In traditional studies, the relationship between low high-density lipoprotein-cholesterol (HDL-C) levels and coronary heart disease risk has been well reported [1,2]. However, following genetic studies [3] and trials of HDL-C raising drugs [4], there is further uncertainty on whether HDL is protective against atherosclerosis or if HDL-C is just a biomarker. Conversely, very recent genetic studies analysing characteristics of HDL particles revealed a protective effect against coronary artery disease [5]. Furthermore, many researchers and physicians are still interested in the influence of therapeutics based on HDL and reverse cholesterol transport (RCT) on vascular disease [6,7].

We previously reported associations between variants of CDKAL1, encoding Cdk5 regulatory subunit associated protein 1-like 1 (Cdkal1), and cholesterol efflux capacity (CEC) using a human genome-wide association and replication study. In that study, 631 variants were associated in the discovery set, and five of these, including four near CDKAL1, were associated with CEC in the replication set [8]. Based on these results, we planned to investigate the pathways by which Cdkal1 affects CEC and whether this gene influences RCT and atherosclerosis.

In prior studies, genetic variants of Cdkal1 were linked to impaired insulin response and the risk of type 2 diabetes mellitus in diverse ethnic populations [9]. As a mammalian methylthiotransferase, Cdkal1 has been reported to catalyse modification of tRNA needed in protein translation [10]. Mice with β cell-specific knockout of Cdkal1 showed a decrease in proinsulin secretion with impaired blood glucose control. This might be due to the low translational efficiency of hypomodified tRNA that causes reduction of proinsulin synthesis [10]. However, no study to date has reported its effects on HDL metabolism or related parameters.

Therefore, the aim of this study was to investigate the effect of Cdkal1 deficiency associated with CEC on HDL metabolism as well as atherosclerosis and its underlying mechanisms. Liver-specific Cdkal1-deficient- mice were generated, and lipid profiles, CEC, and RCT were compared in Alb-Cre:Cdkal1fl/fl and Cdkal1fl/fl mice. As mentioned above, a strong metabolic phenotype has been reported in mice with β-cell specific Cdkal1 deletion. However, as the liver plays important roles in HDL metabolism and RCT [11], we used liver-specific knockout mice in the current study. In addition, aortic atherosclerosis was compared in Apoe−/−Alb-Cre:Cdkal1fl/fl and Apoe−/− mice fed high-fat diets. To elucidate associated biological pathways, regulatory effects on target molecules involved in HDL metabolism were assessed.