Liver Receptor Homolog-1 Deficiency Impairs Alcohol-Associated Liver Disease Owing to Decrease of Aldehyde...

Ethanol is detoxified in the liver, and its intake causes hepatic lipid accumulation. The liver receptor homolog-1 (LRH-1) regulates lipid and bile acid metabolism, but its role in ethanol metabolism remains unclear. This study aimed to explore the relationship between ethanol-induced lipid accumulation and LRH-1. To investigate the role of LRH-1 in hepatic ethanol metabolism, LRH-1^f/f and liver-specific LRH-1^f/cre+ mice were fed a Lieber-DeCarli diet for 3 weeks. The results showed that ethanol-fed LRH-1^f/cre+ mice exhibited increased neutral fat, total cholesterol, liver damage markers, and acetaldehyde levels. Moreover, ethanol-fed LRH-1^f/cre+ mice displayed decreased fatty acid oxidation, impaired mitochondrial function, and increased reactive oxygen species levels. To identify LRH-1 targets in ethanol metabolism, RNA sequencing analysis revealed significant changes in genes involved in fatty acid metabolism between the control and ethanol groups. Notably, in the absence of LRH-1, ethanol metabolism genes showed a reduction in aldehyde dehydrogenase 1 family member b1 (ALDH1B1) expression. Furthermore, LRH-1 overexpression in HepG2 cells led to increased ALDH1B1 expression, and ChIP sequencing data confirmed the LRH-1 binding peaks in the ALDH1B1 promoter region. In conclusion, this study confirms that LRH-1 depletion results in decreased ALDH1B1 expression, leading to acetaldehyde accumulation and accelerated intrahepatic fat accumulation.