Liver-specific ablation of KRAB associated protein 1 in mice leads to male-predominant hepatosteatosis and development of liver adenoma

The liver is characterized by sexually dimorphic gene expression translating into sex-specific differences in lipid, drug, steroid hormone and xenobiotic metabolism, with distinct responses of males and females to environmental challenges. Here, we investigated the role of the KRAB-associated protein 1 (KAP1) epigenetic regulator in this process. Liver-specific KAP1 knockout led to strikingly sexually dimorphic phenotypic disturbances, including male-predominant steatosis and hepatic tumors with upregulation of AKT and ERK1/2 mitogen-activated protein kinase signaling. This correlated with sex-specific transcriptional dysregulation of a wide range of metabolic genes, notably those involved in retinol and sex hormone processing as well as in detoxification. Furthermore, chromatin immunoprecipitation followed by deep sequencing indicated that a number of dysregulated genes are direct targets of the KRAB/KAP1 repression system. Those genes include sexually dimorphic Cyp2d9, Gstϕ, Slp Cyp2a, Cyp2b and Cyp3a gene clusters. Additionally, we identified a male-restricted KAP1 binding site in the fsp27 (fat specific protein 27) gene, correlating with its male-predominant upregulation upon Kap1 deletion, suggesting that the latter might be an important trigger in the development of male-specific hepatosteatosis and secondary tumorigenesis. Conclusion: This work reveals KRAB/KAP1-mediated transcriptional regulation as a central event in the metabolic control hormones, drugs and xenobiotics in the liver, and further links disturbances in these processes with hepatic carcinogenesis.