Analysis of mouse livers fed with high cholesterol diet and alcohol by spatial transcriptomics

Approach and results: 8-week-old male mice were fed ad libitum with low fat high cholesterol diet (Research Diets, cat# D24120501, 1% cholesterol) in combination with 20% EtOH in the drinking water for 10 weeks. Compared to high-cholesterol diet alone, alcohol treated mice showed elevated levels of serum ALT and AST, INR/PT, increased liver inflammation, fibrosis, ductular reaction and signs of liver failure such as reduced HNF4α and albumin production.

To assess the mechanism of alcohol-induced pathology, we performed spatial transcriptomic analysis using 5k gene Xenium panel (10x Genomics). We found that the liver adapted to high cholesterol diet by increasing cholesterol metabolism in hepatocytes. In contrast, alcohol impaired liver adaptation to high cholesterol diet by reducing cholesterol metabolism, HDL production, and hepatic cholesterol secretion, thus driving inflammation and fibrosis.

Hepatocyte specific Kdm5b knockout mice were partially protected from alcohol effects by restoring cholesterol secretion in part through an upregulation of Abcg8. Accordingly, these mice were protected against alcohol-induced fibrosis development and inflammation. Conclusion: In summary, alcohol impairs liver adaptation to high cholesterol diet.

Increasing liver cholesterol secretion by KDM5B inhibition protects liver from ALD development.