The reader that already knows about lipid metabolism can skip directly to the second part of the article if you wish.
PART ONE –
In this article, we will discuss the early effect of fats on the molecular pathophysiology of atheromas and how it influence the cardiovascular disease and cerebrovascular disease. The chemical structure of a fatty acid (fats) consists of bonds of carbon atoms, where at one end there is a carboxyl group (COOH-) and at the other end a methyl group (CH3).
Chemical structure of Capric acid with ten atoms carbon. Left carboxyl end, right metyl end.
Clasification of fatty acids
In nutrition and medicine, fatty acids can be classified according to three aspects:
According to the presence or absence of double bonds between the carbon atoms.
Fatty acids without the presence of double bonds are called saturated fatty acids.
Fatty acids with the presence of double bonds are called unsaturated fatty acids, and depending on the location of the double bond they are subclassified into omega 3, omega 6, (polyunsaturated fatty acids, PUFAs); and, omega 9 unsaturated fatty acids.
In the image the chemical structure of various fatty acids, from top to bottom: Stearic acid (saturated); Oleic acid (monounsaturated omega 9); Linoleic acid (polyunsaturated omega 6); and Alpha-linolenic acid (polyunsaturated omega 3).
The importance of this classification is that there is a delicate balance between omega 6 and omega 3 fatty acids, the ideal ratio is 3: 1 or less.
Omega 6 fatty acids are more prevalent and are found in abundant amounts in oils derived from highly processed vegetable seeds (sunflower, corn, palm, canola oil) that are sold in supermarkets.
While omegas 3 are scarce, they are found in oily fish (salmon, tuna) and, due to the low availability in nature, they must be supplemented.
Although there are natural sources of vegetable omegas 3 (chia, linseed, sacha inchi ), these vegetables offer omega 3 in the form of a precursor ALA (alpha-linolenic acid), which has very little bioavailability and from them little amounts of the active omega 3 forms DHA (docohexaenoic acid) and EPA (eicosapenaenoic acid) are obtained.
Omega 3 fatty acids have an anti-inflammatory effect, omega 6 fatty acids have the opposite effect, they stimulate inflammation; taking into account that the formation of atheromas in the arteries has an inflammatory component, we can already deduce what type of fatty acid we should prefer.
Metabolic pathways for omega 3 and omega 6 fatty acids, Proinflammatory (red) and anti-inflammatory (green). Both metabolic pathways compete for the same enzymes, so by increasing the intake of precursors of the omega 3 pathway (ALA), the production of inflammatory cytokines decreases; and on the contrary, the intake of omega 6 (LA) precursors decreases the production of anti-inflammatory cytokines. Cyclooxygenase (blue) and lipoxygenase (yellow) enzymatic processes are indicated. AA, arachidonic acid; ALA, alpha-linolenic acid; COX, cyclooxygenase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HDHA, hydroxydocosahexaenoic acid; HEPE, hydroxyeicosapentaenoic acid; HETE, hydroxyeicosatetraenoic acid; HODE, hydroxyoctadecadienoic acid; HPETE, hydroperoxy-eicosatetraenoic acid; LA, linoleic acid; LOX, lipoxygenase; LT, leukotriene; LX, lipoxin; HODE, hydroxyoctadecadienoic acid; HX, hepoxilin; MaR, maresin; PD1, protectin D1; PG, prostaglandin; Rv, resolvin; TX, thromboxane. Source: researchgate.net
Omega 9 is found in high amounts of olive oil, and is the basis of the Mediterranean diet.
Clasification according to the numbers of carbons that make up the fatty acids.
The fatty acids are clasificated according to the number of carbons can be subclassified in: Short Chain Fatty Acids (SCFA) that have between 2 and 4 carbon atoms; Medium Chain Fatty Acids (MCFA) that have between 4 and 12 carbon atoms; and Long Chain Fatty Acids (LCFA) that have 16 or more carbon atoms.
This classification for the number of carbons is more applicable to unsaturated fatty acids, the importance of this classification lies in the fact that the properties, the health benefits, the way it is metabolized in the body, and the health benefits differ depending on whether they are SCFA, MCFA or LCFA.
SCFAs circulate freely and have characteristics that make them more like ions; they can move from one compartment to another in the human cells. SCFAs are the main food source for enterocytes (cells of the intestine), are produced by the intestinal microbiota and, have beneficial functions in the intestine and other organs, for example, the immune system and brain.
For this reason, it is important to have a healthy intestinal microbiota and the study of the intestinal microbiome (genes of the microbiota) is imperative when there are diseases of the gastrointestinal, immune and, nervous systems.
MCFAs are more easily metabolized, therefore, they tend to generate energy (burn), rather than accumulate; In addition, several investigations have concluded that they have nutritional application in neurodegenerative diseases. The main natural source of these MCFAs is coconut oil, in some mainly neurological and liver diseases they must be supplemented.
LCFAs are abundant in nature, especially in seed oils of vegetable origin (sunflower, corn, palm, canola oil). Although they are needed especially as hormone precursors and structurally in the membrane of all human cells, it is also true that they are the ones that tend to accumulate the most as visceral fat.
In addition, LCFAs in the industrial manufacturing process, to preserve their palatability and durability on supermarket shelves, are subjected to hydrogenation (hydrogenated oils or trans fats) changing their three-dimensional conformation. Their high consumption has been linked to arteriosclerosis, myocardial infarction and, cerebrovascular disease. In my personal opinion, they are the main carcinogen responsible for a large part of cancer problems worldwide.
Classification of fatty acids according to their binding to other compounds.
Fatty acids in the human body are rarely alone, the most common is that they are esterified to other molecules.
Triglycerides.
the most common is the union to an alcohol called glycerol, the union of three fatty acids to glycerol forms triglycerides, and if they are two diglycerides, it is the way fat is stored in adipocytes.
Triglycerides chemical structure. Glycerol joint to palmitic acid on the first carbon of glycerol; oleic acid (omega 9) in the middle carbon of glycerol; and ALA (omega 3) at the third carbon of glycerol.
Phospholipids.
The phospholipids are a triglycerid esterified to a phosphate group (PO4H3) it could joint to anothers molecules. Phospholipids are the main lipidic structure of cell membranes.
The name of phospholipid depends of the molecule that is combined:
Phosphatidilcholine: colina.
Phosphatidylserine: serine.
Phosphatidylethanolamine.
Phosphatidylinositol.
Graffic of a phospholipid in which the polar head is shaded in green and two amphipathic fatty acids in the tail; above stearic acid (18-carbon saturated fatty acid), and below oleic acid (18-carbon monounsaturated omega 9 fatty acid). Note that the omega 9 fatty acid bends, which, as will be seen later, facilitates the fluidity of the plasma membrane.
Sphyngomielin.
Although it is considered a phospholipid, sphyngomielin has different characteristics that allow it to perform insulating functions in the nervous system. This insulating effect is due that, instead of a glycerol backbone, it has a sphingosine chain.
Cholesterol.
Cholesterol is the precursor of steroid hormones, sex hormones, bile acids, and vitamin D, so an irregularity in cholesterol metabolism can be related to several pathologies.
More than half of the cholesterol in the body arises by synthesis of the same organism (700 mg/day) and the biosynthesis is carried out from Acetyl CoA, the main regulatory enzyme is 3Hydroxy 3Melil Glutaryl CoA Reductase (HMG-CoA).
Cholesterol is taken up by the cell through membrane LDL receptors (apo B-100), therefore, an increase in cholesterol intake, an increase in biosynthesis or, an increase in the expression of membrane receptors, can also cause arteriosclerosis, myocardial infarction, and cerebrovascular disease (thrombosis).
Biosynthesis of Cholesterol and the hormones and medicines that with their action on the HMG-CoA.
PART TWO
The lipids of the cell membrane, the real ones responsible for myocardial infarction and cerebrovascular disease.
In each part of this article, the cell membrane is the protagonist, the cell membrane is composed mainly of phospholipids, cholesterol, and proteins.
Changes in the lipids of the cell membrane are the key to the molecular pathophysiology of cardiovascular diseases – Acute myocardial infarction and cerebrovascular disease.
The cell membrane model proposed by Singer and Nicholson in 1972 is universal acceptance in the scientific field, it consists of a lipid bilayer that is mainly composed of phospholipids the fatty acid tails are hydrophobic and are located in the center, while the heads of the phospholipids have made up of glycerol and the phosphate group is polar.
This model stipulates that the cell membrane is a structure characterized by fluidity, where phospholipids undergo lateral movements and are constantly redistributed. The membrane proteins also need fluidity to function properly.
Diagram of the cell membrane fluid mosaic model proposed by Singer and Nicholson (1972). The cell membrane is composed of lipid bilayers: Proteins, some integral transmembrane and others peripheral; Cholesterol that acts as a buffer to modify the fluidity of the membranes; Phospholipids with polar heads towards the outside and inside and tails of fatty acids (saturated and unsaturated) in between. Source: Encyclopedia Britannica.
The fluidity of cell membranes is highly dependent on the lipid composition of the membrane. The fluidity of a membrane affects its function and therefore its propensity to generate atheromas; also affects the functioning of membrane receptors such as insulin. Good membrane fluidity allows receptors to function more efficiently.
Taking into account that the lipid composition affects the fluidity, and, therefore, the function of the membrane, we can conclude that those lipids that allow greater membrane fluidity is more beneficial for cell function than those other lipids that rather make the membrane rigid.
PUFAS normally have a «cis» isometric conformation, while hydrogenated fats from ultra-processed plant seeds are artificially converted to a «trans» isometric conformation.
The key to the functioning of the cell membrane is largely determined by the fact that the phospholipids that compose it have in their tails a sufficient amount of fatty acids in the isometric “cis” conformation, rather than unsaturated fatty acids, in such a way that the Isometric «blend or elbow» allow greater fluidity of the membrane to fulfill its functions.
Conclusion.
The reduced intake of monounsaturated and polyunsaturated fatty acids (omega-3 and 9) and the high intake of long-chain saturated fatty acids and trans-hydrogenated fatty acids are directly related to the initial molecular pathophysiology of myocardial infarction and cerebrovascular disease. The gateway to these diseases lies in the quality of the phospholipid tails that make up the cell membrane.
Andrés Naranjo Cuéllar.
Physisian and Surgeon.
Master Degree in Nutrition.
Multinational MBA.
Master in Pharmaceutical Marketing.
www.linkedin.com/in/andrés-naranjo-cuéllar-65830212
Bibliography
Farooqui, A. (2021). Molecular Aspects of Neurodegeneration, Neuroprotection, and Regeneration in Neurological Disorders (E. Inc. (ed.); 1st ed.). AP.
Gordillo Bastidas Daniela, Gordillo Bastidas Elizabeth. Nutrición Molecular 1 Ed. McGrawHill 1 Ed 2015.
Harper Langer, Bioquímica Ilustrada. 2017. 31 Ed McGrawHill.
Rosembergs Molecular and Genetic Basis of Neurological and Psychiatric Diseases. 2019. Ed Academic Press.
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