DNA 6mA Demethylase ALKBH1 Orchestrates Fatty Acid Metabolism and Suppresses Diet-Induced Hepatic Steatosis.
Cell Mol Gastroenterol Hepatol
; 14(6): 1213-1233, 2022.
Article
en En
| MEDLINE
| ID: mdl-36058506
ABSTRACT
BACKGROUND & AIMS:
Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity and mortality whereas the pathogenic mechanism remains largely elusive. DNA N6-methyladenosine (6mA) modification is a recently identified epigenetic mark indicative of transcription in eukaryotic genomes. Here, we aimed to investigate the role and mechanism of DNA 6mA modification in NAFLD progression.METHODS:
Dot blot and immunohistochemistry were used to detect DNA 6mA levels. Liver-specific AlkB homolog 1 (ALKBH1)-knockout mice and mice with ALKBH1 overexpression in liver were subjected to a high-fat diet or methionine choline-deficient diet to evaluate the critical role of ALKBH1-demethylated DNA 6mA modification in the pathogenesis of hepatic steatosis during NAFLD. RNA sequencing and chromatin immunoprecipitation sequencing were performed to investigate molecular mechanisms underlying this process.RESULTS:
The DNA 6mA level was increased significantly with hepatic steatosis, while ALKBH1 expression was down-regulated markedly in both mouse and human fatty liver. Deletion of ALKBH1 in hepatocytes increased genomic 6mA levels and accelerated diet-induced hepatic steatosis and metabolic dysfunction. Comprehensive analyses of transcriptome and chromatin immunoprecipitation sequencing data indicated that ALKBH1 directly bound to and exclusively demethylated 6mA levels of genes involved in fatty acid uptake and lipogenesis, leading to reduced hepatic lipid accumulation. Importantly, ALKBH1 overexpression was sufficient to suppress lipid uptake and synthesis, and alleviated diet-induced hepatic steatosis and insulin resistance.CONCLUSIONS:
Our findings show an indispensable role of ALKBH1 as an epigenetic suppressor of DNA 6mA in hepatic fatty acid metabolism and offer a potential therapeutic target for NAFLD treatment.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedad del Hígado Graso no Alcohólico
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell Mol Gastroenterol Hepatol
Año:
2022
Tipo del documento:
Article
País de afiliación:
China