As part of my M.S. in Human Nutrition program, I am learning about nutrigenomics, which is the scientific study of the interaction between nutrition and genes. I am really fascinated with this topic, and have decided to share some of the information I am learning as I go along. This post is about the different ways in which variations in lipid metabolism genes interact with dietary fat intake. Note that understanding this area of nutrition is a work-in-progress, but my hope is that the information discussed here might interest you, and (if you have done genetic testing such as 23andme) perhaps help you better understand how your diet and genetics are interacting within your own body, influencing factors such as blood lipid levels and body weight.
For many years, dietary fats have been the source of much contention in the nutrition world. The 2015-2020 U.S. Dietary Guidelines recommend that Americans consume 5 tsp of oil per day (based on a 2,000 kcal diet). The Guidelines also recommend that saturated fat intake be limited to less than 10% of kcal per day, and that they be replaced with polyunsaturated and monounsaturated fats when possible. In addition, trans fat intake is to be kept at as low a level as possible, due to this type of fat’s tendency to raise LDL cholesterol and increase the risk of cardiovascular disease. Finally, while the recommendation to limit cholesterol consumption has been removed in this most recent incarnation of the U.S. Dietary Guidelines, the Guidelines state that “this change does not suggest that dietary cholesterol is no longer important to consider when building healthy eating patterns. As recommended by the IOM, individuals should eat as little dietary cholesterol as possible while consuming a healthy eating pattern” (“A Closer Look Inside Healthy Eating Patterns,” n.d.).
While these dietary fat intake recommendations are treated as broad-spectrum recommendations for Americans, the reality of the issue is much more nuanced. This is due to the fact that genetic differences in lipid metabolism exist in humans. Single nucleotide polymorphisms in the following human genes have been found to affect lipid metabolism and transport, along with plasma cholesterol and triglyceride levels, in conjunction with dietary fat intake: PPARG, CETP, LPL, APOC3, and APOA1 (Costa, Casamassimi, & Ciccodicola, 2010). In light of these genetic differences, several of the dietary guidelines regarding fat intake may not only be unnecessary, but may also be deleterious in regards to health.
While there is a 20-year old body of research studying the relationship between nutrition and lipid-related genes, much of the information is controversial, and many of the studies offer contradictory results. Nonetheless, there are some important findings that have been elucidated from this research. In regards to the APOA1 gene, a diet high in polyunsaturated fatty acids (PUFAs) increased HDL cholesterol in female carriers of the A allele for the gene, whereas females who were homozygous for the G allele experienced the opposite effect – PUFA intake decreased their HDL cholesterol levels (Ordovas et. al., 2002). This finding has significant implications in regards to the dietary recommendations regarding PUFA intake; HDL cholesterol is considered the “good” type of cholesterol, so recommending increased PUFA intake would be appropriate for female A allele carriers for the APOA1 gene, but would actually be detrimental for women homozygous for G alleles for the gene, as this dietary modification would lower their HDL levels.
Another study that examined the relationship between dietary fat intake and the APOA1 gene found that a diet high in all types of fatty acids (including saturated, monounsaturated, and polyunsaturated fatty acids) was more likely to cause lower levels of LDL cholesterol levels in women who were carriers of the A allele for the gene than in those who were homozygous for the G allele. This effect was not found in men with the A allele for APOA1 (Mata, Lopez-Miranda, et. al., 1998). LDL cholesterol is generally considered to be the “bad” form of cholesterol, as increased levels of it have been correlated with an increased risk of CVD. Since this study indicated that a high intake of fats resulted in lower LDL cholesterol in women with the A allele for APOA1, this information suggests that a high-fat diet may not be a risk factor for abnormal blood lipids in women with this particular single nucleotide polymorphism. Conversely, a high intake of fats (even healthy fats such as monounsaturated fats) may not be healthy for women with the G allele of the APOA1 gene, since their LDL cholesterol rose with increased fat intake. However, there also may be a couple confounding factors in this study, since polyunsaturated, monounsaturated, and saturated fats were not examined separately in relation to the different APOA1 SNPs and LDL particle number.
Finally, a third example of a single nucleotide polymorphism that has been shown to influence lipid metabolism, and may therefore impact the effectiveness of the Dietary Guidelines for dietary fat intake, is the relationship between SNPs in the APOC3 gene and triglyceride metabolism. APOC3 is an inhibitor of an enzyme called Lipoprotein lipase (LPL), which breaks down triglycerides in VLDL particles and allows tissues to take them up. Increased LPL expression leads to increased triglyceride storage whereas LPL deficiency prevents triglyceride storage. Increased triglyceride storage is associated with obesity. In an animal study, mice that had homozygous alleles for APOC3 had increased LPL activity, decreased plasma triglycerides, increased triglyceride storage in adipose tissue, and increased obesity. Heterozygous mice for APOC3, on the other hand, did not experience these same deleterious effects (Duivenvoorden, Teusink, Rensen, et. al., 2005). While this research was done on mice rather than humans, it suggests that genetic polymorphisms, not just dietary intake of fats, may affect triglyceride levels in organisms. Therefore, broad-spectrum recommendations to lower dietary fat intake may actually not be useful for all individuals who are making efforts to decrease triglyceride levels. Since concerns about blood lipids are a major area of interest for health professionals, I think this nutrigenomic information regarding the relationship between dietary fat intake and lipid metabolism genes is extremely important. The implementation of dietary treatment strategies that take into account these genetic differences could potentially be life-changing for many people.
- PPAR gamma 2 gene Pro12Ala mutation is associated with higher food efficiency, meaning more energy is obtained from food per unit of body weight. This means that carriers of the Pro12Ala snp are able to store more energy (as fat) and thus have a higher BMI compared to non-carriers of the snp, even when food intake is similar between the two groups (Vaccaro, Lapice, Monticelli, et. al., 2007).
- CETP B1B1: Alcohol consumption can increase HDL cholesterol.
- APOA1 A allele female: Decreased LDL cholesterol with increased saturated, monounsaturated, and polyunsaturated fat intake. HDL cholesterol increase with increased polyunsaturated fat intake. A moderate-to-high fat diet might work for individuals with this snp.
- APOA1 G allele female: LDL cholesterol was not lowered with increased saturated, monounsaturated, and polyunsaturated fat intake. Decreased HDL cholesterol with increased polyunsaturated fatty acid (PUFA) intake. Decreasing PUFA intake may help increase HDL cholesterol.
- APOC3 homozygous: Increased lipoprotein lipase activity, decreased plasma triglycerides, increased triglyceride storage in adipose tissue, increased obesity.
- APOC3 heterozygous: Reduced fatty acid uptake into adipose tissue, reduced incidence of obesity.
A Closer Look Inside Healthy Eating Patterns. (n.d.). Dietary Guidelines 2015-2020. Retrieved from https://health.gov/dietaryguidelines/2015/guidelines/chapter-1/a-closer-look-inside-healthy-eating-patterns/#callout-dietaryfats.
Costa, V., Casamassimi, A., and Ciccodicola, A. (2010). Nutritional genomics era: opportunities toward a genome-tailored nutritional regimen. Journal of Nutritional Biochemistry, 21(2010): 457-467. Retrieved from file:///C:/Users/Lindsay/Downloads/Nutritional%20Genomics.pdf.
Duivenvoorden, I., Teusink, B., Rensen, P.C., Romijn, J.A. Havekes, L.M., and Voshol, P.J. (2005). Apolipoprotein C3 Deficiency Results in Diet-Induced Obesity and Aggravated Insulin Resistance in Mice. Diabetes, 54(3): 664-671. Retrieved from http://diabetes.diabetesjournals.org/content/54/3/664.long.
Mata P, Lopez-Miranda J, Pocovi M, Alonso R, Lahoz C, Marin C, et al. (1998). Human apolipoprotein A-I gene promoter mutation influences plasma low density lipoprotein cholesterol response to dietary fat saturation. Atherosclerosis, 137:367–76. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/9622280.
Ordovas, J.M., Corella, D., Cupples, L.A., Demissie, S., Kelleher, A., Coltell, O., . . . Tucker, K. (2002). Polyunsaturated fatty acids modulate the effects of the APOA1 G-A polymorphism on HDL-cholesterol concentrations in a sex-specific manner: the Framingham Study. American Journal of Clinical Nutrition, 75(1): 38-46. Retrieved from http://ajcn.nutrition.org/content/75/1/38.full.
Vaccaro, O., Lapice, E., Monticelli, A., Giacchetti, M., Castaldo, I., Galasso, R., Pinelli, M., Donnarumma, G., Rivellese, A..A, Cocozza, S., Riccardi, G. (2007). Pro12Ala polymorphism of the PPARgamma2 locus modulates the relationship between energy intake and body weight in type 2 diabetic patients. Diabetes Care, 30(5): 1156-1161. Retrieved from http://care.diabetesjournals.org/content/30/5/1156.long.