Hepatocyte-specific CEBPA-ORM1 axis restricts alcohol-associated liver disease

Alcohol-associated liver disease (ALD) affects millions of people worldwide, while pharmacological therapies are limited. CCAAT/enhancer binding protein α (CEBPA) in hepatocytes is known to regulate the progression of liver fibrosis; however, the role of hepatocyte-specific CEBPA in modulating the ALD progression is still unknown. Here, hepatic CEBPA expression was found to be decreased during ALD progression in humans. CebpaΔHep mice had enhanced ALD induced both in short-term and long-term alcohol feeding. Temporal and spatial hepatocyte-specific CEBPA loss at the later stage of ALD in CebpaΔHep,ERT2 mice functionally promoted ALD. Mechanistically, hepatocyte CEBPA loss directly deactivated Orm1 expression in hepatocytes that resulted in reduced secretion of ORM1 and enhancement of ALD progression. Both hepatocyte ORM1 expression and serum ORM1 levels were found to be negatively correlated with the ALD progression in humans, while loss of hepatocyte ORM1 in mice sharply enhanced ALD. Both forced hepatocyte-specific CEBPA overexpression and hepatocyte-specific ORM1 overexpression by adeno-associated viruses rescued the progression of ALD in CebpaΔHep mice. Notably, treatment of recombinant ORM1 protein improved the progression of ALD in CebpaΔHep mice. These results reveal a key role for hepatocyte-specific CEBPA-ORM1 axis in ALD progression, which supports hepatocyte CEBPA to be a novel therapeutic target for the treatment of ALD.