Gamma-linolenic acid (GLA) is a long-chain (≥ 12 carbon (C) atoms), polyunsaturated (> 1 double bond) fatty acid (Engl. PUFAs, polyunsaturated fatty acids), which belongs to the group of omega-6 fatty acids (n-6-FS, first double bond is located at the sixth C-C bond as seen from the methyl (CH3) end of the fatty acid chain) – C18:3; n-6 [2, 14-16, 24, 29, 42, 44]. GLA can be supplied both through the diet, mainly by vegetable oils, such as borage seed oil (circa 20%), black currant seed oil (15-20%), evening primrose oil (circa 10%), and hemp seed oil (circa 3%), and synthesized in the human organism from the essential (vital) n-6 FS linoleic acid (C18:2).
Synthesis
Linoleic acid is the precursor (precursor) for the endogenous (endogenous) synthesis of GLA and enters the body exclusively from the diet through natural fats and oils, such as safflower, sunflower, corn germ, soybean, sesame, and hemp oils, as well as pecans, Brazil nuts, and pine nuts. The conversion of linoleic acid to GLA occurs in the healthy human organism by desaturation (insertion of a double bond, turning a saturated compound into an unsaturated one) in the smooth endoplasmic reticulum (structurally rich cell organelle with a channel system of cavities, surrounded by membranes) of leukocytes (white blood cells) and liver cells with the help of 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).. GLA in turn serves as the starting substance for the endogenous synthesis of dihomo-gamma-linolenic acid (C20:3; n-6-FS), from which arachidonic acid (C20:4; n-6-FS) is derived. While GLA synthesis from linoleic acid is relatively slow, metabolization (metabolization) of GLA to dihomo-gamma-linolenic acid is very rapid. In order to maintain the activity of delta-6-desaturase, an adequate supply of certain micronutrients, especially pyridoxine (vitamin B6), biotin, calcium, magnesium and zinc is necessary. A deficiency of these micronutrients leads to a decrease in desaturase activity, resulting in impaired synthesis of gamma-linolenic acid and subsequently dihomo-gamma-linolenic acid and arachidonic acid. In addition to micronutrient deficiency, delta-6 desaturase activity is also inhibited by the following factors:
- Increased intake of saturated and unsaturated fatty acids, such as oleic acid (C18:1; n-9-FS), linoleic acid (C18:2; n-6-FS), and alpha-linolenic acid (C18: 3; n-3-FS) as well as arachidonic acid (C20:4; n-6-FS), eicosapentaenoic acid (EPA, C20:5; n-3-FS), and docosahexaenoic acid (DHA, C22:5; n-3-FS).
- Alcohol consumption in high doses and over a long period of time, chronic alcohol consumption.
- Atopic eczema (neurodermatitis)
- Excessive nicotine consumption
- Obesity (obesity, BMI ≥ 30 kg/m2)
- Hypercholesterolemia (elevated cholesterol)
- Hyperinsulinemia (elevated insulin levels).
- Insulin-dependent diabetes mellitus
- Liver disease
- Viral infections
- Stress – release of lipolytic hormones, such as adrenaline, which leads to cleavage of triglycerides (TG, triple esters of the trivalent alcohol glycerol with three fatty acids) and release of saturated and unsaturated fatty acids through stimulation of triglyceride lipase.
- Aging
- Physical inactivity
A primary reduction in the activity of delta-6 desaturase, which is pathologically significant, occurs in atopic eczema (chronic, noncontagious skin disease), premenstrual syndrome (PMS) (extremely complex symptoms in women occurring in each menstrual cycle, beginning 4 days to 2 weeks before menstruation and usually disappearing after menopause), benign mastopathy (common, benign change in the glandular tissue of the breast), and migraine. According to numerous studies, supplementation with GLA leads to a significant improvement of the respective clinical picture.In addition to metabolizing (metabolizing) linoleic acid (C18:3; n-6-FS), delta-6-desaturase is also responsible for the conversion of alpha-linolenic acid (C18:3; n-3-FS) to other physiologically important polyunsaturated fatty acids, such as eicosapentaenoic acid (C20:5; n-3-FS) and docosahexaenoic acid (C22:6; n-3-FS), and for the conversion of oleic acid (C18:1; n-9-FS). Thus, linoleic acid, alpha-linolenic acid, and oleic acid compete as substrates for the same enzyme system. The higher the supply of linoleic acid, the higher the affinity for delta-6-desaturase and the more GLA can be synthesized. However, if the intake of linoleic acid significantly exceeds that of alpha-linolenic acid, this can lead to increased endogenous synthesis of the proinflammatory (proinflammatory) n-6-FS arachidonic acid and decreased endogenous synthesis of the anti-inflammatory (anti-inflammatory) n-3-FS eicosapentaenoic acid. This illustrates the relevance of a quantitatively balanced ratio of linoleic acid to alpha-linolenic acid in the diet. According to the German Nutrition Society (DGE), the ratio of omega-6 to omega-3 fatty acids in the diet should be 5:1 in terms of a preventively effective composition.
Absorption
GLA can be present in the diet both in free form and bound in triglycerides (TG, triple esters of the trivalent alcohol glycerol with three fatty acids) and phospholipids (PL, phosphorus-containing, amphiphilic lipids as essential components of cell membranes), which are subject to 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 are emulsified and thus broken down into small oil droplets (0.1-0.2 µm) that can be attacked by lipases (enzymes that cleave free fatty acids (FFS) from lipids → lipolysis). Pregastric (base of tongue, primarily in early infancy) and gastric (stomach) lipases initiate cleavage of triglycerides and phospholipids (10-30% of dietary lipids). However, the main lipolysis (70-90% of lipids) occurs in the duodenum (duodenal) and jejunum (jejunum) under the action of pancreatic (pancreatic) esterases, such as pancreatic lipase, carboxylester lipase, and phospholipase, whose secretion (secretion) is stimulated by cholecystokinin (CCK, peptide hormone of the gastrointestinal tract). The monoglycerides (MG, glycerol esterified with a fatty acid, such as GLA), lyso-phospholipids (glycerol esterified with a phosphoric acid), and free fatty acids, including GLA, resulting from TG and PL cleavage combine in the small intestinal lumen together with other hydrolyzed lipids, such as cholesterol, and bile acids to form mixed micelles (spherical structures 3-10 nm in diameter, in which the lipid molecules are arranged so that the water-soluble molecule portions are turned outward and the water-insoluble molecule portions are turned inward) – micellar phase for solubilization (increase in solubility) – that enable the uptake of lipophilic (fat-soluble) substances into the enterocytes (cells of the small intestinal epithelium) of the duodenum and jejunum. Diseases of the gastrointestinal tract associated with increased acid production, such as Zollinger-Ellison syndrome (increased synthesis of the hormone gastrin by tumors in the pancreas or upper small intestine), can lead to impaired absorption of lipid molecules and thus to steatorrhea (steatorrhea; pathologically increased fat content in the stool), since the tendency to form micelles decreases with a decrease in pH in the intestinal lumen. Fat absorption under physiological conditions is between 85-95% and can occur by two mechanisms. On the one hand, MG, lyso-PL, cholesterol and GLA can pass through the phospholipid double membrane of enterocytes by means of passive diffusion due to their lipophilic nature, and on the other hand by involvement of membrane proteins, such as FABPpm (fatty acid-binding protein of the plasma membrane) and FAT (fatty acid translocase), which are present not only in the small intestine but also in other tissues, such as liver, kidney, adipose tissue – adipocytes (fat cells), heart and placenta (placenta), to allow lipid uptake into the cells. A high-fat diet stimulates intracellular expression of FAT.In enterocytes, GLA, which was incorporated 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 in particular in the brush border of the jejunum. Subsequent activation of protein-bound GLA by adenosine triphosphate (ATP)-dependent acyl-coenzyme A (CoA) synthetase (→ GLA-CoA) and transfer of GLA-CoA to ACBP (acyl-CoA-binding protein), which serves as an intracellular pool and transporter of activated long-chain fatty acids (acyl-CoA), enables the resynthesis of triglycerides and phospholipids in the smooth endoplasmic reticulum (richly branched channel system of planar cavities enclosed by membranes) on the one hand and – by removing fatty acids from diffusion equilibrium – the incorporation of further fatty acids into enterocytes on the other. This is followed by incorporation of GLA-containing TG and PL, respectively, into chylomicrons (CM, lipoproteins), which are composed of lipids-triglycerides, phospholipids, cholesterol and 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, and are responsible for the transport of dietary lipids absorbed in the intestine to peripheral tissues and the liver. Instead of being transported in chylomicrons, GLA-containing TGs and PLs, respectively, can also be transported to tissues incorporated in VLDLs (very low density lipoproteins). The removal of absorbed dietary lipids by VLDL occurs particularly in the starvation state. Re-esterification of lipids in enterocytes and their incorporation into chylomicrons may be impaired in certain diseases, such as Addison’s disease (primary adrenocortical insufficiency) and gluten-induced enteropathy (chronic disease of the mucosa of the small intestine due to gluten intolerance), resulting in decreased fat absorption and eventually steatorrhea (pathologically increased fat content in the stool). Intestinal fat absorption may likewise be impaired in the presence of deficient bile acid and pancreatic juice secretion, for example, in cystic fibrosis (inborn error of metabolism associated with dysfunction of exocrine glands due to dysfunction of chloride channels), and in the presence of excessive intake of dietary fiber (indigestible food components that form insoluble complexes with fats, among others).
Transport and distribution
Lipid-rich chylomicrons (consisting of 80-90% triglycerides) are 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 (atrium cordis dextrum). 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 that decreases exponentially with time is halved) of about 30 minutes. During transport to the liver, most of the triglycerides from chylomicrons are cleaved into glycerol and free fatty acids, including GLA, under the action of lipoprotein lipase (LPL) located on the surface of endothelial cells of 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, mediated by apolipoprotein E (ApoE), bind to specific receptors in the liver. 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 cleavage of free fatty acids, including GLA, from lipids in CM-R. After binding of the released GLA to FABPc, its activation by ATP-dependent acyl-CoA synthetase and transfer of GLA-CoA to ACBP, reesterification of triglycerides and phospholipids occurs. The resynthesized lipids may be further metabolized (metabolized) in the liver and/or incorporated into VLDL (very low density lipoproteins) to pass through them via the bloodstream to extrahepatic (“outside the liver”) tissues. As VLDL circulating in the blood binds to peripheral cells, the triglycerides are cleaved by action of LPL and the fatty acids released, including GLA, are internalized by passive diffusion and transmembrane transport proteins, such as FABPpm and FAT, respectively. This results in the catabolism of VLDL to IDL (intermediate density lipoproteins). IDL particles can either be taken up by the liver in a receptor-mediated manner and degraded there or metabolized in the blood plasma by a triglyceride lipase to the cholesterol-rich LDL (low density lipoproteins), which supplies peripheral tissues with cholesterol. In the cells of target tissues, such as blood, liver, brain, heart, and skin, GLA can be incorporated into the phospholipids of cell membranes as well as the membranes of cell organelles, such as mitochondria (“energy powerhouses” of cells) and lysosomes (cell organelles with acidic pH and digestive enzymes), depending on the function and needs of the cell, as a starting substance for the synthesis of dihomo-gamma-linolenic acid and thus of anti-inflammatory (anti-inflammatory), vasodilatory (vasodilator) and platelet aggregation inhibitory eicosanoids (hormone-like substances that act as immune modulators and neurotransmitters), such as prostaglandin E1 (PGE1), stored in the form of triglycerides, and/or oxidized to produce energy. Numerous studies have shown that the fatty acid pattern of phospholipids in cell membranes is strongly dependent on the fatty acid composition of the diet. Thus, high GLA intake causes an increase in the proportion of GLA in plasma membrane phospholipids, which has implications for membrane fluidity, electron transport, activity of membrane-associated enzyme and receptor systems, hormonal and immunologic activities, membrane-ligand interactions, permeability (permeability), and intercellular interactions.
Degradation
Catabolism (breakdown) of fatty acids occurs in all body cells, especially liver and muscle cells, and is localized in mitochondria (“energy powerhouses” of cells). Exceptions are erythrocytes (red blood cells), which have no mitochondria, and nerve cells, which lack the enzymes that break down fatty acids. The reaction process of fatty acid catabolism is also called ß-oxidation, since oxidation occurs at the ß-C atom of the fatty acids. In ß-oxidation, the previously activated fatty acids (acyl-CoA) are oxidatively degraded to several acetyl-CoA (activated acetic acid consisting of 2 C atoms) in a cycle that is run repeatedly. In this process, acyl-CoA is shortened by 2 C atoms – corresponding to one acetyl-CoA – per “run”. In contrast to saturated fatty acids, whose catabolism occurs according to the ß-oxidation spiral, unsaturated fatty acids, such as GLA, undergo several conversion reactions during their degradation – depending on the number of double bonds – because they are cis-configured in nature (both substituents are on the same side of the reference plane), but for ß-oxidation they must be in trans-configuration (both substituents are on opposite sides of the reference plane). In order to be made available for ß-oxidation, the GLA bound in triglycerides and phospholipids, respectively, must first be released by hormone-sensitive lipases. In starvation and stress situations, this process (→ lipolysis) is intensified due to increased release of lipolytic hormones such as adrenaline. The GLA released in the course of lipolysis is transported via the bloodstream – bound to albumin (globular protein) – to energy-consuming tissues such as the liver and muscles.In the cytosol of cells, GLA is activated by ATP-dependent acyl-CoA synthetase (→ GLA-CoA) and transported across the inner mitochondrial membrane into the mitochondrial matrix with the help of carnitine (3-hydroxy-4-trimethylaminobutyric acid, quaternary ammonium (NH4+) compound), a receptor molecule for activated long-chain fatty acids. In the mitochondrial matrix, GLA-CoA is introduced into ß-oxidation, the cycle of which is run twice – as follows.
- Acyl-CoA → alpha-beta-trans-enoyl-CoA (unsaturated compound) → L-beta-hydroxyacyl-CoA → beta-ketoacyl-CoA → acyl-CoA (Cn-2).
The result is a GLA shortened by 4 C atoms, which must be enzymatically trans-configured at its cis double bond before entering the next reaction cycle. Since the first double bond of GLA – as seen from the COOH end of the fatty acid chain – is located on an even-numbered C atom (→ alpha-beta-cis-enoyl-CoA), it occurs under the influence of a hydratase (enzyme, which stores H2O in a molecule), alpha-beta-cis-enoyl-CoA is converted to D-beta-hydroxyacyl-CoA and then, under the influence of an epimerase (enzyme that changes the asymmetric arrangement of a C atom in a molecule), is isomerized to L-beta-hydroxyacyl-CoA, which is an intermediate product of ß-oxidation. After another run of a ß-oxidation cycle and shortening of the fatty acid chain by another C2 body, the trans configuration of the next cis-double bond of GLA occurs, which – seen from the COOH end of the fatty acid chain – is localized on an odd-numbered C atom (→ beta-gamma-cis-enoyl-CoA). For this purpose, beta-gamma-cis-enoyl-CoA is isomerized under the action of an isomerase to alpha-beta-trans-enoyl-CoA, which is introduced directly into its reaction cycle as an intermediate of ß-oxidation. Until the activated GLA is completely degraded to acetyl-CoA, another conversion reaction (hydratase-epimerase reaction) and 5 more ß-oxidation cycles are necessary, so that in total ß-oxidation is run 8 times, 3 conversion reactions (1 isomerase, 2 hydratase-epimerase reactions) – corresponding to 3 existing cis-double bonds – take place and 9 acetyl-CoA as well as reduced coenzymes (8 NADH2 and 5 FADH2) are formed. The acetyl-CoA resulting from GLA catabolism are introduced into the citrate cycle, in which oxidative degradation of organic matter occurs for the purpose of obtaining reduced coenzymes, such as NADH2 and FADH2, which together with the reduced coenzymes from ß-oxidation in the respiratory chain are used to synthesize ATP (adenosine triphosphate, universal form of immediately available energy). Although unsaturated fatty acids require conversion reactions (cis → trans) during ß-oxidation, whole-body analyses in fat-free fed rats revealed that labeled unsaturated fatty acids exhibit similar rapid degradation as saturated fatty acids.
Excretion
Under physiological conditions, fat excretion in feces should not exceed 7% at a fat intake of 100 g/day because of the high absorption rate (85-95%). A malassimilation syndrome (impaired nutrient utilization due to decreased breakdown and/or absorption), for example, due to deficient bile acid and pancreatic juice secretion in cystic fibrosis (inborn error of metabolism, associated with dysfunction of exocrine glands due to dysfunction of chloride channels) or diseases of the small intestine, such as celiac disease (chronic disease of the mucosa of the small intestine due to gluten intolerance), can lead to reduction of intestinal fat absorption and thus to steatorrhea (pathologically increased fat content (> 7%) in the stool).
