Should You Avoid the Keto Diet & Saturated Fat? (PPARA, a Fat-Burning Gene)

The PPARA gene is responsible for producing a protein called PPAR-α or PPAR alpha (short for peroxisome proliferator-activated receptor alpha) [R]. 

PPAR alpha is a key regulator of fat burning. More broadly, it controls energy balance and the metabolism of fats, carbohydrates, and amino acids [R, R]. 

The PPARA gene is important for determining your response to diet because PPAR alpha is under the strong influence of nutrients, especially fats. Its main natural activators are polyunsaturated fatty acids (PUFAs) [R]. 

When it comes to synthetic compounds, PPAR alpha is activated by drugs used to treat high blood fats (dyslipidemias). Other PPAR-alpha activators are being developed, which further emphasizes this protein’s role in maintaining fatty acid balance in the body [R]. 

PPARA is a key fat-burning gene that's under the strong influence of diet. 

PPAR Alpha and the PPAR Family

PPAR alpha is part of the larger PPAR family, which also includes PPAR gamma (PPARG) and PPARB/D (PPARβ/δ). 

In general, PPARs bind to polyunsaturated fatty acids. However, different fatty acids activate different PPARs, triggering diverse downstream effects [R]. 

For example, we know that PPAR alpha stimulates fat burning. But its close relative, PPAR gamma, seems to do the opposite. PPAR gamma helps preserve fat stores, making quick weight loss harder [R, R, R].   

You can read more here about how certain PPARG variations might help you lose weight on the Mediterranean diet. 

Although both belong to the same family, PPAR gamma appears to be a “maintenance” gene, whereas PPAR alpha is undoubtedly a metabolism-activating, catabolic one.

How PPAR Alpha May Rev Up Fat Burning

PPAR alpha is found mostly in the liver and brown fat–the “good” fat that turns food into body heat. Smaller amounts of PPAR alpha can also be expressed in the heart, kidneys, gut, and immune cells [R, R].

Therefore, PPAR alpha seems to be strategically positioned to make us burn fat for energy. Fat burning starts in the liver, which releases energy and breakdown products into the bloodstream (via fatty acid oxidation)  [R, R, R].  

The fat-burning process is continued in brown fat tissue, which is packed with mitochondria. As the end result, these dense mitochondria effectively turn calories from the liver’s fat breakdown products into heat [R, R, R]. 

This hints at PPAR alpha’s role in ketosis–and individual differences in response to ketogenic diets. 

PPAR Alpha Enables Ketosis

PPAR alpha can be activated when the body turns to burning fat for energy. Normally, we mainly burn carbohydrates for energy. The switch to burning fat as the primary energy source happens only during fasting or starvation, caloric restriction, and carbohydrate restriction (as on the keto diet) [R, R]. 

When the body needs to break down fat for energy, fat tissues release fatty acids. These fatty acids travel to PPAR alpha in the liver and immune cells. In turn, PPAR alpha enhances the production of ketone bodies–the key step to entering nutritional ketosis [R, R]. 

If PPAR alpha is not functioning well, fat burning and ketone body production may become impaired [R, R]. 

Recent experiments suggest that dietary fats are stronger activators of liver PPAR alpha than the fatty acids released from fat tissue. This might mean that ketogenic diets activate PPAR alpha better than fasting or caloric restriction does, but clinical evidence is still lacking to back up the link [R]. 

Good PPAR alpha activity helps the body burn fat for energy and enter nutritional ketosis. 

Does PPAR Alpha Make the Keto Diet Anti-Inflammatory?

As part of this ketogenic pathway, PPAR alpha activation may also block inflammatory signals like NF-kB. Thus, PPAR alpha is often described as an anti-inflammatory protein [R, R].  

This mechanism might, at least in part, also explain the proposed anti-inflammatory and antioxidant effects of the keto diet [R, R].  

Indeed, drugs that activate PPAR alpha (fibrates) seem to reduce both blood lipids and blood vessel inflammation. Researchers suspect that the reverse is also true: poor PPAR alpha function may trigger or worsen inflammation. However, we need more human studies to know this for certain [R]. 

Given PPAR alpha’s involvement in fat metabolism and energy balance, associations between PPARA genetic variants and abnormal lipid levels (dyslipidemia), heart disease, and type 2 diabetes do not come as a big surprise. Yet many of these associations remain to be confirmed in larger studies [R]. 

Scientists are optimistic that they’ll be able to identify ways to personalize dietary recommendations by studying the interactions between PPARA genetic variants and the response to different diets  [R].   

So far, the most well-studied PPARA SNP in nutrigenomics is rs1800206. 

The less common (minor) G allele of rs1800206 (also known as the L162V polymorphism) reduces PPAR alpha activity, according to the available data [R].  

Carrying the G allele (GG or GC genotypes) has been associated with [R]:

• Increased heart disease risk in whites, with higher levels of triglycerides, total cholesterol, LDL cholesterol, apoA1, and apoB and decreased levels of HDL
• Poor response to saturated fat, which worsens heart disease risk, making ketogenic diets high in saturated fat a dangerous choice
• Beneficial response to polyunsaturated fatty acids (especially omega-3s/fish oil), which may support heart health and general well-being
• Possible, but uncertain impact on diabetes development

The negative effects of this genotype seem to be more pronounced in men than in women and in whites than in Asians. Data on other ethnicities are sparse [R]. 

G-allele carriers of rs1800206 might have trouble entering ketosis, possibly due to lower PPARA activity.  

Please have in mind that many other genetic and non-genetic factors also influence a person’s response to diet and different nutrients. Additionally, remember that dietary interventions should always be part of a holistic approach to health that also takes lifestyle factors and your medical conditions into account. 

With this in mind, let’s take a look at the specific dietary modifications that each genotype might benefit from–and how the keto diet plays in. 

Keto-Suited? Response to Total and Saturated Fat Intake

A study of 674 participants found that PPARA rs1800206 G-allele carriers seem to do worse on a diet high in total and saturated fat (7% or more of daily energy intake) [R]. 

Specifically, people carrying at least one G allele who consumed high amounts of saturated fat had smaller LDL particles than those with lower intakes, putting them at a greater risk of heart disease. Smaller, densely packed LDL particles are considered to be more dangerous and worse for heart health than bigger particles. 

Before the importance of LDL density was discovered, saturated fat was unfairly demonized. Research then revealed that low-carb diets high in saturated fat–similar to most paleo-style, high-protein keto diets–do increase total LDL. But this turned out to be entirely due to an increase in large, less dangerous LDL particles [R]. 

Further studies opened more questions, and the whole saturated fat dispute remains unresolved. For example, researchers showed that a diet low in carbs and high in saturated fat and beef protein may increase LDL particles across the full size spectrum [R]. 

Nonetheless, higher saturated fat intake is mainly linked with more large, “good” LDL particles in most people, according to the evidence. Genetics is there to fill in the gap and give us clues about what people who don’t fit into the “normal” majority should do [R]. 

And based on the data we have, carriers of the less common G allele (GG or GC genotypes) don’t seem to be well suited for a ketogenic diet that is high in saturated fat [R].

The opposite may be true for CC carriers, the majority, who may indeed reap the benefits of saturated fat. Therefore, most people seem to be well suited for ketogenic diets [R]. 

Among people with the CC genotype, those with higher saturated fat intakes had larger LDL particles than those with lower saturated fat intakes. Thus, CC carriers were somewhat protected against heart disease–at least when it comes to LDL density–with higher saturated fat intake. 

Hypothetically, the observed effects might be explained by varying PPAR alpha function. 

CC rs1800206 carriers might be more efficient at burning fat and generating ketones for energy. This process may also support heart health and general well-being by activating anti-inflammatory pathways, but more research is needed.

Potential Keto Diet Modifications: PUFA Intake & Heart Health 

A pivotal analysis that included 2373 people from the Framingham Offspring Study stresses the importance of PUFAs for carriers of the rare PPARA rs1800206 allele. 

This analysis initially found an association between the G allele of rs1800206 and higher total and LDL cholesterol in men and apolipoprotein B in both genders. The LDL cholesterol link was even stronger in carriers of the “good” E2 APOE allele, suggesting close relationship between these two genes [R]. 

A follow-up study investigated how dietary fat intake might affect this association. They included 2106 people from the same cohort and concluded that G-allele carriers had greater triglyceride and apoC-III levels when they consumed a low-PUFA diet (6% or less of energy from PUFAs). But when their PUFA intake was high, they had lower triglyceride and apoC-III levels. ApoC-III is an emerging marker of heart disease and high triglycerides [R, R].

The authors pointed out that the more PUFAs G-allele carriers ate, the more their triglycerides and apoC-III levels dropped–and vice versa: the lower their PUFA intake, the more these markers spiked. 

For example, when the diets of G-allele carriers had <4% PUFA out of total calories, their triglycerides were about 28% higher than the levels in CC carriers. But when PUFA their intake was >8%, they had 4% lower triglycerides than their CC counterparts. The same was true for both omega-3 and omega-6 fatty acids–the two main PUFA classes.

Theoretically, a higher PUFA intake might make up for lower PPARA activity in G-allele carriers. Many other factors might explain this link too, and more research is needed to better understand them. 

All in all, people carrying the less common G allele do better on a diet high in PUFAs: omega-3 and omega-6 fatty acids. They can still consume a modified, Mediterranean-style keto diet, but they don’t do well when their diet is poor in PUFAs.  

Omega-3s from fish are especially important since they’re known to be heart-healthy and anti-inflammatory. Most Western diets lack omega-3 fatty acids and overabound in omega-6 fatty acids, which might worsen inflammation [R].

A diet high in omega-3 PUFAs is still the healthiest choice even for people carrying the more common CC genotype. However, these studies only suggest that CC carriers might be less prone to triglyceride spikes if their diet happens to be a bit lower in PUFAs, as most diets that rely on animal fat are [R].  

People with the more common PPARA SNP were less likely to get high triglycerides from a variety of fats, while those with the less common variants required more PUFAs (omega-3s like fish oil).

Limitations 

More research is needed to understand how gender impacts this genetic variation. Based on the existing data, the negative impact of the rare G allele of PPARA rs1800206 may be more pronounced in men. 

In the Framingham Offspring Study, the G allele was associated with raised total and LDL-cholesterol and apo B levels in men. In women, only the apoB rise was statistically significant. Similar gender differences were reported in another Canadian study [R]. 

PPAR Alpha’s Downstream Genetic Effects

As one of the main switches for fat balance in the body, PPARA can influence many other genes. These include genes involved in fat transport (APOA1, APOA2, and APOA5), fat burning (CPT-I, CPT-II, delta-6-desaturase), HDL metabolism (PLTP), and ketone production (HMGCS2) [R].

You can see your genotypes for the main PPARA SNP in the table below. However, keep in mind that these results are based purely on association studies, and much more research will be needed to know what role—if any—these variants play in actually directly impacting a person’s response to diet.

By extension, just because a person might have some “risk-associated” genotypes for some of these SNPs does not necessarily mean that they will actually develop the health condition associated with it!

This is because there are many different genetic, lifestyle, and environmental factors that can affect lipid levels, heart health, and diet compatibility. In other words, having a “bad” PPARG genotype does not necessarily predict anything specific about a person’s response to diet— rather, these results illustrate just one of the many different genetic factors potentially related to it.

With that in mind, the following table summarizes your results for the main PPARG SNP that have been linked to the health effects of a ketogenic diet high in saturated fat:

SNP Summary and Table

Primary SNP: PPARA rs1800206 

• ‘CC’ = Well suited for the keto diet; good response to most types of fat, including saturated fat and omega 3s/fish oil.
• ‘CG’ and ‘GG’ = Not well suited for a keto diet high in saturated fat; good response to PUFAs like omega 3s/fish oil. 

Population Frequency

Overall, about 96% of the worldwide population have the CC genotype for rs1800206, 4% have the CG genotype, and only 0.2% have GG. The GG genotype is so rare that it’s sometimes not even reported, and CG and GG genotypes are always viewed together in studies. 

There are some interesting differences across ethnicities. To break the numbers down:

• No East Asians or Peruvians seem to carry the G allele (100% are CC)
• Only 1% of Africans are CG or GG
• About 5% of South Asians are CG or GG
• Around 6% of Latin Americans are CG or GG
• 11% of people of European descent are CG or GG

Also, around 11% of people in Columbia have the CG genotype. 

There are some exceptions among South Asians: approximately 7% of Punjabi and 8% Sri Lankan Tamil populations are CG. 

Among Europeans, about 14% of British people, 19% of the Iberian population in Spain and 9% of people living in Tuscany (Italy) have the CG genotype.