Palmitic Acid; not our friend?

[Julie G]

Here’s a relatively new data-rich paper that supports Dr. Gundry’s assertion that E4 carriers should avoid animal fat.

APOE genotype influences insulin resistance, apolipoprotein CII and CIII according to plasma fatty acid profile in the Metabolic Syndrome
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524844/

Metabolic markers associated with the Metabolic Syndrome (MetS) may be affected by interactions between the APOE genotype and plasma fatty acids (FA). In this study, we explored FA-gene interactions between the missense APOE polymorphisms and FA status on metabolic markers in MetS. Plasma FA, blood pressure, insulin sensitivity and lipid concentrations were determined at baseline and following a 12-week randomized, controlled, parallel, dietary FA intervention in 442 adults with MetS (LIPGENE study). FA-APOE gene interactions at baseline and following change in plasma FA were assessed using adjusted general linear models. At baseline E4 carriers had higher plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) compared with E2 carriers; and higher TC, LDL-C and apo B compared with E3/E3. Whilst elevated plasma n-3 polyunsaturated FA (PUFA) was associated with a beneficially lower concentration of apo CIII in E2 carriers, a high proportion of plasma C16:0 was associated with insulin resistance in E4 carriers. Following FA intervention, a reduction in plasma long-chain n-3 PUFA was associated with a reduction in apo CII concentration in E2 carriers. Our novel data suggest that individuals with MetS may benefit from personalized dietary interventions based on APOE genotype.

As you can see below, our genotype yielded a higher HOMA-IR score with higher levels of C16:0, or palmitic acid. Palmitic acid can be found in full-fat dairy and red meat.

An interesting finding in the present analysis was the detrimental association between high plasma C16:0 on markers of insulin resistance, defined by HOMA-IR > 2.656, in E4 carriers. Although E4 carriers with low plasma C16:0 at baseline were not ‘insulin resistant’ (HOMA-IR, =2.35), those with high plasma C16:0 had a 31% greater HOMA-IR. This represents a novel finding and may suggest that E4 carriers with MetS are particularly sensitive to the detrimental metabolic effects of high palmitic acid (C16:0) levels. It is of note that increased plasma C16:0 has been associated with risk of type 2 diabetes, which could be in part due to increased insulin resistance57; our findings indicate that this relationship is amplified in E4 carriers. Previous studies have also shown a negative impact of diets rich in C16:0 and SFA on insulin sensitivity index (SI) in overweight individuals58, 59. However, several studies including the LIPGENE study, found no impact of reducing SFA on SI 29. The lack of effect found in the primary LIPGENE analysis highlights the importance of the APOE genotype (E4) on insulin-glucose homeostasis in metabolically challenged individuals.

[Spittinchips]

Thanks for the paper, Julie.

Personally, when I see something like this, the first thing to seek out is exactly what they mean by "high fat diet". In a separate paper, they elaborate. http://tinyurl.com/yb6z9slz

The high SFA diet had them eating 41-43% carbohydrate and 16% SFA (38% total fat). They also ate slightly less protein than the lower fat diets.

Sure, you can compare that with the MUFA diet and say MUFA was better, but in the context of 40%+ carbs, I can't see how this tells us anything useful.

"The reintroduction of fat involved the use of specifically designed study foods manufactured by Unilever Food & Health Research Institute"

"The study foods included spreads, cooking oils, baking fats and mayonnaises. These foods contained fat that was easily manipulated and exchanging these foods within the volunteers’ diet had minimal impact on their usual dietary habits. Three types of spreads were available and formulated to be either high in SFA, high in MUFA or low in fat."

The food for the HSFA diet include "spread, oil replacement, biscuit"

I don't know what a study biscuit would taste like, but I'm pretty sure no-one around here would be putting one in their mouth.

Cheers.

[Russ]

Good find Julie. Seemingly important caveats made by Spittinchips that may make much moot, though? Even aside from carb loads, anything involving synthetic processed fats is suspect out of the gate for me anyway. In an un-noted detail, I would also note that all study subjects were walking around already inflamed at baseline (Table 2 CRP =4.4-5.3) which is not a surprise (and is likely case for all studies done to date), although not clear what the impact might be on this study's outcomes?

Of course I would be remiss in not including the obligatory education moment w/r grassfed beef . Although much attention is often paid to n3's and CLA, there is a notable difference in literature in C16 (palmitic) and C18 (stearic) acids profiles. Below chart is proportion of just fat (i.e. removing effect of leanness), where you can see fraction of SFA's stays about the same (~40%), but notable increase in C18 clearly associated with decline in C16.

Relative Fatty Acid Profile of Grass vs Grainfed Beef (Daley).png

[circular]

Exploring this a little further, to Spittinships point about dietary fat in the context of high carbs, I found:

Poor Diet, Plus Alzheimer’s Gene, May Fuel Disease (Not sure if it's already been posted here.)

A diet high in cholesterol, fat and sugar may influence the development of Alzheimer’s disease in people who carry the ApoE4 gene...

For the study, researchers at the USC Leonard Davis School of Gerontology compared the effects of a poor diet on groups of mice that either had the Alzheimer’s-associated ApoE4 gene or the relatively benign variant of the gene, ApoE3. After eating an unhealthy diet, the mice with the ApoE4 gene showed more Alzheimer’s plaques – a marker for inflammation – in their brains, but those with ApoE3 did not...

The results in the mice indicate a relationship between [fatty, sugary] diet and the growth of plaques and other signs of brain inflammation for mice with ApoE4.

[He goes on to say ...]

"... further study is needed to understand the relationship between the two. Research already has shown that even a brief spate of poor diet can inflame glia, the brain cells responsible for immunity response.

“That means there are probably components directly in the diet, and one of those are fatty acids, like palmitic acid, that trigger inflammation because they can go in and directly affect glia,” Pike said. “But that may be just one inflammation-related component of Alzheimer’s disease.”

Glia are helpful inflammation signalers in the brain, except when they're not. Research is focused on how to modulate glia rather than quell all their activity. I wonder just how palmitic acid 'affects' glia? Does it disrupt pathways, and moreso in ApoE4s, that modulate glia appropriately?

Now consider this recent paper:

Sex differences in the phagocytic and migratory activity of microglia and their impairment by palmitic acid.

These findings extend previous observations of sex differences in microglia and suggest that palmitic acid impairs the protective responses of these cells.

A Google search points to other interesting connections between palmitic acid and glia, and between palmitic acid and coronary disease (no surprise there), but I haven't delved.

To Russ's point, if this page has accurate information (I can't find out anything about who is behind it), there's a rather wide difference in palmitic acid amounts in different food sources, not even considering the grass fed option. Given the spread of palmitic acid through plant and animal foods it's worth a look. I could see individual diets unwittingly ending up quite high in palmitic acid even when it's thought this is being avoided.

Palmitic Acid: Structure, Properties, and Foods

Unfortunately I rely a lot on sardines and eggs for protein, so may have to adjust some things to keep the palmitic acid intake down. Interestingly, crustaceans are very low, Dr. Gundry's fave for animal protein.

What are the benefits, if any, of palmitic acid? There was a paper mentioning its importance in early years. Maybe this is a time-of-life dependent nutrient.

[circular]

One more paper before I'm off to bed ...

Palmitic acid induces neurotoxicity and gliatoxicity in SH-SY5Y human neuroblastoma and T98G human glioblastoma cells

PA, a long chain 16:0 SFA, is the most common FA found in animals and plants such as palm oil, palm kernel oil, butter, cheese, milk and meat (Gunstone, Harwood & Dijkstra, 2010). Despite its crucial biological functions such as energy storage, acting as a signalling molecule and maintaining integrity of cellular membranes (Gunstone, Harwood & Dijkstra, 2010), PA has been found to be increased in diseased brains. Particularly, PA level appeared to be increased in the frontal cortex lipid rafts in PD (Fabelo et al., 2011); and in parietal cortex in AD (Fraser, Tayler & Love, 2010). Furthermore, PA was found to cause lipotoxicity to several cell lines in vitro. For instance, PA triggered the release of tumour necrosis factor-α and interleukin-6, activating inflammatory signalling in astrocytes (Gupta et al., 2012). PA also induced apoptosis in human hepatoma cell line, HepG2 (Zhang et al., 2004), neural progenitor cells (Park et al., 2011) and neuronal cell line, SH-SY5Y (Hsiao et al., 2014).

Other than neurons, the brain also comprises and depends on surrounding non-neuronal cells such as glial, epithelial cells, pericytes and endothelia, for them to function correctly (Freire-Regatillo et al., 2017). Glial cells were once thought of to serve as a supportive system for neurons. Now they are found to possess modulatory, trophic and immune functions in the brain (Gupta et al., 2012). Astrocyte is a type of glial cell, which is the most plentiful and varied non-neuronal cell in the CNS (Argente-arizón et al., 2015). Of note, marked astrogliosis was observed in the hypothalamus of HFD-induced or genetically obese mice (Buckman et al., 2013), suggesting that astrocyte plays a role in reactive gliosis leading to CNS pathologies.

...

[circular]

Mark Sisson addresses the dark side of palmitic acid by discussing how its negative effects might having palmitic acid. While the studies he cites appear preliminary (in rats and dishes), they're at least encouraging that with the right balance we may be safe from negative effects of palmitic acid.

And here's a paper just out this month showing DHA reverses the athrosclerotic effects of palmitic acid in a dish.
Docosahexaenoic acid attenuates the de ... g pathway.

These data support the notion that incubation of atherosclerotic human endothelial cells with docosahexaenoic acid could return the detrimental effects of palmitic acid by modulation of the atherosclerosis signaling pathway.

The paper appears to have a fraternal twin in the same issue:

Docosahexaenoic acid reversed atherosclerotic changes in human endothelial cells induced by palmitic acid in vitro.

SIGNIFICANCE OF THE STUDY:
The current experiment showed that docosahexaenoic acid could reverse atherosclerotic changes in human endothelial cells induced by palmitic acid. The increased levels of interleukin-6 and prostaglandin E2 in atherosclerotic cells were returned to near-to-normal status. Gene expression analysis showed a reduced activity of genes participating in atherosclerotic endothelial cells treated by docosahexaenoic acid. The expression of genes related to cell clotting activity was also similar to that of normal cells.