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The Interdependency and Co-Regulation of the Vitamin D and Cholesterol MetabolismWarren, Tara; email: firstname.lastname@example.org; McAllister, Roisin; email: email@example.com; Morgan, Amy; email: firstname.lastname@example.org; Rai, Taranjit Singh; email: email@example.com; McGilligan, Victoria; email: firstname.lastname@example.org; Ennis, Matthew; email: Ennis-M4@ulster.ac.uk; Page, Christopher; email: Page-C7@ulster.ac.uk; Kelly, Catriona; email: email@example.com; Peace, Aaron; orcid: 0000-0001-9556-7509; email: Aaron.Peace@westerntrust.hscni.net; Corfe, Bernard M.; email: Bernard.Corfe@newcastle.ac.uk; et al. (MDPI, 2021-08-06)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.