Hepatocyte CEBPA-ORM1 axis restricts alcohol-associated liver disease

BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) represents a global health burden with limited therapeutic strategies. While the hepatocyte transcription factor CCAAT/enhancer-binding protein α (CEBPA) regulates hepatic gene expression and liver fibrosis, its role in ALD pathogenesis remains undefined. Here, hepatocyte CEBPA was examined for its modulation of alcohol-associated hepatic steatosis and ALD. APPROACH AND RESULTS: Hepatocyte-specific CEBPA knockout mice, adeno-associated virus serotype transduction studies, and reporter gene assays were carried out using acute and chronic mouse ALD models. Western blotting was performed on liver tissues from human patients with ALD. Hepatic CEBPA expression decreased during ALD progression in human patient cohorts. Hepatocyte-specific Cebpa -knockout mice exhibited exacerbated alcohol-associated steatosis in both the acute and chronic ALD models. Inducible ablation of CEBPA in hepatocytes during late-stage ALD, accelerated disease progression, demonstrating the persistent protective function of CEBPA. Global transcriptomics identified Orm1 encoding orosomucoid 1 (ORM1) as the top CEBPA-upregulated gene in hepatocytes, while reporter assays and chromatin immunoprecipitation (ChIP) revealed that CEBPA directly activated Orm1 transcription by binding CEBPA response elements upstream of the Orm1 promoter. Loss of hepatocyte ORM1 potentiated the severity of ALD in mice. Conversely, restoring CEBPA or ORM1 via i.v. adeno-associated virus serotype 8 delivery or i.p. administeration of recombinant ORM1 protein rescued hepatic lipid accumulation and reduced disease progression. Consistently, serum ORM1, a hepatocyte-secreted hepatokine, inversely correlated with ALD severity in patients. CONCLUSIONS: These findings identify the hepatocyte CEBPA-ORM1 axis as a critical suppressor of ALD, offering therapeutic targets and nominating serum ORM1 as a potential biomarker for staging ALD severity.