Hepatic Cdkal1 deletion enhances cholesterol efflux capacity with regulation of HDL metabolism

Abstract

Previous studies have reported that individuals with CDKAL1 variants were associated with promoted cholesterol efflux capacity (CEC) by genome-wide association studies (GWAS). In this study, we investigated the effect of liver-specific deletion of Cdkal1 on mouse CEC and atherosclerosis. In this study, liver-specific Cdkal1 gene-deleted mouse was prepared and blood, CEC, high density lipoprotein (HDL) metabolism-related protein, and RNA-seq were identified. To confirm the direct effect on atherosclerosis, double knockout (KO) mice were produced by crossing Apoe KO and liver-specific Cdkal1 KO mice. CEC was higher in Cdkal1 KO mice than in wild-type (WT) mice (p = 0.007) and higher in Apoe/Cdkal1 KO mice than in Apoe KO mice (p = 0.034). Serum enzyme activities of LCAT, PLTP, and LPL were similar between WT and Cdkal1 KO mice. Liver tissue western blotting revealed reduced EL (p = 0.002), HL (p < 0.001) and elevated SR-B1 (p = 0.007) in Cdkal1 KO mice. In the high cholesterol diet-induced atherosclerosis model, atherosclerotic plaques tended to decrease in the Cdkal1 KO group, but there was no significant difference (p = 0.067). As a result of comparative analysis of hepatocytes from Cdkal1 KO mice and those from WT mice by RNA sequencing, it was confirmed that the bile secretion pathway was upregulated. The current study demonstrated that CEC is promoted in mice with liver-specific deletion of Cdkal1 with regulation of proteins for HDL metabolism. This study suggests CDKAL1 could be a target of intervention to improve HDL function and vascular pathology.