Blood Cholesterol and Plant Sterols (PS) - PowerPoint Presentation

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Blood Cholesterol and Plant Sterols (PS)

Itzel Vazquez-Vidal and Peter J.H. JonesUniversity of Manitoba, Richardson Centre for Functional Foods and Nutraceuticals.

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Principles of Nutrigenetics and

Nutrigenomics

Diet and Cardiovascular Disease

Cardiovascular disease (CVD) represents 31% of all global deaths1.Diets rich in specific lipid components including mono- and polyunsaturated fatty acids (MUFAs and PUFAs), low in saturated fat, and rich in plant sterols/stanols reduce the risk of CVD by 20-25%2-3

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Plant Sterols (PS)

The similar structure of plant sterols to cholesterol causes a decrease in the synthesis and excretion of bile acids, leading to a reduction in cholesterol absorption and therefore lowering circulating levels4.Dosage of 1.0 to 3.0 g/day of PS decreases LDL-cholesterol levels by approximately 12 mg/dL (0.31 mmol/L)5.

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The Evidence from Genetics in the responsiveness of LDL-C to PS

Previous studies identified genetic variations in the APOE and CYP7A1 genes predicting the response to PS intervention5. A recent study demonstrated that a combinatory pattern between APOE and CYP7A1

genes predict a more significant decrease in LDL-C concentrations in response to consumption of 2g/d of PS for 28d5.

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Objective

The goal of this review is to summarize the genetic variants responsible for the responsiveness of blood cholesterol concentrations to dietary PS. Currently, these responses appear to be associated with genetic variations in ABCG8, APOE, CETP, CYP7A1, and NPC1L1.

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Apolipoprotein E (APOE)

gene The APOE gene provides instructions for making a protein called apolipoprotein E6.

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There

are at least three slightly different versions (alleles) of the

APOE

gene:

ε

2,

ε

3

, and

ε

4

6

.

This protein combines with fats (lipids) in the body to form molecules called

lipoproteins

6

.

Apolipoprotein E (APOE) gene and PS

Previous studies showed that carriers of the APOEε3 and ε2 alleles had lower levels of TC and LDL-C levels after consuming 1.1 or 2.2 g/d of PS compared to their cholesterol levels consuming a placebo diet7,5. A recent study showed in 63 mildly hypercholesterolemic individuals who consumed 2 g/d of PS for 28 d that only carriers of the

APOE ε4 isoform had greater LDL-C lowering compared to carriers of the APOEε3

isoform (-0.31 ± 0.007 vs -0.13 ± 0.05 mmol/L, respectively)

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Cytochrome P450 family 7 subfamily A member 1 (CYP7A1) gene

This gene encodes an enzymes involved in the synthesis of cholesterol, steroids and other lipids9.Carriers of the TT genotype of CYP7A1-rs30808607 and carriers of APOEε3 showed an increase in LDL-C levels in response of PS (Δ+0.09 ± 0.08 mmol/L) (Fig. 1)8.

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Fig

1. SNP-SNP interactions between APOE

and CYP7A1 genes on changes in LDL-C concentrations in response to consumption of 2g/day of PS for 28d. Adapted from Mackay et al.

ATP-binding cassette sub-family G member G5 (ABCG5) and G8 (ABCG8) genes

9ABCG5 and ABCG8 are half-size ABC transporters involved in the excretion of sterols from the epithelial cells into the intestinal lumen10 Mutations in ABCG5/G8 genes could impair the function of sterol excretion in the intestine and the liver, thus inducing PS accumulation

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ATP-binding cassette sub-family G member G8 (ABCG8)

geneA crossover study including 19 post-menopausal women showed that after consumption of 1.5 g/d of PS in a based fruit drink (250mL)/d for 4 weeks, CC carriers of the ABCG8 SNP rs6544718 had a higher decrease in TC levels compared to decreases seen in CT/TT carriers (-0.10 vs. -0.070mmol/l)11. Another study including 82 hypercholesterolemic men, carriers of the A-allele of ABCG8 SNP rs4148217 showed 3.9-fold higher reductions in serum TC and LDL-C levels compared to C-allele carriers in response to 2g/d of PS for

28d12.

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Cholesteryl ester transfer (CETP) gene

Cholesteryl ester transfer (CETP) protein collects TGs from lipoproteins (VLDL or LDL) and exchanges them for cholesteryl esters from HDL particles13. A randomized crossover study showed that carriers of the GG genotypes of CETP SNP rs5882 had a more significant decrease in TG levels compared to AA or AG carriers (Δ-0.46 ± 0.13 vs. Δ-0.03 ± 0.08mmol/L) after consumption of 2g/d for 28d of PS14.

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NPC1 Like Intracellular Cholesterol Transporter 1 (NPC1L1)

gene12The protein encoded by this gene plays a major role in cholesterol homeostasis15

.Polymorphic variations in this gene are associated with plasma total cholesterol and LDL-C concentrations and CVD risk15

.A recent study found that CC homozygous carriers for the

NPC1L1-rs2072183 SNP showed an increase in TC and LDL-C levels after consuming PS (+0.38 and +0.33 mmol/L, respectively)11.

Summary

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Table 1

. Summary of studies reporting gene-diet interactions on blood cholesterol concentrations in response to

PS.

Take home message

Polymorphisms in ABCG8, APOE, CETP, CYP7A1, and NPC1L1 genes modify the responsiveness of blood cholesterol to PS. Interactions between polymorphisms in the APOE

and CYP7A1 genes modify the responsiveness of blood cholesterol to PS.

These is evidence of the high susceptibility for certain individuals to have an adverse response to PS

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References

1. Statistics Canada. Table 102-0561 – The ten leading causes of death, 2012. [Internet]. Available from: https://www.canada.ca/en/public-health/services/publications/diseases-conditions/heart-disease-canada-fact-sheet.html.2. Rosato V et al: Meditewrranean diet and cardiovascular disease: a systematic review and meta-analysis of observational studies. Eur

J Nutr 2-19, 2017.3. Kohler J et al: Plant sterol enriched functional food and atherosclerosis. Br. J

Pharmacil 174:1281-1289, 2017.

4. Gylling H et al: Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease. Atherosclerosis 232:346-360, 2014.5. Jones PJ. Inter-individual variability in response to plant sterol and stanol consumption. J AOAC Int 98(3):724-728, 2015.

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References

6. Gene cards, Weizmann Institute of Science [Internet]. Available: https://www.genecards.org/cgi-bin/carddisp.pl?gene=APOE. 7. Sanchez-Muniz FJ et al: Serum lipid and antioxidant responses in hypercholesterolemic men and women receiving plant sterol esters vary by apolipoprotein E genotype. J Nutr 139(1):13-19, 2009.8. MacKay DS et al: CYP7A1-rs3808607 and APOE isoform associate with LDL cholesterol lowering after plant sterol consumption in a randomized clinical

trial.Am J Clin Nutr

102(4):951-957, 2015a.9. Gene

cards, Weizmann Institute of Science [Internet]. Available: https://www.genecards.org/cgi-bin/carddisp.pl?gene=CYP7A1.10. Gene cards, Weizmann Institute of Science [Internet]. Available https://www.genecards.org/cgi-bin/carddisp.pl?gene=ABCG511.

Granado-Lorencio F et al: beta-Cryptoxanthin modulates the response to phytosterols in post-menopausal women carrying NPC1L1 L272L and ABCG8 A632 V polymorphisms: an exploratory study. Genes Nutr 9(5):428-435, 2014.16

References

12. Zhao HL et al: Genetic variation in ABC G5/G8 and NPC1L1 impact cholesterol response to plant sterols in hypercholesterolemic men. Lipids 43(12):1155-1164, 2008.13. Gene cards, Weizmann Institute of Science [Internet]. Available https://www.genecards.org/cgi-bin/carddisp.pl?gene=CETP14. Mackay DS et al: Cholesterol ester transfer protein polymorphism rs5882 is associated with triglyceride-lowering in response to plant sterol consumption. Appl Physiol

Nutr Metab 40(8):846-849, 2015b.15. Gene cards, Weizmann Institute of Science [Internet].

Available: https

://www.genecards.org/cgi-bin/carddisp.pl?gene=NPC1L1&keywords=NPC1L117