After studies carried out in the 60s on experimental animals, it was established that saturated fatty acids (SFA, acronym for Saturated Fatty Acids), such as palmitic and stearic, have toxicity for the organism, while monounsaturated acids (MUFA, acronym for Monounsaturated Fatty Acid), like oleic, prevent it and promote detoxification. (Tove SB1964, The Journal of Nutrition vol 84, n°3; 237-43)
Fatty acids (FA, acronym for Fatty acid) they have an energetic role and other biological functions: among these they are mediators of cell signaling. They participate in the construction and functionality of some structures, such as cell membranes, site of receptors and intra-extracellular exchanges, such as mitochondria, sites of metabolism, such as the membranes of the endoplasmic reticulum (ER), sites of biosynthesis/maturation of lipids and steroids, site of storage of intracellular calcium, and not lastly, the detoxifying function.
In recent years, epigenomics and metabolomics have demonstrated, in different types of cell cultures, that FAs bind to cell surface receptors (e.g. GPCRs, G protein-coupled receptors) or to intracellular transcription factors such as PPAR-gamma (acronym Peroxisome Proliferator-Activated Receptor). In this way, oleic binds to the GPR40 receptor, increasing insulin secretion when this is stimulated by the presence of glucose.
These omics investigations have demonstrated that SFAs are cytotoxic because:
- they decrease the fluidity of the cell membrane altering functionality. Membranes rich in SFA form less fluid, inelastic islands than those with MUFA, as demonstrated by Yihui Shen et al. in 2017 with Stimulated microscopy of Raman scattering, using SFA with hydrogen atoms replaced with the deuterium isotope. (in Proc Natl Acad Sci USA; DOI: 10.1073/pnas.1712555114).
– When included in ergastoplasma phospholipids determine stress with calcium release from deposits which damages both ER and mitochondria. The latter release cytochrome C and activate the caspase pathway resulting in cell death (lipoapoptosis).
– A signal of cell death is given by the calcium released from the resulting deposits stress. of the ER which changes the oxidoreductive potential of the mitochondria as well as the activity of the enzymes that stabilize the folding of the new proteins synthesized by the ribosomes. In this case the proteins that take on the definitive spatial structure, if misfolded, accumulate and cause toxicity with consequent cell death.
The addition of MUFA in a cell culture inhibits lipoapoptosis, induced by SFA.
– SFAs are less potent ligands than MUFAs towards PPAR receptors. The activation of PPAR (α, β/δ, γ) by oleic promotes the oxidation of SFAs or their sequestration in the cell, preventing their subsequent cytotoxicity.
PPAR-α, when activated by oleic acid, induces the transcription of enzyme-related genes of mitochondrial β-oxidation [a physiological, spiral, degradation mechanism of fats where, e.g., from a single molecule of acid palmitic (C16:0) 106 molecules of ATP are formed, a form of chemical energy, and 16 molecules of carbon dioxide which are eliminated with exhalation), this is also a detoxifying system for SFAs. MUFAs, such as oleic, activate PPAR-γ which determines the uptake of SFA-glycerides and stores them so as not to damage structures, such as ER membranes.
– The lipolysis of triglyceride deposits releases SFA which, together with those coming from the diet, are transformed into Acyl-CoA; subsequently MUFAs activate PPAR-α which facilitates their enzymatic oxidation.
- SFAs are less well incorporated into triglycerides, compared to MUFAs, since the DGAT (diacyl-glycerol-acyl-transferase) enzyme preferentially incorporates unsaturated chains.
- The SFAs, whose fate is not storage (via PPAR-γ) or beta-oxidation (via PPAR-α), they activate the nuclear transcription factor NFkB which is a key mediator of pro-inflammatory states, vice versa, oleic acid inhibits it.
In fact, NFkB is a factor that can activate the gene expression of 200 genes linked to inflammation with the production of many inflammatory proteins/enzymes (cyclooxygenase, lipoxygenase, phospholipase, metalloproteinase…) or genes that encode inflammatory cytokines (IL-1, IL 2, IL 6, IL 8, IL12, TNF), or chemokines (MLP1, IL 18, MIP2, CXCL1, CXCL10), or cell adhesion molecules (ICAM and VCAM), or molecules that activate macrophages (which in turn produce pro-inflammatory cytokines),o molecules that activate T lymphocytes, or regulatory molecules of the cell cycle or oxygen free radical molecules.
– SFA, to be metabolised in β-oxidation, must be converted into acyl-CoA (where the acyl group is the long chain of the fatty acid, both saturated and unsaturated linked to Coenzyme A); the next step, of the acyl-CoAs from SFA, is to become substrates for the synthesis enzyme (DGAT); this is the crucial moment when SFA must be converted into a monounsaturated form, like MUFA, through the action of the enzyme CoA-desaturase 1 (SCD-1).
MUFA, experimentally, even in a diet rich in SFA, induce the upregulation of RNAm/SCD-1 levels which has a protective action, allowing the desaturation of the bond, leading to the metabolization of SFA.
– The toxicity of SFA is also due to the increase in oxidative cellular stress markers with development of oxygen free radicals (ROS), determined both by mitochondrial dysfunction and by the decrease in antioxidant defenses. The electrons, lost by the complexes of the mitochondrial transport chain (Coenzyme Q and cytochrome C reductase), combine with oxygen to generate superoxide ions, hydroxyl radicals, and hydrogen peroxides that are harmful to cellular structures for cytotoxicity.
– The contribution of SFA increases diacylglycerol and ceramides which are cytotoxic while cardiolipin which stabilizes the membranes decreases.
Research has shown that SFAs increase cytotoxicity from oxidative stress, inflammation and apoptosis, MUFAs are cytoprotective. Let's now look at the epidemiological data given that SFA are present in many foods such as beef, pork, vegetable oils such as palm and coconut, cocoa butter, dairy products, processed meats, pre-packaged snacks and finally also in olive oil (8-25%).
Russel J. de Souza's working group (British Medical Journal 2015), analyzing 20.413 publications, found no observational evidence between increased intake of SFA and all causes of mortality, cardiovascular disease, mortality and coronary heart disease (CHD), ischemic stroke, type 2 diabetes, among healthy adult subjects.
An association was found, with a 28% increase in CHD mortality, 21% increase in CHD risk, only with foods containing UNSATURATED FATTY ACIDS, with TRANS isomerism, FROM INDUSTRIAL PROCESSING and not from trans fatty acids from natural foods or coming from ruminant animals (beef, sheep, goat meat, milk and dairy products...).
Ruminants have predominantly bacteria in their intestines Butyrivibrio fibrisolvens, which biohydrogenate polyunsaturated fatty acids, especially linoleic and linolenic, into trans isomers while in the human organism, and in EVOO, unsaturated FAs are in the CIS conformation. Cellular enzymes effectively transform molecules into cis conformation, rarely into trans and in some cases block activity such as delta-6-desaturase from which prostaglandins, leukotrienes and eicosanoids are derived.
- FA trans, from industrial transformation, they come from hydrogenated unsaturated FAs, an operation carried out to make them less oxidizable and to give a semi-solid consistency (e.g. vegetable margarines) and for their low cost. Trans FAs are also formed during the rectification of olive oil and in heating, at high temperatures, such as frying.
The American Heart Association recommends that the diet contain lipids between 25 and 35% of total daily calories, mostly as unsaturated fats and less than 5% as saturated fat.
At least 40 countries have adopted specific measures against TRANS FATTY ACIDS, the WHO recommends consumption of less than 1% of total daily calories, while for the EU it is still a matter of discussion.
Bibliography:
Vujovic A. Olive oil between history and science. 2020, Tozzuolo Editore. Chapter 17.8; pg. 361-364
Vujovic A. How toxic are saturated fatty acids in foods really? TN 22/09/2019
