Lipids | Dietary Lipids Metabolism | PDF

12/16/2024 Dietary Lipids Metabolism 1 2 1  12/16/2024 The average daily intake of lipids by U.S. adults is about 81 g, of which more than 90% is normally triacylglycerol (TAG ‫)الشحوم الثﻼثي...

12/16/2024 Dietary Lipids Metabolism 1 2 1  12/16/2024 The average daily intake of lipids by U.S. adults is about 81 g, of which more than 90% is normally triacylglycerol (TAG ‫)الشحوم الثﻼثية‬. The remainder of the dietary lipids consists primarily of cholesterol, cholesteryl esters, phospholipids, and unesterified (“free”) fatty acids. 3 4 2  12/16/2024 5 Lipids Defined on the basis of solubility. Lipids: heterogeneous group of water insoluble (hydrophobic) organic molecules, They are chemically diverse compound but have one feature: water insoluble Many distinct chemical species in a “lipid fraction” 6 3  12/16/2024 Functions -The biological functions of lipids are diverse as their chemistry Lipids perform three biological functions: 1. Lipids in form of a bilayer are essential components of biological membranes. 2. Lipids containing hydrocarbon side chains serve as energy stores. 3. Many intra-and intercellular signaling events involve lipid molecules. 7 Lipid Classification 1. Storage lipids Triglycerides, Waxes and Fatty acids. Fats and oils are stored forms of energy and are derivatives of fatty acids. 2. Structural lipids in membranes Glycerophospholipids, Sphingolipids, Sterols, are major structural elements in biological membranes 3. Lipids as signals, cofactors and pigments. These lipids presents in small quantities but play crucial roles -Phosphatidylinositols, Eicosanoids - Prostaglandins. - Thromboxanes. - Leukotrienes. - Steroid hormones carry messages between tissues. Common lipid signaling molecules: lysophosphatidic acid (LPA) - Vitamins A and D are hormone precursors. sphingosine-1-phosphate (S1P) platelet activating factor (PAF) anandamide or arachidonoyl ethanolamine (AEA) - Vitamins E and K are oxidation-reduction cofactors. 8 4  12/16/2024 Fats and oils are derivatives of Fatty acids. Fatty acids (F.A) are carboxylic acids with long hydrocarbon chain ranging from 4-36 carbon atom. 16- and 18-C long are most abundant. - Even number of carbons, 16, 18… - The odd are also present but rare. - The hydrocarbon chain can be fully saturated (without double bonds), or with one, two or three double bonds (cis-configuration only) -Usually they are unbranched, some cases have methyl, hydroxyl, or three- carbon ring as branch 9 Nomenclature The nomenclature of these acids is rather complicated. There are at least five systems in use. Here are some of the above in the different systems: 1- The delta system numbers the double bonds from the carboxyl group (the α carbon), specify the chain length and the number of double bonds separated by colon Palmitic acid is saturated F. A with 16 C atoms  16:0 Stearic acid  18:0 2- Whereas the omega system indicates where the first double bond is counting from the other end of the molecule (the methyl group, the ω carbon). Linoleic acid  18:2( 9,12) Arachodonic acids 20:4 ( 5,8,11,14) 10 5  12/16/2024 Omega Fatty acids -Essential F.A Linoleic (18:29,12) 6 Linolenic (18:39,12,15) 3 Arachidonic (20:45,8,11,14) 6 11 12 6  12/16/2024 Essential fatty acids  Two fatty acids are dietary essentials in humans because of our inability to synthesize them: Linoleic acid, which is the precursor of arachidonic acid, the substrate for prostaglandin synthesis, and α-linolenic acid, the precursor of other fatty acids important for growth and development. Plants provide us with the essential fatty acids. [Note: Arachidonic acid becomes essential if linoleic acid is deficient in the diet.] 13 Physical properties of fatty acids Physical properties of F. A and the compounds containing them are largely determined by the length and degree of unsaturation of the hydrocarbon chain. Solubility: The non-polar hydrocarbon chain account for the poor solubility of F. A in water Lauric acid 12:0 Molecular Weight (M. wt) 200 sol. In water 0.063 mg/g Glucose Molecular Weight (M. wt) 180  water sol. Is 1.1mg/g *The carboxyl group is polar, and this accounts for the slight solubility of short chain fatty acid in water *The longer the fatty acid acyl and fewer the double bonds, the lower is the solubility in water Melting points Melting points are strongly influenced by the length and degree of unsaturation At room tem. (R.T) the saturated F. A with length chain 12-24 have waxy consistency while the unsaturated F. A are liquid 14 7  12/16/2024 Fully saturated molecule  free rotation around each C-C This gives the hydrocarbon chain great freedom and flexibility  adopt the most stable conformation which is the fully extended form in which the steric hindrance of neighboring atoms is minimized The molecules can pack together tightly in nearly crystalline arrays. So, the Vander Waal interaction and the hydrophobic interaction are maximized High thermal energy required to disorder (melt) these highly ordered F.A molecules  higher melting points Saturated chains pack tightly and form more rigid, organized aggregates 15 In the unsaturated F. A the cis configuration double bond forces a kink (bend) in the hydrocarbon chain Unsaturated chains bend and pack in a less ordered way, with greater potential for motion F.A with one or more kinks cannot pack together as tightly as fully saturated F.A and their interactions are weaker So the unsaturated F.As take less thermal energy to disorder these poorly ordered arrays of unsaturated F.As  they have lower melting points 16 8  12/16/2024 Waxy (Fat) Liquid (Oil) The saturated F.As take high thermal The unsaturated F.As take less thermal energy required to disorder (melt) these energy to disorder these poorly ordered highly ordered F.A molecules  higher arrays of unsaturated F.As  they have melting points lower melting points 17 Storage of fatty acids as components of triacylglycerols Mono-, di-, and triacylglycerols consist of one, two, or three molecules of fatty acid esterified to a molecule of glycerol. Fatty acids are esterified through their carboxyl groups, resulting in a loss of negative charge and formation of “neutral fat.” 18 9  12/16/2024 Triacylglycerols or Triglycerides Fatty acid triesters of glycerol Most contain two or three different types of fatty acid residues. Triglycerides are non-polar and hydrophobic molecules (the polar groups of both glycerol and F. A are linked in ester linkage  non-polar molecule ) Simple triacylglycerols: containing the same kind of F.A in all three positions of glycerol Simple triacylglycerols of – 18:0 = tristearin – 16:0 tripalmitin – 18:1 triolein Mixed triacylglycerols: different fatty acids esterified with glycerol 19 Lipid: Glycerol+ 2 or 3 Fatty Acids Di-glycerides are mostly plant oils & waxes Glycerol: Tri-glycerides are mostly animal fats (Fatty Acids= Carbon Chains) 20 10  12/16/2024 Fats and oils * Plant oils are usually richer in unsaturated fatty acids residues than animal fats * Fats and oils are complex mixtures of mixed triacylglycerols and simple triacylglycerols *Triacylglycerols can be found in most eukaryotic cell as oily droplets in the aqueous cytosol serving as metabolic fuel *In vertebrates specialized cells called Adipocytes (fat cell) store amounts of triglycerides as fat droplets that fill the cell. Triglycerides also stored as oil in the seeds of many types of plants. *Adipocytes contain lipases catalysis the hydrolysis of stored triglycerides releasing F.A for export to sites where they can be used as fuel. 21 Two advantages for using the triglycerides as stored fuel rather than polysaccharides as glycogen and starch: 1- the carbon atoms of F.A are more reduced than that of carbohydrates  oxidation of triglycerides yields more than twice as much energy (gm/gm) as the oxidation of CHO (F.A  9 Kcal, CHO  4 Kcal). 2- triglycerides are hydrophobic unhydrated, the organism that carries fat as fuel does not have to carry the extra weight of water of hydration that is associated with stored polysaccharides (2gm water/1gm polysaccharides). 22 11  12/16/2024 Fats function as energy reservoirs in animals The fat content of normal humans allows them to survive starvation for 2 or 3 months. While human store of glycogen can supply only for one day, but carbohydrates are quick sources for metabolic energy because of water solubility. Fat stores: skin, abdominal cavity and mammary gland Triacylglycerols. Triacylglycerols function to insulate protect the body from the outer environments 23 Vegetable oils: are composed of Triacylglycerols with unsaturated fatty acids  liquid at room temp. Vegetable oils can be into solid by catalytic hydrogenation which reduce the double bonds to single bonds. 24 12  12/16/2024 Exposure of the lipid rich food to oxygen for long time  may spoil and the lipid is said to be Rancid. Rancidity results from the cleavage of double bond in unsaturated F A that produce aldehyde and carboxylic acid with low M.wt  bad smell 25 Waxes serve as energy store and water repellents Biological waxes are esters of – long chain (C14-C36) saturated and unsaturated fatty acid – with long chain alcohol (C16-C30) – melting points about 60-100 ºC C14-C36 sat. & unsat. F.A C16-C30 long chain alcohol Function of Biological waxes -Skin glands of some vertebrates secret waxes to protect hair and skin to keep it pliable, lubricated and waterproof. -Leaves of many tropical plants are coated by waxes to prevent excessive evaporation of water and protect against parasites -Waxes can be used in pharmaceutical industries in lotions, ointments and polishes 26 13  12/16/2024 Polar vs. Nonpolar lipids Non-Polar Lipids –Energy storage Polar lipids are the basis of Bilayers Biological membranes feature double layer of lipid act as barrier to the passage of polar molecules and ions. Amphipathic: one end of the molecule is hydrophobic, and the other is hydrophilic The hydrophobic interactions between molecules and the hydrophilic interactions with water direct their packing into sheets called membrane bilayer 27 OVERVIEW OF PHOSPHOLIPIDS Phospholipids are polar, ionic compounds composed of an alcohol that is attached by a phosphodiester bridge to either diacylglycerol or sphingosine.. Like fatty acids, phospholipids are amphipathic in nature, that is, each has a hydrophilic head (the phosphate group plus whatever alcohol is attached to it, for example, serine, ethanolamine, and choline, and a long, hydrophobic tail (containing fatty acids or fatty acid–derived hydrocarbons 28 14  12/16/2024 Phospholipids are the predominant lipids of cell membranes. In membranes, the hydrophobic portion of a phospholipid molecule is associated with the nonpolar portions of other membrane constituents, such as glycolipids, proteins, and cholesterol. The hydrophilic (polar) head of the phospholipid extends outward, interacting with the intracellular or extracellular aqueous environment. Membrane phospholipids also function as a reservoir for intracellular messengers, and, for some proteins, phospholipids serve as anchors to cell membranes. Nonmembrane-bound phospholipids serve additional functions in the body, for example, as components of lung surfactant and essential components of bile, where their detergent properties aid in the solubilization of cholesterol. 29 STRUCTURE OF PHOSPHOLIPIDS There are two classes of phospholipids: – those that have glycerol as a backbone A – those that contain sphingosine B. Both classes are found as structural components of membranes, and both play a role in the generation of lipid-signaling molecules. 30 15  12/16/2024 A- Glycerophospholipids (Phospholipids) Phospholipids that contain glycerol are called glycerophospholipids (or phosphoglycerides). Glycerophospholipids constitute the major class of phospholipids. All contain (or are derivatives of) phosphatidic acid (diacylglycerol with a phosphate group on the third carbon). Phosphatidic acid is the simplest phosphoglyceride and is the precursor of the other members of this group. 31 1- Glycerophospholipids are formed from phosphatidic acid (PA) and an alcohol: The phosphate group on PA can be esterified to another compound containing an alcohol group For example: – Ethanolamine + PA → phosphatidylethanolamine (cephalin) – Choline + PA → phosphatidylcholine (lecithin) – Serine + PA → phosphatidylserine – Inositol + PA → phosphatidylinositol – Glycerol + PA → phosphatidylglycerol 32 16  12/16/2024 Group of lipids present in small amounts play various essential function - Have active roles in metabolic processes as metabolite and messenger - Potent signals and hormones carried in the blood from one tissue to others - Intracellular messengers generated to response to outer signal - Can function as cofactors - Pigments - Fat soluble vitamins 33 Lipids as Signals, cofactors and pigments Intracellular messengers are released from the Phosphotidyl inositol in response to extra cellular signals interacting with receptors on the outer surface of the membrane. * Signals act through a series of steps Phosphatidyl inositol: act as intracellular signals: 34 17  12/16/2024 IP3 35 36 18  12/16/2024 *Some animal tissues are rich in ether lipids: one of the acyl group is attached to glycerol in ether rather than ester linkage. The ether-linked chain can be saturated alkyl ether lipid or may unsaturated alkene- ether linked chain 1- Plasmalogen: ether linked alkene found in heart tissue, 50% of the phosphlipid in the heart is Plasmalogen 2- Platelet activating factor: released from leukocyte (basophiles) and stimulate platelet aggregation and the release of serotonin 37 B- Sphingolipids Sphingolipids are major membrane components, with polar head and non-polar tail They are derivatives of the C18 amino alcohol sphingosine The double bond in sphingosine is trans C1, C2, C3 of sphingosine molecule are structurally similar to the three carbons of glycerol in phospholipids N-acyl fatty acid derivatives of sphingosine are known as ceramides Ceramides are the parent compounds of the more abundant General structure of Sphingolipids, if X is H, sphingolipids. the compound is Ceramide 38 19  12/16/2024 39 Sphingomyelins: contain phosphocholine or phosphoethanolamine as their polar group and so can be classified as phospholipids. Sphingomyelins resemble phosphotidylcholines in their general properties and three- dimensional structure and in having no net charge on their head groups The myelin sheath that surrounds and insulates nerve cells is rich in Sphingomyelins 40 20  12/16/2024 Glycosphingolipids (Glycolipids): occur largely in the outer face of plasma membrane, have one or more sugars connected directly to the –OH at C1 of the ceramide moiety and can be classified A- Neutral Glycolipids (uncharged) no net charge at pH=7 1- Cerebroside: single sugar linked to ceramide usually Glucose or Galactose 2- Globoside: Di, tri or tetrasaccharide linked to ceramide as Glu, Gal, N-acetly galactosamine 41 B- Ganglioside: The most complex glycolipid, have oligosaccharide as their polar head groups and one or more residues of Sialic acid Ganglioside are primarily components of membranes on cell surfaces and constitute 6% of brain lipids Sphingolipids: act as a site of biological recognition, act as receptors for hormones and glycoproteins 42 21  12/16/2024 VIII. PROSTAGLANDINS AND RELATED COMPOUNDS Prostaglandins, and the related compounds thromboxanes and leukotrienes, are collectively known as eicosanoids to reflect their origin from poly-unsaturated fatty acids with 20 carbons. They are extremely potent compounds that elicit a wide range of responses, both physiologic (inflammatory response) and pathologic (hyper-sensitivity). They ensure gastric integrity and renal function, regulate smooth muscle contraction (intestine and uterus are key sites) and blood vessel diameter, and maintain platelet homeostasis.. 43 Although they have been compared to hormones in terms of their actions, eicosanoids differ from the true hormones in that: - they are produced in very small amounts in almost all tissues rather than in specialized glands. - They also act locally rather than after transport in the blood to distant sites, as occurs with true hormones such as insulin. - Eicosanoids are not stored, and they have an extremely short half-life, being rapidly metabolized to inactive products. - Their biologic actions are mediated by plasma membrane G protein–coupled receptors, which are different in different organ systems 44 22  12/16/2024 Eicosanoids Eicosanoids are derived from membrane lipids and mainly from Arachodonic acid [20:4(5,8,11,14 ] 1- Prostaglandins C20 compounds Five carbon ring Affect a wide range of cellular and tissue function Act at low concentration and are involved in the production of pain and fever, regulation of blood pressure, blood coagulation and reproduction Produced and used locally Regulate the synthesis of the intracellular messenger (cAMP) which mediate the action of different hormones. -Stimulate the contraction of smooth muscle in the uterus. -Affect the blood flow -Elevate the body temperature and mediate the inflammation and pain 45 2- Thromboxanes: Six-memebred ring containing an ether, Produced by the platelets (thrombocytes) and play role in formation of the blood clots 3- Leukotriens: Contain conjugated double bonds, Found in the leukocytes, Powerful biological signals, induce contraction of muscles lining the airways of the lung. Over production cause asthmatic attack 46 23  12/16/2024 47 48 24  12/16/2024 NSAIDs and Aspirin Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and derivatives of ibuprofen and acetaminophen, they Inhibit Cyclooxygenase activity of PGH2 Synthase, by non covalently binding to PGH2 synthase, also Preventing arachidonic acid from reaching the enzyme active site. They inhibit formation of prostaglandins involved in fever, pain and inflammation. They inhibit blood clotting by blocking thromboxane formation in blood platelets. Aspirin acetylates a serine hydroxyl group residue of the enzyme PGH2 synthase (Cyclo oxygenase enzyme) near the active site, preventing arachidonic acid from reaching the enzyme active site. The inhibition by aspirin is irreversible. 49 Leukotrienes have been implicated in various inflammatory and hypersensitivity disorders (such as asthma). They are synthesized from arachidonate by an aspirin-insensitive pathway However, in most body cells re-synthesis of PGH2 Synthase would restore cyclooxygenase activity. Steroidal anti-inflammatory drug Prednisone and prednisolone inhibit the phospholipase A2 that release the Arachodinic acid from the phospholipids in the membrane  the synthesis of all eicosanoid will be inhibited 50 25  12/16/2024 3-Sterols Structural lipids present in the membranes of some eukaryotic cells. Characterized by the steroid nucleus consisting of four fused rings three rings with 6 C atoms and one ring with 5 C atoms, the steroid nucleus is relatively rigid and planar. Cholesterol is the major sterol in animal tissues, and it is amphipathic with a polar head (the –OH group), and the non-polar body is the steroid nucleus Similar sterols are present in eukaryotes: Stigmasterol plants Ergosterol fungi Functions - Membrane constituents - Precursors of different product with vital biological activities (steroidal hormones that regulate the gene expression) - Bile acids are derivatives of cholesterol that act as emulsifying agent in the intestine 51 STEROID HORMONES Cholesterol is the precursor of all classes of steroid hormones: glucocorticoids (for example, cortisol), mineralocorticoids (for example, aldosterone), and sex hormones—androgens, estrogens, and progestins. [Note: Glucocorticoids and mineralocorticoids are collectively called corticosteroids.] Synthesis and secretion occur in the adrenal cortex (cortisol, aldosterone, and androgens), ovaries and placenta (estrogens and progestins), and testes (testosterone) 52 26  12/16/2024 Steroidal Hormones Steroids: oxidized form of the sterol, with the steroid nucleus but lack the alkyl chain -More polar than cholesterol -Move through the blood on proteins carriers from site of production to target tissue. Then bind to their receptors  enter the nucleus  affect the gene expression and metabolism -male and female sex hormones (Testosterone and estradiaol) -adrenal cortex hormone: cortisol and aldesterone -Prednisone and prednisolone are synthetic steroids 53 54 27