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Dietary fatty acids influence the cell membrane

Research Article

PUFAs coming from diet incorporate into the plasma membrane and affect its biophysical properties.

About the author


Olga (Olya) Vvedenskaya
Sci. Communications Officer

Dr. Dr. Olya Vvedenskaya studied medicine, and further obtained her PhD in the field of molecular oncology. She loves to deliver scientific messages in a clear and accessible manner.

Resources


Lipidomic and biophysical homeostasis…

Levental et al. | Nat com (2020)


Mouse lipidomics reveals inherent flexibility…

Surma et al. | SciRep (2021)


Systematic screening for novel lipids by…

Papan et al. | Anal. Chem. (2014)


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Summary

• PUFAs affect the plasma membrane properties
• Dietary PUFAs are incorporated in the plasma membrane
• Mammalian cells have adaptation mechanisms to maintain membrane functions in case of PUFAs incorporation

MAINTAINING the proper functioning of membrane characteristics is crucial for the survival of cells in diverse and unpredictable surroundings. In organisms that do not regulate their body temperature, the stability of membrane equilibrium faces a significant challenge due to fluctuations in temperature. When temperatures are low, the movement of lipid acyl chains is constrained, leading to a contraction of membranes, increased rigidity, and higher viscosity. In response to such disturbances, these organisms adjust their membrane lipid composition by decreasing the presence of tightly packed lipids (which have saturated acyl chains) and increasing the abundance of loosely packed lipids that incorporate unsaturated chains or methylations into their lipid tails. This adaptive reaction is termed “homeoviscous adaptation,” as these alterations in lipid structure ensure a remarkable consistency in membrane fluidity despite temperature and other changes in growth conditions.

Apart from specific cases such as hibernation, mammals and other warm-blooded animals generally experience minimal fluctuations in body temperature. Consequently, the exploration of homeostatic membrane adaptability in these organisms has been somewhat limited. However, it is known that the homeostasis of mammalian membranes faces significant challenges due to dietary influences. Kandice Levental and colleagues tested the concept that mammalian membranes demonstrate homeostatic adaptation in response to dietary factors in order to maintain the membrane fluidity and other biophysical properties. The authors accomplished this by analyzing the changes in lipid composition and physical properties of plasma membranes when supplementing cultured mammalian cells and rodents with polyunsaturated fatty acids.

An infographic about the effects of polyunsaturated fatty acids enrichment on membrane properties.

Higher abundance of polyunsaturated fatty acids (PUFAs), for example docosahexaenoic acid (DHA), within the structure of membrane phospholipids can have a significant impact on membrane characteristics, for example it can lead to increased membrane fluidity. Phospholipids enriched with PUFAs, known for their high flexibility and fluidity, play a pivotal role in facilitating membrane fusion and division. The curvature of a membrane exposes the hydrophobic tails of phospholipids to the cytosol. Additionally, membrane thickness is affected. Membranes predominantly composed of saturated phospholipids and cholesterol are thicker than those containing DHA-rich phospholipids. The thinner membranes may show increased permeability to ions and small molecules.

Utilizing lipidomics technology, the researchers demonstrated the integration of PUFAs from the diet into membrane phospholipids, leading to significant alterations in membrane lipid composition, that may affect biophysical properties including membrane fluidity. The investigation encompassed human mesenchymal stem cells, as well as cultured human and rodent cells. The results revealed that the incorporation of external DHA into membrane lipids was not exclusive to specific cell types. Employing a supplementation strategy intended to mimic DHA-enriched diets in mammals resulted in a nearly 15-fold increase in the proportion of phospholipids containing DHA.

Incorporation of supplemented PUFAs into membrane phospholipids. Supplementary PUFAs effectively integrate into membrane phospholipids both in vitro (left side) and in vivo (right side). Upper left panel: Membrane lipids containing ω−3 PUFAs in cells when supplemented with DHA. Lower left panel: Membrane lipids containing ω−6 PUFAs when supplemented with arachidonic acid. Upper right panel: A diet enriched with fish oil (FO) yields a significantly higher presence of lipids containing ω−3 PUFAs compared to mice fed corn oil (CO) in mice cardiac tissue. Lower right panel: Incorporation of dietary ω−3 PUFAs leads to a rise in lipids within cardiac tissue containing acyl chains with high unsaturation (5 or 6 double bonds). * p < 0.05, ** p < 0.01, *** p < 0.001.

Incorporation of supplemented PUFAs into membrane phospholipids. Supplementary PUFAs effectively integrate into membrane phospholipids both in vitro (left side) and in vivo (right side). Upper left panel: Membrane lipids containing ω−3 PUFAs in cells when supplemented with DHA. Lower left panel: Membrane lipids containing ω−6 PUFAs when supplemented with arachidonic acid. Upper right panel: A diet enriched with fish oil (FO) yields a significantly higher presence of lipids containing ω−3 PUFAs compared to mice fed corn oil (CO) in mice cardiac tissue. Lower right panel: Incorporation of dietary ω−3 PUFAs leads to a rise in lipids within cardiac tissue containing acyl chains with high unsaturation (5 or 6 double bonds). * p < 0.05, ** p < 0.01, *** p < 0.001.
Levental et al., Nat com (2020)11:1339, 10.1038/s41467-020-15203-1

Interestingly, when supplementing experimental models with monounsaturated fatty acid (oleic acid; oleate) or saturated fatty acid (palmitic acid; palmitate), only minimal adjustments in the lipidomic profile were observed. The authors proposed that this discrepancy might be linked to the accessibility of these fatty acids within the cell culture medium. Specifically, cultured cells possess an adequate supply of oleate and palmitate, which makes the supplementation at the utilized concentrations ineffective in inducing significant changes. In contrast, the levels of PUFAs in natural diets are limited, making supplementation with physiologically relevant concentrations notably effective in facilitating substantial uptake and integration.

The changes induced by dietary PUFAs were balanced by rapid alterations in lipid composition, particularly in the augmentation of saturated lipids and cholesterol. Despite the substantial integration of external PUFAs into membrane lipids and the consequential rise in overall membrane unsaturation, cell cultures did not exhibit differences in growth rates at these supplementation levels. This finding was somewhat unexpected considering the essential role of lipid unsaturation in determining membrane biophysical properties including fluidity. The authors suggested that mammalian cells might counteract disturbances from external fatty acids by modifying their lipid profiles. Both arachidonic acid and DHA supplementation resulted in a decrease in the abundance of other polyunsaturated lipid species, specifically those with two or three double bonds.

The remodeling of lipidome induced by dietary PUFA incorporation in vitro. The effect of arachidonic acid and docosahexaenoic acid dietary supplementation on lipid saturation. Both, arachidonic acid and docosahexaenoic acid, lead to an increase in saturated lipids and decrease di- and tri-unsaturated containing lipids. Large panel: mol% of fully saturated acyl chains in phospholipids; ** p < 0.01, *** p < 0.001. Small panel: student’s t test compared to untreated; *** p < 0.001.

The remodeling of lipidome induced by dietary PUFA incorporation in vitro. The effect of arachidonic acid and docosahexaenoic acid dietary supplementation on lipid saturation. Both, arachidonic acid and docosahexaenoic acid, lead to an increase in saturated lipids and decrease di- and tri-unsaturated containing lipids. Large panel: mol% of fully saturated acyl chains in phospholipids; ** p < 0.01, *** p < 0.001. Small panel: student’s t test compared to untreated; *** p < 0.001.
Levental et al., Nat com (2020)11:1339, 10.1038/s41467-020-15203-1

This phenomenon could potentially be explained by the replacement of these PUFA-rich lipids with ones containing arachidonic acid or DHA. What was even more striking was the two-fold rise in fully saturated lipids resulting from PUFA supplementation. This increase was attributed to a significant boost in the abundance of saturated fatty acids integrated into phospholipids.

In mice, a very similar compensatory harmonizing lipidomic response was observed after introducing highly polyunsaturated PUFAs to the mice diet: these PUFAs incorporated into cardiac membrane lipids. Specifically, it was noted that mice on fish oil (FO) diet displayed approximately twofold greater levels of saturated lipids compared to mice on corn oil (CO) diet. Interestingly, the CO diet does contain PUFAs in the structure of linoleic acid.

The remodeling of lipidome induced by dietary PUFA incorporation in vivo. The effect of dietary corn oil and fish oil on lipid saturation in murine heart tissue. Incorporation of ω-3 PUFAs into membrane lipids is associated with lipidomic remodeling, namely higher levels of saturated lipids. Large panel: mol% of fully saturated acyl chains in phospholipids; * p < 0.05, ** p < 0.01. Small panel: student’s t test compared to untreated; * p < 0.05.

The remodeling of lipidome induced by dietary PUFA incorporation in vivo. The effect of dietary corn oil and fish oil on lipid saturation in murine heart tissue. Incorporation of ω-3 PUFAs into membrane lipids is associated with lipidomic remodeling, namely higher levels of saturated lipids. Large panel: mol% of fully saturated acyl chains in phospholipids; * p < 0.05, ** p < 0.01. Small panel: student’s t test compared to untreated; * p < 0.05.
Levental et al., Nat com (2020)11:1339, 10.1038/s41467-020-15203-1

Since PUFA-containing lipid species have a fluidizing effect when incorporated into a membrane, the cell needs to switch on a compensatory mechanism to maintain the membrane’s biophysical properties. This reaction involves an increase in saturated lipids, which counteracts the fluidizing impact of PUFA-rich elements, which was indeed observed both in murine cardiac tissue and in cell culture. Sterols play a pivotal role in regulating the characteristics of membranes in eukaryotic organisms. The introduction of DHA resulted in a substantial rise in membrane cholesterol levels, both in murine cardiac tissue fed with fish oil and in cultured cells. This suggests that the elevation of cholesterol is an early and potent response to disruptions in membrane integrity.

Cholesterol upregulation by dietary docosahexaenoic acid. Membranes isolated from murine cardiac tissue had higher cholesterol level when mice were fed with fish oil compared to corn oil. ***, p < 0.001.

Cholesterol upregulation by dietary docosahexaenoic acid. Membranes isolated from murine cardiac tissue had higher cholesterol level when mice were fed with fish oil compared to corn oil. ***, p < 0.001.
Levental et al., Nat com (2020)11:1339, 10.1038/s41467-020-15203-1

The described alteration restores the standard permeability of the membrane and the arrangement of lipids in the membrane. These reactions are influenced by the transcriptional regulatory mechanism related to sterols, which involves the activity of Sterol Regulatory Element-Binding Protein 2 (SREBP2). The disruption of this mechanism through genetic or pharmacological means disrupts both lipidomic composition and the biophysical homeostasis of the membrane. To be more specific, the incorporation of DHA in the diet leads to an increase in the “mature” form of the SREBP2 transcription factor while having minimal impact on the precursor form. Overall, the researchers provided support for the idea that SREBP2 could potentially contribute to the remodeling of the lipidome induced by PUFA.

In conclusion, this research demonstrates swift and thorough lipid composition remodeling depending on the lipid dietary content. This involves an elevation in lipids that decrease membrane fluidity and boost lipid packing, such as saturated lipids and cholesterol, as a response to the introduction of PUFA-containing lipids that augment membrane fluidity.

Lipotype Lipidomics technology offers support to researchers studying lipid plasma membrane composition in intact cells, or giant plasma membrane vesicles or nano plasma membrane vesicles. These detailed results play an essential role in understanding the fundamental processes of membrane adaptation to environmental factors such as growth temperature or dietary interventions. 

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