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What are the health consequences for having the CG variant of the proliferator-activated receptor alpha (PPAR-α) gene?
Hello! Thanks for your question about the health consequences of having the CG variant of the PPAR-alpha gene. The most useful sources I found to answer your question are the National Center for Biotechnology Information and selfhacked.com. The short version is that the effects of a CG variant of the proliferator-activated receptor alpha gene is largely new and unknown, but are associated with regulation of one's metabolism. Below you will find a deep dive of my findings.
WHAT ARE PEROXISOMES AND PPARs?
Peroxisomes are found in plants and animals, and contain enzymes that assist in cholesterol and lipid metabolism. Proliferators expand the size and quantity of peroxisomes, working through specific hormone receptors called PPARs.
PPARs affect genes responsible for cell proliferation and differentiation, as well as immunity and inflammation responses. Three subtypes of PPARs have been identified (alpha, beta/delta, and gamma). Since the request focused on the alpha subtype, this response will only focus on the alpha subtype.
HOW PPARa WORKS
Subtype alpha (PPARa) is a "nuclear transcription factor" and plays a role in regulating metabolism by increasing fat breakdown. The highest instances of PPARa are found in the liver. One study focusing on the effects of PPARa on the liver found that PPARa impacts activities such as fatty acid uptake and activation, ketogenesis, triglyceride turnover, bile synthesis/secretion, and other secreted proteins dealing with endocrine functions.
Research shows that PPARa regulates metabolism in the liver during fasting by regulating glucose production. It is also responsible for amino acid metabolism, and is a receptor for hypolipidemic fibrate drugs. In humans, these fibrates increase plasma HDL and reduce plasma triglycerides, which is useful in treating dyslipidemia. However, research has found that chronic administration of PPARa to rodents leads to liver cancer, raising concern over the administration of drugs to humans.
PPARa plays an important role in metabolizing fat and losing weight. Chronic high-fat diets, such as the ketogenic diet, may activate PPAR. "A ketogenic diet is almost entirely devoid of carbohydrate and elicits a metabolic state of low insulin, high plasma free fatty acids, and enhanced ketogenesis, that resembles fasting. ... The lower the amount of sucrose and the higher the proportion of poly-unsaturated fatty acids, the stronger the activation of PPARa."
Aside from breaking down fatty acids and regulating blood sugar levels during fasting, PPARa also helps with metabolizing drugs and toxins, was found to inhibit diseases such as Multiple Sclerosis, protect against heart disease, and increase muscle.
On the other hand, it is known to cause insulin resistance in the liver. Also, genetic variants within PPARa have been linked to developing dyslipidemia and cardiovascular disease by causing fasting, and speeding up the progression of type 2 diabetes.
For example, one study found that patients with diabetes but without non-alcoholic fatty liver disease (NAFLD) did not have any significant difference in serum levels of the protein adiponectin regardless of genotype. However, those patients with diabetes and NAFLD had lower levels of adiponectin if their genotype was GG rather than those with a CG or CC genotype. The research suggests that the G/G variant is associated with hypoadiponectinemia and susceptibility to NAFLD.
Another study found that the C variant is associated with a diagnosis of increased total cholesterol, LDL cholesterol, and risk of nonfatal myocardial infarction at a significantly earlier age in white subjects with type 2 diabetes. In contrast, some C variant carriers had significantly lower total cholesterol and LDL cholesterol levels (those with and without a confirmed diagnosis of coronary artery disease). However, the presence of the C allele showed a positive association with dyslipidemia (i.e., a plasma cholesterol concentration of ≥200 mg/dL, a TG concentration ≥180 mg/dL, or the intake of lipid-lowering drug)s in an Indian population. Although inconsistencies associated with CG variant polymorphism exist, the discrepancy may be explained by environmental factors, genetics, medications, and concentrations of fats in the diet.
To wrap it up, "lifestyle, drugs, and dietary modifications, including consumption of foods that can activate PPARa, can affect its metabolic responses; however, the specific response will depend on the interactions between these factors and the genetic variants. Therefore, environmental factors and genetic background should be considered to determine the effect of different polymorphisms on disease risk." While research shows that diet can have long-lasting effects on PPARa gene expression, current studies of PPARa genetic variations and their effects are few. Thanks for using Wonder! Please let us know if we can help with anything else!