Highlights
- •Liver-specific Cdkal1 deficient mice showed higher CEC and RCT with less tendency of atherosclerosis.
- •This study verified the effect of CDKAL1 found in our previous human genetic data.
- •Downregulation of EL and HL and upregulation of SR-B1 indicated altered HDL catabolism mediators.
- •Cholesterol concentrations were higher in the large HDL subclass in these mice.
- •CDKAL1 and related molecules could be therapeutic targets against vascular pathology.
Abstract
Background and aims
Associations between CDKAL1 variants and cholesterol efflux capacity (CEC) have been reported. This study aimed
to investigate the effects of Cdkal1 deficiency on high-density lipoprotein (HDL)
metabolism, atherosclerosis, and related pathways.
Methods
Lipid and glucose metabolic profiles, CEC, and in vivo reverse cholesterol transport (RCT) were compared in liver-specific Alb-Cre:Cdkal1fl/fl and Cdkal1fl/fl mice. Aortic atherosclerosis was compared in Apoe−/−Alb-Cre:Cdkal1fl/fl and Apoe−/− mice fed high-fat diets. HDL subclasses and mediators of HDL metabolism from Alb-Cre:Cdkal1fl/fl mice were examined.
Results
HDL-cholesterol level tended to be higher in the Alb-Cre:Cdkal1fl/fl mice (p = 0.050). Glucose and other lipid profiles were similar in the two groups of mice,
irrespective of diet. The mean CEC was 27% higher (p = 0.007) in the Alb-Cre:Cdkal1fl/fl mice, as were the radioactivities of bile acids (mean difference 17%; p = 0.035) and cholesterol (mean difference 42%; p = 0.036) from faeces. The radioactivity tendency was largely similar in mice fed
a high-fat diet. Atherosclerotic lesion area tended to be smaller in the Apoe−/−Alb-Cre:Cdkal1fl/fl mice than in the Apoe−/− mice (p = 0.067). Cholesterol concentrations in large HDLs were higher in the Alb-Cre:Cdkal1fl/fl mice (p = 0.024), whereas in small HDLs, they were lower (p = 0.024). Endothelial lipase (mean difference 39%; p = 0.002) and hepatic lipase expression levels (mean difference 34%; p < 0.001) were reduced in the Alb-Cre:Cdkal1fl/fl mice, whereas SR-B1 expression was elevated (mean difference 35%; p = 0.007).
Conclusions
The promotion of CEC and RCT in Alb-Cre:Cdkal1fl/fl mice verified the effect of CDKAL1 seen in human genetic data. These phenotypes were related to regulation of HDL catabolism.
This study suggests that CDKAL1 and associated molecules could be targets for improving RCT and vascular pathology.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: May 22, 2023
Accepted:
May 16,
2023
Received in revised form:
May 13,
2023
Received:
September 19,
2022
Identification
Copyright
© 2023 Elsevier B.V. All rights reserved.
