Lipids 1(6) PDF

Lipid metabolism  Types of lipids Fatty acids (FA) Triacylglycerols, triglycerides (ТАG, ТG) Phospholipids Sphingolipids Cholesterol and its derivatives (steroid hormones, Vit D3 hormone) Fat-soluble vitamins (A, E and K) Common feature...

Lipid metabolism  Types of lipids Fatty acids (FA) Triacylglycerols, triglycerides (ТАG, ТG) Phospholipids Sphingolipids Cholesterol and its derivatives (steroid hormones, Vit D3 hormone) Fat-soluble vitamins (A, E and K) Common feature of all lipids: insolubility in water (hydrophobic molecules)  Lipids are hydrophobic molecules They are compartmentalized – membrane-associated lipids or – droplets of TAG in adipocytes Transported in plasma in association with protein – as lipoprotein particles 3  Structures of some common classes of lipids 4  Functions of lipids Major source of energy (FA, TAG) Energy storage (TAG in adipose tissue) Structural (phospholipids, cholesterol) – Provide the hydrophobic barrier - partitioning of the aqueous contents of cells and subcellular structures Regulatory (steroid hormones, vit. D3 hormone, carotenoids, tocopherols) Substrate for eicosanoid synthesis (arachidonic acid, released from membrane phosphatidylinositoles) Antioxidant defense (carotenoids, tocopherols) Intracellular signalization (phospholipids - membrane phosphatidylinositoles) 5  Digestion, absorption, secretion and utilization of dietary lipids 1. Content and amount of dietary lipids: ~ 60 to 150 g of lipids per day 90% TAG + 10% Ch, ChE, PL, FA 6  Lipid digestion Only complex lipids undergo digestion : TAG Phospholipids Cholesterol esters Digestion in the mouth: Lingual lipase (released from glands at the back of the tongue, acid stable enzyme, pH=3-6) Digestion in the stomach: Lingual lipase (its action continues in the stomach) Gastric lipase (secreted by gastric mucosa, pH 7) – Degrades TAG containing short- and medium chain FA (С10-С14), that are present predominantly in milk (this enzyme is important rather for sucklings and babies) – Hydrolysis is incomplete – FA and 1,2-DAG are the products –  30% of TAG are hydrolyzed Intestinal digestion: Intestinal lipid digestion is catalyzed by pancreatic enzymes: Lipase – Hydrolyzes TAG to FA and 2MAG (2-monoacyl glycerol) (removes FA on position 1 and 3) – Lipase is activated by colipase – a protein secreted by the pancreas 2MAG Colipase binds the lipase at a ratio of one to one anchors lipase at the aqueous interface of the lipid droplet orientates the lipase active site to the substrate Orlistat an anti-obesity drug, inhibits gastric and pancreatic lipases  Phospholipase А2 (PLA2) -Cleaves PL to FA and lysophospholipids -Removes FA on position 2 PLA2  Cholesterol esterase - Hydrolysis of cholesterol esters to cholesterol and free FA H2O O R С O RCOOH HO холестеролов холестерол Cholesterol ester естер FA Cholesterol Action of all lipases in intestines is favored by the action of bile acids!  Significance of bile acids for lipid digestion At physiological pH bile acids are present as bile salts (because they are dissociated) How do bile salts participate in lipid digestion: Participate in emulsification process – big lipid droplets are “split” into many small droplets thus increasing the surface area for the action of the pancreatic lipases Activate lipases Participate in micelle formation – Micelles are complexes, containing bile acids and products of lipid digestion. Products of lipid digestion are absorbed in form of micelles.  Bile acids and bile salts Made in the liver Stored in the gallbladder Synthesized from cholesterol Composed of sterol ring + a side chain + glycine or taurine (R2) covalently attached (amide linkage) 12  Fate of the products of lipid digestion 1. Absorption 2. Re-synthesis 3. Packaging in chylomicrons 4. Excretion in the form of chylomicrons 1. Absorption Products of lipid digestion are absorbed in the intestinal epithelial cells as mixed micelles Micelles contain: – FAs – Ch – 2-MAG – lysophospholipids – bile salts Short and medium-chain FAs are directly absorbed, they do not need micelles for transportation  Lipid malabsorption Leads to loss of lipids, incl. essential FA and fat soluble vitamins and eventually deficiency of essential FA and fat soluble vitamins Caused by: – Bile secretion prevented – Pancreatic juice secretion prevented – Defective intestinal mucosal cell function 16  2. Resynthesis In epithelial intestinal cells products of lipid digestion are used in process of resynthesis TAG, PL and ChE are produced 2MAG ТAG Cholesterol + acyl-CoA ChE Lysophospholipids Pl Resynthesis is followed by the next steps: 3. Packaging as chylomicrons 4. Chylomicrons secretion by enterocytes 6. Resynthesis of triacylglycerol (TAG synthase complex) and cholesteryl esters (acyltransferases) Acyl CoA 18 Degradation of dietary lipids by pancreatic enzymes is hormonally controlled Cholecystokinin Stimulates: – gall bladder contraction – pancreatic enzyme secretion Secretin stimulates the release of bicarbonate in the pancreatic juice in order to neutralize acidic stomach content and provide optimal pH for the lipases This hormones are released by duodenal cells as a response to the low duodenal pH (secretin) and presence of fatty acids (cholecystokinin) as a result of chymus entrance in duodenum. 19  7. Secretion of lipids from enterocytes Lipids are secreted in form of chylomicrons in the lymph at first Chylomicrons belong to the lipoprotein compexes group 20  Lipoprotein complexes Spherical particles, composed of: proteins lipids  Structure of lipoprotein complexes Lipid droplets: surrounded by a monolayer composed of: PLs unesterified Ch and apolipoproteins (a single protein molecules) The hydrophobic TAG and ChE are situated in the centre  Apoprotein function Structural: Аpо В100, Аpо В48 Receptor binding: Аpо В100, Аpо В48*, АpоЕ Enzyme activation: Аpо СII Lipid exchange between LPs: АpоD (ChETP)  Use of dietary lipids by the tissues Metabolism of chylomicrons Secreted by intestines chylomicrons (nascent) from the lymph go to the blood There they receive Apo CII and Apo E from HDL, thus being transformed into mature chylomicrons 24  Metabolism of chylomicrons HDL Nascent ApoCII chylomicrons Apo B-48 Apo E Mature chylomicrons HDL Apo B-48 ApoCII Apo E 25  Metabolism of chylomicrons During their circulation in the blood capillary lipoprotein lipase (LPL), secreted by skeletal muscle and adipose tissues breaks down the TAG to FAs + glycerol The remainings of the chylomicrons (chylomicron remnants) are recycled in the liver (enter the hepatocytes by a R-mediated endocytosis) Lysosomal enzymes digest the remnants and release the content, which is utilized by the liver 26  Role of apolipoproteins in CM Apo E and Apo B-48 – recognized by the R of the hepatocytes Apo CII – activates the capillary LPL 27  ChM Content: ~90% TAG (from the food) Density: LPs with lowest density Place of synthesis: Intestinal cells (small intestines) Main apoproteins: аpоB48, аpоCII, аpоE Functions: Transport of exogenous TAG small intestines⇛extra-hepatal tissues Transport of exogenous cholesterol and phospholipids small intestines⇛liver (as chylomicron remnants)  Chylomicron metabolism Stages: 1. Biosynthesis of nascent* CM in enterocytes – Contain apoB48 only 2. Secretion of nascent CM in the lymph 3. Entrance of nascent CM in blood 4. In blood the nascent CM obtain apoCII and apoE from HDL becoming mature CM – contain apoB48, apoCII, apoE 5. Mature CM reach capillaries 6. АpоCII activates capillary LPL 7. Activated LPL hydrolyzes TAG to glycerol and FA 8. CM become CM remnants 9. CM remnants give back apoCII to HDL 10. CM remnants are recognized by receptors in liver cells - receptor mediated endocytosis (receptors can recognize and bind apoB48 in combination with apoE) - cholesterol from the food enters the liver as a content of CM remnants  Chylomicron metabolism ChM nascent TAG>Ch>ChE Аpо B48  Chylomicron metabolism ChM nascent TAG>Ch>ChE Аpо B48 Secreted first in the lymph and then reach the blood stream  Chylomicron metabolism ChM nascent TAG>Ch>ChE Аpо B48 Blood stream ChM nascent TAG>Ch>ChE Аpо B48  Chylomicron metabolism ChM nascent TAG>Ch>ChE Аpо B48 Apо СII Apо Е  Chylomicron metabolism ChM mature ChM TAG>Ch>ChE nascent Аpо B48 TAG>Ch>ChE Apо СII Аpо B48 Apо СII Apо Е Apо Е HDL Аpо CII Аpо E  Chylomicron metabolism ChM mature Capillary ChM ChM TAG>Ch>ChE LPL remnants nascent Аpо B48 ↓ТАG; TAG>Ch>ChE Apо СII Ch, ChE Аpо B48 Apо СII Apо Е В48 Apо Е CII, E HDL Аpо CII Аpо E  Chylomicron metabolism ChM mature Capillary ChM ChM TAG>Ch>ChE LPL remnants nascent Аpо B48 ↓ТАG; TAG>Ch>ChE Apо СII Ch, ChE Аpо B48 Apо СII Apо Е В48 Apо Е CII, E HDL Аpо CII Apо СII Аpо E  Chylomicron metabolism Receptor mediated endocytosis Receptors in liver recognize Apo B48 in combination with ApoE ChM mature Capillary ChM ChM TAG>Ch>ChE LPL remnants nascent Аpо B48 ↓ТАG; TAG>Ch>ChE Apо СII Ch, ChE Аpо B48 Apо СII Apо Е В48 Apо Е CII, E HDL Аpо CII Apо СII Аpо E  Chylomicron metabolism ChM remnants ↓ТАG; Ch, ChE Receptor mediated endocytosis В48 Receptors in liver recognize Apo B48 in combination with ApoE E ChM mature Capillary ChM ChM TAG>Ch>ChE remnants LPL nascent Аpо B48 ↓ТАG; TAG>Ch>ChE Apо СII Ch, ChE Аpо B48 Apо СII Apо Е В48 Apо Е CII, E HDL Аpо CII Apо СII Аpо E  Capillary LPL Synthesized and secreted by: – adipose tissue (high Km) – muscle cells (low Km) – lactating mammary glands Less active in other tissues (lungs, aorta, endocrine glands; not present in brain and liver) An extracellular enzyme that is anchored by heparan sulfate to the capillary walls with its active site towards the capillary lumen Activated by Apo CII in LP complexes Responsible for hydrolysis of TAG, present in VLDLs and ChMs 40  Capillary lipoprotein lipase (LPL) cell LPL Localization Capillary walls of: LPL adipose tissue Heart and skeletal muscles LPL missing in liver Active site Towards the lumen of the blood vessel  Capillary lipoprotein lipase (LPL) Cell Activators for LPL: LPL Аpо CII in Chylomicrons and E VLDL/ChM VLDL ТАG>Ch>ChЕ LPL В100/B48 СII LPL  Capillary lipoprotein lipase (LPL) Cell Activators for LPL: E LPL Аpо CII in Chylomicrones and VLDL/CM VLDL ТАG>Ch>ChЕ LPL В100/B48 СII LPL  Capillary lipoprotein lipase (LPL) Substrate: cell ТАG inVLDL and ChM E VLDL/CM LPL ТАG>Ch>ChЕ В100/B48 СII LPL LPL  Capillary lipoprotein lipase (LPL) cell End products: E LPL VLDL/CM Glycerol ТАG>Ch>ChЕ Fatty acids (FA) LPL В100/B48 СII LPL FA glycerol  Capillary lipoprotein lipase (LPL) cell End products: E LPL VLDL/CM Glycerol ТАG>Ch>ChЕ Fatty acids LPL В100/B48 СII LPL FA glycerol  Capillary lipoprotein lipase (LPL) cell End products: E LPL VLDL/CM Glycerol ТАG>Ch>ChЕ Fatty acids LPL В100/B48 СII LPL FA storage glycerol (Adipose tissue) For energy (muscles)  Capillary lipoprotein lipase (LPL) cell End products: E LPL VLDL/CM Glycerol ТАG>Ch>ChЕ Fatty acids LPL В100/B48 СII LPL FA storage glycerol (Adipose tissue) For energy (muscles) FA albumin  Capillary lipoprotein lipase (LPL) cell End products: E LPL VLDL/CM Glycerol ТАG>Ch>ChЕ Fatty acids LPL В100/B48 СII LPL FA storage glycerol (Adipose tissue) For energy (muscles) FA albumin  Capillary lipoprotein lipase (LPL) cell End products: E LPL VLDL/CM Glycerol ТАG>Ch>ChЕ Fatty acids LPL В100/B48 СII LPL FA storage glycerol (Adipose tissue) For energy (muscles) FA albumin  Capillary lipoprotein lipase (LPL) Localization: capillary walls cell E LPL VLDL/CM Active site: ТАG>Ch>ChЕ Towards the blood vessel lumen LPL В100/B48 СII Activators for LPL: LPL Аpо CII in VLDL and ChM Substrates: ТАG in VLDL and ChM FA storage glycerol (Adipose End products: tissue) Glycerol For energy FA (muscles) FA albumin 52  Fate of products of capillary LPL action FA and glycerol are transported to the tissues which oxidize them for energy Glycerol: Is transported to liver Oxidation to DHAP – Glycolysis, PPP – GNG Esterification to TAGs FA: FA oxidation with energy yield: Skeletal muscles heart kidney liver Brain, RBC, adipose tissue do not oxidize FA TAG synthesis (adipose tissue, liver*) transport to other tissues (bound to albumin)  Utilization of glycerol in liver Glycerol kinase Glycerol Not present in adipose tissue. In adipose tissue G-3- TAG synthesis TAG Glycerol-3-P P comes from PPP (exportation as Glycerol-3-P dehydrogenase VLDLs) DHAP glycolysis GNG energy 54  Utilization of FA FA β-oxidation TAG synthesis (energy) skeletal muscles adipose tissue heart (storage) kidney liver (VLDL) liver 55 How are FA transported in blood? – Long-chain – bound to albumin – Inside the cells the long-chain FA are bound to a FA- binding protein – Short and medium-chain FA – more soluble and they are transported as non-ionized acids or FA anions 56 The End