Alpha-linolenic acid (ALA) belongs to the group of omega-3 fatty acids. It consists of 18 carbon atoms and is a triple-unsaturated fatty acid. The three double bonds are located between the ninth C atom and the methyl end – C18:3, n-3. ALA is one of the essential fatty acids. The reason for this is the methyl end at the double bonds. Non-essential fatty acids have a carboxyl end, which is why the enzymes of the human organism are able to insert double bonds. This is not possible with a methyl end, as the enzymes 12- and 15-desaturase required for this are missing. Therefore, ALA must be taken in through the diet primarily through vegetable oils.
Synthesis (conversion of ALA to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA))
The essential alpha-linolenic acid enters the body exclusively through the diet, mainly through vegetable oils such as flax, walnut, canola, and soybean oils. Alpha-linolenic acid is the substrate of omega-3 fatty acids and is metabolized (metabolized) into eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by elongation (elongation of the fatty acid chain by 2 C atoms) and desaturation (conversion of saturated to unsaturated compounds by insertion of double bonds). This process takes place in the smooth endoplasmic reticulum (structurally rich cell organelle with a channel system of cavities surrounded by membranes) of human leukocytes (white blood cells) and liver cells. The conversion of alpha-linolenic acid to EPA proceeds as follows.
- Alpha-linolenic acid (C18:3) → C18:4 by delta-6 desaturase (enzyme that inserts a double bond at the sixth C-C bond – as seen from the carboxyl (COOH) end of the fatty acid chain – by transferring electrons).
- C18:4 → C20:4 by fatty acid elongase (enzyme that elongates fatty acids by a C2 body).
- C20:4 → eicosapentaenoic acid (C20:5) by delta-5 desaturase (enzyme that inserts a double bond at the fifth C-C bond – as seen from the carboxyl (COOH) end of the fatty acid chain – by transferring electrons).
The conversion of alpha-linolenic acid to DHA proceeds as follows:
- First conversion of ALA (C18:3) to EPA (C20:5) – see above, then:
- C20:5 → docosapentaenoic acid (C22:5) → tetracosapentaenoic acid (C24:5) by fatty acid elongase.
- C24:5 → tetracosapentaenoic acid (C24:6) by the delta-6 desaturase.
- C24:6 → docosahexaenoic acid (C22:6) by ß-oxidation (oxidative shortening of fatty acids by 2 C atoms at a time) in peroxisomes (cell organelles in which fatty acids and other compounds are oxidatively degraded)
To ensure endogenous synthesis of EPA and DHA, sufficient activity of both delta-6 and delta-5 desaturase is required. Both desaturases require certain micronutrients to maintain their function, in particular pyridoxine (vitamin B6), biotin, calcium, magnesium, zinc and vitamin E. Deficiency of these micronutrients leads to decreased desaturase activity and subsequently to impaired EPA as well as DHA synthesis.
Absorption
Alpha-linolenic acid is bound in the diet in triglycerides (triple esters of the trivalent alcohol glycerol with three fatty acids) and undergoes mechanical and enzymatic degradation in the gastrointestinal tract (mouth, stomach, small intestine). Through mechanical dispersion – chewing, gastric and intestinal peristalsis – and under the action of bile, dietary lipids (dietary fats) are emulsified and thus broken down into small oil droplets (0.1-0.2 µm) that can be attacked by lipases (enzymes that break down fatty acids free from lipids). Pregastric and gastric (stomach) lipases initiate the cleavage of triglycerides and phospholipids (10-30% of dietary lipids). However, the main lipolysis (dissolution of 70-90 % of lipids) occurs in the duodenum and jejunum under the action of pancreatic esterases, such as pancreatic lipase, carboxylester lipase and phospholipase, whose secretion is stimulated by cholecystokinin (CCK, peptide hormone of the gastrointestinal tract).The monoglycerides (glycerol esterified with a fatty acid), lyso-phospholipids (glycerol esterified with a phosphoric acid) and free fatty acids resulting from triglyceride and phospholipid cleavage combine in the small intestinal lumen together with other hydrolyzed lipids, such as cholesterol, and bile acids to form mixed micelles (spherical structures with a diameter of 3-10 nm in which the lipid molecules are arranged in such a way that the water-soluble molecule portions are turned outward and the water-insoluble molecule portions are turned inward). The micellar phase serves to solubilize (increase the solubility of) the lipids and allows lipophilic (fat-soluble) substances to be absorbed into the enterocytes (cells of the small intestinal epithelium) of the duodenum and jejunum. Fat absorption under physiological conditions is between 85-95% and can occur by two mechanisms. On the one hand, monoglycerides, lyso-phospholipids, cholesterol and free fatty acids can pass through the phospholipid double membrane of enterocytes by means of passive diffusion due to their lipophilic nature. On the other hand, lipid uptake occurs through the involvement of membrane proteins, such as FABPpm (fatty acid-binding protein of the plasma membrane) and FAT (fatty acid translocase), which are present in other tissues besides the small intestine, such as liver, kidney, adipose tissue – adipocytes (fat cells), heart and placenta. A high-fat diet stimulates intracellular (inside the cell) expression of FAT. In enterocytes, ALA, which has been ingested as a free fatty acid or in the form of monoglycerides and released under the influence of intracellular lipases, is bound to FABPc (fatty acid-binding protein in the cytosol), which has a higher affinity for unsaturated than for saturated long-chain fatty acids and is expressed (formed) especially in the brush border of the jejunum. This is followed by the resynthesis of triglycerides and phospholipids in the smooth endoplasmic reticulum (structurally rich cell organelle with a channel system of cavities surrounded by membranes) and the uptake of further fatty acids into the enterocytes. This is followed by the uptake of lipids into the chylomicrons (lipoproteins). These are composed of triglycerides, phospholipids, cholesterol, cholesterol esters, and apolipoproteins (protein portion of lipoproteins, function as structural scaffolds and/or recognition and docking molecules, for example, for membrane receptors) such as Apo B48, AI, and AIV. Chylomicrons are responsible for the transport of dietary lipids absorbed in the intestine to peripheral tissues and the liver. Instead of being transported in chylomicrons, lipids can also be transported to tissues in VLDL (very low density lipoproteins; fat-containing lipoproteins of very low density).
Transport and distribution
Lipid-rich chylomicrons (consisting of 80-90% triglycerides) are secreted (secreted) into the interstitial spaces of enterocytes by exocytosis (transport of substances out of the cell) and transported away via the lymph. Via the truncus intestinalis (unpaired lymphatic collecting trunk of the abdominal cavity) and ductus thoracicus (lymphatic collecting trunk of the thoracic cavity), the chylomicrons enter the subclavian vein (subclavian vein) and jugular vein (jugular vein), respectively, which converge to form the brachiocephalic vein (left side) – angulus venosus (venous angle). The venae brachiocephalicae of both sides unite to form the unpaired superior vena cava (superior vena cava), which opens into the right atrium of the heart. By the pumping force of the heart, chylomicrons are introduced into the peripheral circulation, where they have a half-life (time in which a value is exponentially halved with time) of approximately 30 minutes. During transport to the liver, most of the triglycerides from the chylomicrons are cleaved into glycerol and free fatty acids under the action of lipoprotein lipase (LPL), located on the surface of endothelial cells of the blood capillaries, which are taken up by peripheral tissues, such as muscle and adipose tissue, partly by passive diffusion and partly carrier-mediated -FABPpm; FAT -. Through this process, chylomicrons are degraded to chylomicron remnants (CM-R, low-fat chylomicron remnant particles), which bind to specific receptors in the liver mediated by apolipoprotein E (ApoE). Uptake of CM-R into the liver occurs via receptor-mediated endocytosis (invagination of the cell membrane → strangulation of CM-R-containing vesicles (endosomes, cell organelles) into the cell interior).The CM-R-rich endosomes fuse with lysosomes (cell organelles with hydrolyzing enzymes) in the cytosol of liver cells, resulting in the cleavage of free fatty acids from the lipids in the CM-Rs. Finally, in liver cells (as well as in leukocytes), the conversion of ALA to EPA and DHA occurs.
Production from vegetable oil
Alpha-linolenic acid is bound as an ester in many triglycerides and can be obtained with the help of alkaline saponification. In this process, the corresponding vegetable oils such as linseed, walnut, or rapeseed oil are strongly heated in combination with alkalis. The oil mixture is separated by distillation and ALA can thus be isolated. Linseed oil is usually used for the production. At room temperature and without exposure to air, ALA exists as an oily, colorless and relatively odorless liquid. This fatty acid is insoluble in water and sensitive to oxidation. When exposed to oxygen, yellowing and even gumming of the liquid occurs rapidly.
