Recent studies have shed light on the detrimental effects of the Aldh2 Glu504Lys genetic mutation, prevalent among East Asian populations, on the development of fatty liver disease (FLD). This mutation impairs the body's ability to metabolize acetaldehyde, exacerbated by high alcohol-producing gut bacteria, Klebsiella pneumoniae. Researchers at the Capital Institute of Pediatrics conducted transcriptome analyses to elucidate the biological pathways involved.
This study employed Aldh2-deficient mice to explore how the combination of alcohol consumption and the presence of Klebsiella pneumoniae accelerates liver injury and aggravates NAFLD. The results revealed significant gene expression alterations, with various genes linked to liver metabolism and inflammation pathways identified as potential therapeutic targets.
Aldehyde dehydrogenase 2 (ALDH2) is integral to the metabolism of acetaldehyde, whose accumulation can lead to hepatocyte damage and fatty liver. The mutation leads to reduced enzyme activity, affecting around 36% of East Asians, resulting not only in metabolic issues but also leading to heightened susceptibility to liver-related diseases.
Through the use of CRISPR technology, Aldh2-deficient mice were created, mimicking the genetic characteristics prevalent among affected populations. Following treatment with alcohol and Klebsiella pneumoniae, the mice exhibited pronounced hepatocyte damage and aberrations in liver metabolic processes.
Transcriptomic analysis revealed 2,881 differentially expressed genes (DEGs) linked to pathways involved significantly in amino acid and glucose metabolism relevant to liver function. Among these, genes such as Cyp8b1, Cyp7a1, and Ugt2b1 were highlighted for their role in metabolism, indicating their potential as therapeutic targets.
“These genes emerge as pivotal targets for combating W14-induced NAFLD, and inhibiting their expression could provide effective treatment strategies for East Asian populations,” stated the research team, emphasizing the applicability of the findings.
The study posits the need for developing therapeutic strategies aimed at modulating gut flora and metabolic pathways disrupted by ALDH2 deficiency. Results suggested potential efficacy of small molecules, including 2-arachidonoylglycerol and retinoic acid, which could target identified DEGs implicated in FLD.
Overall, these findings advance our comprehension of the consequences arising from ALDH2 deficiency, framing it as not just a genetic anomaly but as part of larger interactions between genetics, microbiota, and liver health. Further research is required to fully elucidate these interactions and therapeutic avenues.