Abstract
Vitamin D and cholesterol metabolism overlap significantly in the pathways that contribute to their biosynthesis. However, our understanding of their independent and co-regulation is limited. Cardiovascular disease is the leading cause of death globally and atherosclerosis, the pathology associated with elevated cholesterol, is the leading cause of cardiovascular disease. It is therefore important to understand vitamin D metabolism as a contributory factor. From the literature, we compile evidence of how these systems interact, relating the understanding of the molecular mechanisms involved to the results from observational studies. We also present the first systems biology pathway map of the joint cholesterol and vitamin D metabolisms made available using the Systems Biology Graphical Notation (SBGN) Markup Language (SBGNML). It is shown that the relationship between vitamin D supplementation, total cholesterol, and LDL-C status, and between latitude, vitamin D, and cholesterol status are consistent with our knowledge of molecular mechanisms. We also highlight the results that cannot be explained with our current knowledge of molecular mechanisms: (i) vitamin D supplementation mitigates the side-effects of statin therapy; (ii) statin therapy does not impact upon vitamin D status; and critically (iii) vitamin D supplementation does not improve cardiovascular outcomes, despite improving cardiovascular risk factors. For (iii), we present a hypothesis, based on observations in the literature, that describes how vitamin D regulates the balance between cellular and plasma cholesterol. Answering these questions will create significant opportunities for advancement in our understanding of cardiovascular health.
Highlights
Interest in vitamin D has expanded significantly in recent years with the number of publications featuring the fat-soluble vitamin growing rapidly
It is clear that dysregulation of cholesterol and vitamin D metabolism occurs with age and that dysregulation correlates with a rise in age-associated diseases [30,31], but it is poorly understood how this dysregulation develops
Genome Wide Association Studies (GWAS) has identified SNPs of acyl-coA dehydrogenase short/branched chain (ACADSB) associated with vitamin D status and it is to be expected that the same SNPs would affect cholesterol biosynthesis, this has yet to be studied [181]
Summary
Interest in vitamin D has expanded significantly in recent years with the number of publications featuring the fat-soluble vitamin growing rapidly. Evidence suggests that statin therapy, used in the treatment of hypercholesterolaemia, does not influence the plasma levels of vitamin D [27] This is counter-intuitive, as statins inhibit a key mechanism in the biosynthesis pathway shared by both metabolisms. It is clear that dysregulation of cholesterol and vitamin D metabolism occurs with age and that dysregulation correlates with a rise in age-associated diseases [30,31], but it is poorly understood how this dysregulation develops The interplay between these two elaborate metabolic pathways can be best described with the use of systems biology, which enables their complex biochemical interactions to be viewed in an integrated manner. This allows us to explore experimental results and observations in the context of systems level behaviour and to identify which results are consistent with our systems level understanding and which results are in contradiction
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