PLANT STEROLS

Functional foods enriched with plant sterols are mentioned as cholesterol-lowering agents in guidelines for the treatment of dyslipidemia. Regular intake of plant sterols reduces low-density lipoprotein (LDL) cholesterol, but also increases circulating plant sterols. Patients with sitosterolemia, a rare genetic disorder caused by mutations in the ATP-binding cassette transporters G5 and G8 (ABCG5 and ABCG8), have up to a 50-fold increase in circulating plant sterols. Therefore, they are at risk of developing early-onset cardiovascular disease (CVD) (Silbernagel, G. et al., 2013).

 

What is the CYP7A1 Gene?

Conversion of cholesterol into bile acids in the liver and secretion of cholesterol into bile are the quantitatively main means of excreting cholesterol from the body. Cholesterol 7α-hydroxylase (CYP7A1), encoded by CYP7A1, is the first and rate-limiting step in the classical bile acid synthesis pathway. The activity of CYP7A1 (a cytochrome P-450 enzyme) is regulated by bile acids, cholesterol, and hormones. Bile acids have an important role in cholesterol homeostasis. While their synthesis and excretion cause a decrease in hepatic cholesterol levels, their presence in the intestine facilitates the dissolution of dietary fats and is necessary for the absorption of cholesterol and fat-soluble vitamins (Srivastava, A. et al., 2008).

 

What is the CETP Gene?

Cholesteryl ester transfer protein (CETP) regulates cholesterol homeostasis through the transfer of cholesteryl esters from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) in exchange for triacylglycerols (TG) (Yu, L. et al., 2012). CETP is synthesized in the liver and circulates bound to HDL. CETP mRNA and protein concentration increases in response to high cholesterol levels and dietary fat intake, increases the transfer of cholesterol ester to HDL particles, increases the return of cholesterol from plasma to the liver, and reduces plasma cholesterol levels. CETP is anti-atherogenic when associated with high HDL levels. CETP deficiency, in turn, reduces cellular cholesterol flux and promotes atherosclerosis through low HDL-C levels (Terán-García, M. et al., 2007).

PLANT STEROLS 1
Genes	rs	Minor Allele	Minor Allele Description	Reference
CYP7A1	rs3808607	T	High relative risk associated with reduced cholesterol-lowering effect of plant sterols and Beta Glucan.	(Srivastava, A. et al., 2008)
CETP	rs5882	A	High relative risk associated with reduced triglyceride-lowering effect of plant sterols.	(Yu, L. et al., 2012)

The table above includes genes and their polymorphisms that play a role in cholesterol metabolism. A single nucleotide polymorphism that enables the A>C transition in the human CYP7A1 gene plays a crucial role in gene expression. The CC genotype of this polymorphism carries a significant risk for gallstone disease, indicating that the gene plays a role in gallstone pathogenesis, but its role is minor (Srivastava, A. et al., 2008). The I405V (rs5882) polymorphism is associated with decreased CETP, higher HDL levels and increased lipoprotein particle sizes. CETP I405V polymorphism has been shown to cause decreased CETP protein levels and increased HDL levels (Yu, L. et al., 2012).

 

What is the ABCG8 Gene?

ABCG5 and ABCG8 are cholesterol semitransporters that together function as a heterodimer. Expression of these transporters mediates the reflux of cholesterol and plant sterols from the enterocytes into the intestinal lumen and their excretion into the bile, thus limiting their accumulation in the body. In humans, deleterious mutations in any of these genes cause the genetic disease sitosterolemia, which is characterized by elevated levels of plasma plant sterols in blood and tissues and an increased risk of atherosclerosis and CHD, independent of plasma cholesterol concentrations (Junyent, M. et al., 2009).

PLANT STEROLS 2
Genes	rs	Minor Allele	Minor Allele Description	Reference
ABCG8	rs11887534 D19H/G19C	C	Increased relative risk for gallstones and coronary artery disease.	(Kuo, K. et al., 2008)
ABCG8	rs4299376	G	ncreased relative risk for heart disease due to increased cholesterol absorption.

The table above includes genes and their polymorphisms that play a role in cholesterol metabolism. A study in the Taiwanese population found a significant correlation between the distribution of D19H (GC) polymorphisms and gallstone disease. Although the risk associated with D19H is greater in people under the age of 50, serum levels of total cholesterol, LDLC, and HDLC have been shown to be significantly lower in people with gallstones than in those without (Kuo, K. et al., 2008). rs11887534, a SNP in the hepatic cholesterol transporter ABCG8 gene, has been shown to play a role in gallstone disease. In a study, while the overall odds ratio associated with rs11887534 (C) carriers was 2.2, it was found to be 7 times higher for (C;C) homozygotes (Buch, S. et al., 2007).

 

REFERENCES

Buch, S., Schafmayer, C., Völzke, H., Becker, C., Franke, A., Kluck, C., Bässmann, I., Brosch, M., Lammert, F., Miquel, J. F., Nervi, F., Wittig, M., Rosskopf, D., Timm, B., Höll, C., Seeger, M., ElSharawy, A., Lu, T., Egberts, J., . . .  Hampe, J. (2007). A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nature Genetics, 39(8), 995-999. https://doi.org/10.1038/ng2101

Junyent, M., Tucker, K. L., Smith, C. E., Garcia-Rios, A., Mattei, J., Lai, Q., Parnell, L. D., & Ordovas, J. M. (2009). The effects of ABCG5/G8 polymorphisms on plasma HDL cholesterol concentrations depend on smoking habit in the Boston Puerto Rican Health Study. Journal of Lipid Research, 50(3), 565-573. https://doi.org/10.1194/jlr.P800041-JLR200

Kuo, K., Shin, S., Chen, Z., Yang, Y., Yang, J., & Hsiao, P. (2008). Significant association of ABCG5 604Q and ABCG8 D19H polymorphisms with gallstone disease. British Journal of Surgery, 95(8), 1005-1011. https://doi.org/10.1002/bjs.6178

Silbernagel, G., Chapman, M. J., Genser, B., Kleber, M. E., Fauler, G., Scharnagl, H., Grammer, T. B., Boehm, B. O., Mäkelä, K., Kähönen, M., Carmena, R., Rietzschel, E. R., Bruckert, E., Deanfield, J. E., Miettinen, T. A., Raitakari, O. T., Lehtimäki, T., & März, W. (2013). High Intestinal Cholesterol Absorption Is Associated With Cardiovascular Disease and Risk Alleles in ABCG8 and ABO: Evidence From the LURIC and YFS Cohorts and From a Meta-Analysis. Journal of the American College of Cardiology, 62(4), 291-299. https://doi.org/10.1016/j.jacc.2013.01.100

Srivastava, A., Pandey, S. N., Choudhuri, G., & Mittal, B. (2008). Role of genetic variant A-204C of cholesterol 7α-hydroxylase (CYP7A1) in susceptibility to gallbladder cancer. Molecular Genetics and Metabolism, 94(1), 83-89. https://doi.org/10.1016/j.ymgme.2007.11.014

Terán-García, M., Després, P., Tremblay, A., & Bouchard, C. (2007). Effects of Cholesterol Ester Transfer Protein (CETP) gene on adiposity in response to long-term overfeeding. Atherosclerosis, 196(1), 455. https://doi.org/10.1016/j.atherosclerosis.2006.12.005

Yu, L., Shulman, J. M., Chibnik, L., Leurgans, S., Schneider, J. A., De Jager, P. L., & Bennett, D. A. (2012). The CETP I405V polymorphism is associated with an increased risk of Alzheimer’s disease. Aging Cell, 11(2), 228. https://doi.org/10.1111/j.1474-9726.2011.00777.x