthase K673 site may be a downstream mechanism.
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Base de dados:
MEDLINE
Assunto principal:
Hepatopatia Gordurosa não Alcoólica
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article