Fatty Acid Metabolism Wolfgang Bayer, Ph.D. AK World Congress, May 2006,Vienna

H 2 -C-OH + HOOC-(CH 2 ) 14 -CH 3 H-C-OH + HOOC-(CH 2 ) 14 -CH 3 H 2 -C-OH + HOOC-(CH 2 ) 14 -CH 3 glycerol palmitic acid H 2 -C-OOC-(CH 2 ) 14 -CH 3 H-C-OOC-(CH 2 ) 14 -CH 3 H 2 -C-OOC-(CH 2 ) 14 -CH 3 triglycerid Natural fats and oils are comprised of glycerol esters of the higher even-numbered fatty acids = triglycerides = triglycerides - 3 H 2 O Fat – what is it?

glycerol P choline fatty acid 1 fatty acid 2 fatty acid 3 fatty acid 1 fatty acid 2 choline P fatty acid sphingosine P =phosphate fatty acid sphingosine sugar triglyceridphospholipid (phosphatidylcholin) sphingolipid (sphingomyelin) glycolipid (cerebrosid)

fatty acids saturated fatty acids fatty acidsunsaturated monounsaturated polyunsaturated ω-3 fatty acids ω-6 fatty acids

Fatty acids - nomenclature What is the designation for this fatty acid? 118 cis-9,12,15-octadecatrienoic acid δ-endω-end 18:3, ω-3 α -linolenic acid

stearic acid, 18:0 saturated mono- unsaturated poly- unsaturated α-α- oleic acid linoleic acid, α -linolenic acid, docosahexaenoic acid,

H 3 C CH 3 H 3 C H C C C C H H H CH 3 cis trans Cis fatty acids are the naturally occurring forms of fatty acids. Trans fatty acids are produced when fats are hydrogenated (margarine). They have rigid structures and are described as having atherogenic properties. Cis and trans fatty acids

Uptake and synthesis of fatty acids (1) In the duodenum, nutritional fats (triglycerides) are split by lipases into monoglycerides and free fatty acids. Following absorption, triglycerides are resynthesized, then transported to tissues, or stored in fatty tissues, by means of chylomicrons. Fatty acids can be synthesized endogenously from glucose by means of the enzyme fatty acid synthase (FAS). This process results in saturated fatty acids with up to 16 C atoms – palmitic acid (C 16:0).

Uptake and synthesis of fatty acids (2) Triglycerides can be synthesized from the fatty acids produced in the liver. They enter the bloodstream bound to VLDLs. Fats are stored in fat cells (adipocytes), where they are continuously built up and broken down. The amount of body fat is approx kg in men and kg in women. Following reactions result in extended saturated and monounsaturated fatty acids, but not in the poly- unsaturated C 18 fatty acids (ω-3 and ω-6).

= coenzyme A ß-oxidation Fatty acid breakdown by ß-oxidation The fatty acid is short- ened by 2 C atoms in each reaction cycle. Acetyl-CoA is prod- uced, which can then be metabolized to CO 2 and ATP in the citrate cycle. 1 mol of palmitic acid produces 106 mols of ATP, equiv-alent to 3,300 kJ/mol.

fatty tissue fat lipolysis fatty acids plasma fatty acids liver fatty acids ß-oxidation acetyl-CoA ketogenesis ketones muscle ketones acetyl-CoA ox.phos. ATP Fatty acid breakdown and energy production bowels triglycerides split fatty acids

Physiological functions of fatty acids Energy pro- duction in the mitochondria Insulation: mechanical, electrical Building blocks of cell membranes Eicosanoid synthesis: immunoregulation, regulation of vasotonus and brochotonus  Influence lipid metabolism, lower triglyceride levels  Regulate central nervous and sensory functions  Important during pregnancy: development of foetal nervous system and brain

 α -linolenic and linoleic acid, the basic components of the ω-3 and ω-6 fatty acids, cannot be synthe- sized by the human organism. Omega-3 and omega-6 fatty acids  These are essential fatty acids that must be included regulary, in balanced amounts, in the diet. D.A.CH. recommended ratio ω-6/ω-3: 5/1. Ratio of ω -6 to ω -3 fatty acids For further information:

Omega-3 and omega-6 fatty acids  Omega-3 and omega-6 fatty acids cannot be transformed into one another.  Other longer-chained fatty acids can be made from α -linolenic acid and linoleic acid by means of desaturation and elongation steps. (One reads this frequently in the literature – but is it really true?) For further information:

oleic acid 18:1, ω-9 18:1, ω-9 linoleic acid 18:2, ω-6 α -linolenic acid 18:3, ω-3 δ-6-desaturase 18:2, ω-9 γ-linolenic acid 18:3, ω-6 18:4, ω-3 elongation 20:2, ω-9 dihomo-γ-linolenic acid 20:3, ω-6 20:4, ω-3 δ-5-desaturase eicosatrienoic acid 20:3, ω-9 arachidonic acid 20:4, ω-6 eicosapentaenoic acid 20:5, ω-3 elongation 22:5, ω-3 δ-4-desaturase docosahexaenoic acid 22:6, ω-3 omega-9-series omega-6-series omega-3-series eicosanoides eicosanoides eicosanoides series 1 series 2 series 3 PGE1,PGI1,TXA1 PGE2,PGI2,TXA2PGE3,PGI3,TXA3 LTB4, LTC4LTB5, LTC5 LTB4, LTC4LTB5, LTC5 anti- inflammatory pro- inflammatory

1. Prostaglandins can be produced in numerous tissues and posses tissue-specific effects, e.g. in enzymatic systems. 2. Prostacyclins are produced in endothelial cells of the blood vessels. They inhibit thrombocyte aggregation and dilate blood vessels. 3. Thromboxanes, the antagonists of the prostacyclins, are produced in thrombocytes. They lead to thrombocyte aggregation and stenosis of blood vessels. 4. Leukotrienes are produced in leucocytes and other cells and contribute to allergic and inflammatory reactions. The eicosanoids

ω-6 ω-3 anti-inflammatorypro-inflammatory

+ 9 g fish oil Omega-3 fatty acids and markers of inflammation James, M.J. et al.: Am. J. Clin. Nutr. 71, 343S-348S, 2000,ω -6,ω -3

41 years old female patient, intake of 3 table- spoons flaxseed oil 5 times a week for months Fatty acid status