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Gene, Diet, Disease

PPARs and Energy Metabolism

Variations of PPAR genes are associated with type 2 diabetes, dyslipidemia and metabolic syndrome due to diet induced metabolism imbalance.

Dietary food, after it is digested, absorbed and metabolized through a variety of metabolic pathways in human body, is usually turned into building materials or energy for maintaining normal cellular and whole body function.  The excess energy, no matter if it is from carbohydrate, fat or protein, is converted into storage fat, which leads to weight gain. When it is needed, such in the case of fasting or exercise, the storage fat is utilized as the major energy supply, which leads to weight loss.  Fat storage and mobilization for energy are highly regulated energy metabolism pathways. PPAR (peroxisome proliferator-activated receptors) genes are master regulators in these processes.

There are 3 PPAR genes in human: PPARA, PPARD and PPARG.  The protein product of PPARA is PPARα, which is mainly responsible for liver fatty acid oxidation (fat burning to produce energy) during fasting.  The serum triglycerides lowing drug fibrates specifically target this protein. PPARD encodes the protein PPARδ (also known as PPARβ or PPARβ/δ), which promotes fatty acids synthesis in liver while activates fat burning in muscle. The protein product of PPARG is PPARγ, which is mainly responsible for lipid synthesis in adipocytes (energy storage) and also serves as the target of the anti-diabetes drug TZDs (thiazolidinediones).  Interplay of these three PPARs, modulated by environmental factors such as food, exercise and medicine, plays critical roles in regulating energy storage and expenditure. Besides their roles in lipid and glucose metabolism, PPARs are also involved in adipogenesis (fat cell development) and osteogenesis (bone cell development), carcinogenesis, and immune response.  Dysfunction of these genes or imbalance of their activities leads to various diseases including metabolic syndrome, T2DM (type 2 diabetes mellitus), obesity, cardiovascular diseases, and inflammation.  Polymorphisms among these genes result in altered biochemical activity and differential dietary interaction, ultimately reflected in their risk association with chronic diseases such as metabolic syndrome, T2DM and dyslipidemia.  The most common and biologically significant polymorphisms of these genes are PPARγ2 Pro12Ala, PPARα Leu162Val and PPARδ -87T>C (Table 1). Each is associated with risk factors for distinct chronic diseases that are the result of overall energy metabolism imbalance.

Table 1. Allele frequency of three common polymorphisms in PPARs.  Exceptional frequencies are the ones that are out of the range of the ethnic groups. More detailed frequency distribution information is available in later sections.

Polymorphism PPARγ Pro12Ala PPARα Lue162Val PPARδ -87T>C
Alleles Major (Pro) Minor (Ala) Major (Leu) Minor (Val) Major (T) Minor (C)
Africans 98-100% 0-2% 99.4-100% 0-0.6% 71-81% 19-29%
Asians 96-97% 3-4% 95% 5% 72-76% 24-28%
Caucasians 83-93% 7-17% 93-94% 6-7% 76-79% 21-24%
Hispanics 88% 12% Unknown Unknown Unknown Unknown
Exceptional distribution Minor allele in India: 12% Minor allele in India: 38%; Spain: 16%. Minor allele in Israel: 35%

The PPARγ2 Pro12Ala polymorphism is highly related to obesity and T2DM.  The major allele (Pro) of this polymorphism represents one of the “thrift genes” that regulates energy metabolism by converting excess energy intake into body fat for energy storage. It is one of the top genetic factors that are liable for obesity and T2DM caused by long term excess energy intake (positive energy balance). The minor allele (Ala) is less active in its biochemical activity, thus has lost in some degree the function of the “thrift genes”.  It reduces the risk for obesity and T2DM.  Given the same dietary calorie intake, non-overweight Ala carriers are less likely to gain weight.  But once they become overweight, Ala carriers will lose weight much slower than homozygous Pro carriers. In population with the homozygous Pro/Pro genotype, dietary total fat percentage and the P:S (polyunsaturated fatty acid: saturated fatty acids) ratio correlate with weight gain.  A higher percentage of fat as the total energy intake normally leads to a higher BMI. A higher P:S ratio normally leads to a lower BMI.  In contrast, these correlations do not exist in Ala carriers.  Instead, the percentage of MUSF (monounsaturated fatty acids) play important role in dietary response in Ala carriers.  A higher percentage of MUSF in dietary intake correlates with lower BMI and this correlation is not observed in the homozygous Pro/Pro genotype carriers.  Based on these observations, dietary management recommendations for obesity and T2DM prevention in the Pro/Pro genotype include: 1) Perform calorie count to avoid excessive energy intake; 2) Reduce dietary total fat and 3) Increase the P:S ratio of dietary fat.  There are two special dietary recommendations for the minor allele Ala carriers: 1) Perform calorie count to avoid excessive energy intake; 2) Increase the percentage of MUSF as the total energy in diet.

The PPARα Leu162Val polymorphism is associated with dyslipidemia.  The minor allele (Val) is associated increased BMI (body mass index), accompanied by higher level of low density lipoprotein-cholesterol (LDL-C) and other cardiovascular risk factors.  In addition to its effect on fasting lipid parameters, the Val carriers also exhibit a higher risk for stage C heart failure.  The Leu to Val change at amino acid 162 occurs in the DNA binding domain of the PPARα protein. This results in altered protein-fatty acids interactions. In the absence or at low fatty acids concentrations, the activity of the Val allele is about a half of the activity of the Leu allele. At high fatty acids concentrations the Val allele activity can be 5-fold higher than the activity of the Leu allele. Dietary PUFA (polyunsaturated fatty acid) intake interacts with the Leu162Val polymorphism, leading to differentially modulated plasma triglycerides levels in the major and minor allele carriers.  In the homologous major allele (Leu/Leu) carriers, PUFA intake (as the percentage of total energy) is positively correlated with plasma triglycerides levels. Higher PUFA intake leads to a slightly higher plasma triglyceride level. However, in Val allele carriers this correlation is negative.  Higher PUFA intake leads to lower triglyceride level.  Since high plasma triglycerides is a risk factor for cardiovascular diseases, a special dietary recommendation for the Val allele carriers of PPARα Leu162Val polymorphism is to increase PUFA intake to 8% or more of the total energy intake.

The PPARδ -87T>C polymorphism, also known as PPARδ + 294T>C, is caused by a substitution of major allele T for a minor allele C at the 87 nucleotides upstream of the coding region (which is 294 nucleotides downstream of the transcription starting site) of the PPARδ gene.  This change results in the minor allele having a higher transcriptional activity than the major allele.  The PPARδ -87T>C polymorphism is associated with BMI, HDL-C (high-density lipoprotein cholesterol), and leptin (an appetite and energy expenditure controlling hormone) in a gender-dependent manner. In males, the minor allele associates with lower BMI and leptin, and higher HDL cholesterol levels. In females the minor allele associates with an increased BMI and decreased HDL cholesterol but no association with leptin level.  More importantly, the minor allele of this polymorphism is associated with a reduced risk for metabolic syndrome, a constellation of metabolic disorders that features visceral obesity, insulin resistance, dyslipidemia and hypertension. The reduced risk for metabolic syndrome in the minor allele is only observed in population with lower fat intake (less than 34.4% total fat energy).  When the fat intake exceeds 34.4%, the protective effect of the minor allele no longer exists.  In the minor allele carriers, HDL level is higher in those who take low-fat diet (total fat < 34.4%) and lower in those who take high-fat diet (>34.4%). In contrast, the total fat intake does not correlates with the HDL in the homozygous major allele (− 87T/T) carriers. Since HDL correlates with lower risk for cardiovascular diseases and MS, it is recommended for the PPARδ -87T>C polymorphism minor allele carriers (-87T/C and -87C/C) to restrict the total fat intake below 34.4% of the total energy to take the advantage of the protective effect against metabolic syndrome.

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