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Key Event Title
|Level of Biological Organization|
Key Event Components
|cholesterol biosynthetic process||cholesterol||decreased|
|cholesterol transport||cholesteryl ester||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|HMGCR inhibition to male fertility||KeyEvent||Kellie Fay (send email)||Under Development: Contributions and Comments Welcome|
|PPARa Agonism Impairs Fish Reproduction||KeyEvent||Ashley Kittelson (send email)||Open for citation & comment|
|All life stages||Moderate|
Key Event Description
Most cholesterol synthesis in vertebrates occurs within the endoplasmic reticulum of hepatic cells. First, acetyl-CoA is converted to HMG-CoA via HMG-CoA synthase. Next, HMG-CoA is converted to mevalonate via HMG-CoA reductase. Several other steps follow, but conversion of HMG-CoA to mevalonate is the rate-limiting step of cholesterol synthesis (Cerqueira et al. 2016; Risley 2002). Consequently, Statin drugs inhibit HMG-CoA reductase to reduce cholesterol (Pahan 2006).
Cholesterol synthesis may also occur to a limited extent in steroidogenic cells where it’s used to produce steroid hormones (Azhar et al., 2007)
Once cholesterol is produced in the liver, it’s transported in the plasma. Hydrophobic lipids like cholesterol, cholesteryl ester (a cholesterol molecule bound to a fatty acid), and triglycerides are transported via lipoprotein complexes. There are different groups of lipoproteins which use different proteins and ratios of lipids including high-density lipoprotein (HDL), low-density (LDL), and very low-density (VLDL).
How It Is Measured or Detected
Commerical assay kits are available for measuring cholesterol using either colorimetric or fluorometric detection. Total cholesterol assay kits often include cholesteryl esters in the measurement (Cell Bio Labs, ThermoFisher). Additional kits are availalbe for measuring the cholesterol in the different lipoprotein complexes (Cell Bio Labs).
Oil Red O staining can be used for organisms such as zebrafish larvae that are clear, however it stains triglycerides and lipids not just cholesterol (Zhou et al., 2015).
Plasma cholesterol is a common clinical measurement in humans and the Abell-Kendall technique is the standard chemical determination method (Cox et al. 1990), although there are a wide variety of viable methods.
Domain of Applicability
Taxonomic Applicability: Cholesterol is synthesized in plants but acts as a precursor for different products than in animals (Sonawane et al. 2016). Within the animal kingdom most deuterostomes (including vertebrata, cyclostomata, cephalochordate, and echinodermata, but not chordata) possess the genes necessary for cholesterol biosynthesis. However, most protostomes (including arthropoda and nematomorpha) have lost these genes (Zhang et al., 2019). Thus far vertebrates are the primary consideration for this KE.
Lifestage Applicability: Cholesterol can be measured in organisms at all life stages. However, the size of young organisms may limit the ability to collect plasma for cholesterol analysis. Whole-body measurements or pooled samples may be more feasible.
Sex Applicability: Cholesterol measurements are applicable for all sexes
Al-Habsi, A.A., A. Massarsky, T.W. Moon (2016) “Exposure to gemfibrozil and atorvastatin affects cholesterol metabolism and steroid production in zebrafish (Danio rerio)”, Comparative Biochemistry and Physiology, Part B, Vol. 199, Elsevier, pp. 87-96. http://dx.doi.org/10.1016/j.cbpb.2015.11.009
Azhar, S., E. Reaven (2007) “Regulation of Leydig cell cholesterol metabolism”, in A.H. Payne, M.P. Hardy (eds.) The Leydig Cell in Health and Disease, Humana Press. https://doi.org/10.1007/978-1-59745-453-7
Cox RA, García-Palmieri MR. Cholesterol, Triglycerides, and Associated Lipoproteins. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 31. Available from: https://www.ncbi.nlm.nih.gov/books/NBK351/
Dai, W. et al. (2015) "High fat plus high cholesterol diet lead to hepatic steatosis in zebrafish larvae: a novel model for screening anti-hepatic steatosis drugs", Nutrition and Metabolism, Vol. 12(42), Springer Nature. DOI 10.1186/s12986-015-0036-z
Du, Z.Y. et al. (2008) “Hypolipidaemic effect of fenofibrate and fasting in the herbivorous grass carp (Ctenopharyngodon idella) fed a high-fat diet”, British Journal of Nutrition, Vol. 100, Cambridge University Press, pp. 1200-1212. doi:10.1017/S0007114508986840
Guo, X. et al. (2015) “Effects of lipid-lowering pharmaceutical clofibrate on lipid and lipoprotein metabolism of grass carp (Ctenopharyngodon idellal Val.) fed with the high non-protein energy diets”, Fish Physiology and Biochemistry, Vol. 41, Springer, pp. 331-343. doi: 10.1007/s10695-014-9986-8
Cerqueira, N. M., Oliveira, E. F., Gesto, D. S., Santos-Martins, D., Moreira, C., Moorthy, H. N., ... & Fernandes, P. A. (2016). Cholesterol biosynthesis: a mechanistic overview. Biochemistry, 55(39), 5483-5506.
Prindiville, J.S. et al. (2011) “The fibrate drug gemfibrozil disrupts lipoprotein metabolism in rainbow trout”, Toxicology and Applied Pharmacology, Vol. 251, Elsevier, pp. 201-238. doi:10.1016/j.taap.2010.12.013
Pahan, K. (2006). Lipid-lowering drugs. Cellular and molecular life sciences CMLS, 63(10), 1165-1178.
Risley, J. M. (2002). Cholesterol biosynthesis: Lanosterol to cholesterol. Journal of chemical education, 79(3), 377.
Sonawane, P.D. et al. (2016) “Plant cholesterol biosynthetic pathway overlaps with phytosterol metabolism”, Nature Plants, Vol. 3, Nature Publishing Group, https://doi.org/10.1038/nplants.2016.205
Velasco-Santamaría, Y.M. et al. (2011) “Bezafibrate, a lipid-lowering pharmaceutical, as a potential endocrine disruptor in male zebrafish (Danio rerio)”, Aquatic Toxicology, Vol. 105, Elsevier, pp. 107-118. doi:10.1016/j.aquatox.2011.05.018
Zhang, T. et al. (2019) “Evolution of the cholesterol biosynthesis pathway in animals”, Molecular Biology and Evolution, Vol. 36(11), Oxford University Press, pp. 2548-2556. doi:10.1093/molbev/msz167
Zhou, J. et al. (2015) "Rapid analysis of hypolipidemic drugs in a live zebrafish assay", Journal of Pharmacological and Toxicological Methods, Vol. 72, Elsevier, pp. 47-52. http://dx.doi.org/10.1016/j.vascn.2014.12.002