D_04_Lipids_2024.pdf

Unit 4: Lipids 1. Structure and function of lipids. 2. Fatty acids. 3. Membrane lipids. 4. Lipid signalling. 5. Transport of lipids in plasma lipoproteins 1  Lipids are a structurally diverse cla...

Unit 4: Lipids 1. Structure and function of lipids. 2. Fatty acids. 3. Membrane lipids. 4. Lipid signalling. 5. Transport of lipids in plasma lipoproteins 1  Lipids are a structurally diverse class Organic molecules that are characterized by low solubility in 2 water: hidrophobic  Biological Functions of Lipids  Storage of energy Reduced compounds: lots of available energy Hydrophobic nature: good packing  Membrane structure Main structure of cell membranes  Cofactors for enzymes Vitamin K: blood clot formation Coenzyme Q: ATP synthesis in mitochondria  Signaling molecules Paracrine hormones (act locally) Steroid hormones (act body‐wide) Growth factors Vitamins A and D (hormone precursors)  Antioxidants Vitamin E 3  Classification of lipids  Based on the structure and function Lipids that do not contain fatty acids: cholesterol, terpenes, … Lipids that contain fatty acids (complex lipids) – can be further separated into: – storage lipids – membrane lipids 4  Principle Fatty acids are water‐insoluble hydrocarbons used for cellular energy storage. Fatty acids are highly reduced and thus provide a rich source of stored chemical energy for cells. Storage of hydrophobic fats as triacylglycerols is also highly efficient because water is not needed to hydrate the stored fats. Energy storage lipids Fatty acids: Carboxylic acids with hydrocarbon tails 4‐36 carbon atoms Saturated / unsaturated Cis configuration Branched / unbranched Triacylglycerols: Glycerol based Three fatty acids ester‐linked to glycerol Simple/mixed Non polar, hydrophobic Storage in adipocites / adipose tissue lipases = enzymes that catalyze the hydrolysis of stored triacylglycerols, releasing fatty acids for export to sites where they are required as fuel 6  Fats Provide Efficient Fuel Storage  The advantage of fats over polysaccharides: Fatty acids carry more energy per carbon because they are more reduced Fatty acids carry less water per gram because they are nonpolar  Glucose and glycogen are for short‐term energy needs, quick delivery  Fats are for long‐term (months) energy needs, good storage, slow delivery 7  Common Patterns in Fatty Acids most common fatty acids have even numbers of carbon atoms in an unbranched chain of 12 to 24 carbons in monounsaturated fatty acids, the double bond is usually between C‐9 and C‐10 (∆9) in polyunsaturated fatty acids: – the double bonds are usually ∆12 and ∆15 double bonds are usually in the cis configuration  Polyunsaturated Fatty Acids (PUFAs) Polyunsaturated fatty acids (PUFAs) = contain more than one double bond in their backbone – omega‐3 (ω‐3) fatty acids = double bond between C‐3 and C‐4 relative to the most distant carbon (ω) – omega‐6 (ω‐6) fatty acids = double bond between C‐6 and C‐7 relative to ω omega‐3 (ω‐3) fatty acid  PUFAs and Human Nutrition humans must obtain the omega‐3 PUFA α‐linolenic acid (ALA; 18:3(∆9,12,15)) from their diet humans use ALA to synthesize: – eicosapentaenoic acid (EPA; 20:5(∆5,8,11,14,17)) – docosahexaenoic acid (DHA; 22:6(∆4,7,10,13,16,19)) the optimal dietary ratio of ω‐6 to ω‐3 PUFAs is between 1:1 and 4:1 – An imbalance of ω‐6 and ω‐3 PUFAs in the diet is associated with an increased risk of cardiovascular disease  Partial Hydrogenation and “Trans Fats” Oxidative cleavage of double bonds in unsaturated fatty acids to aldehydes and carboxylic acids causes lipid‐rich food to become rancid Partial hydrogenation = process that converts many of the cis double bonds in the fatty acids to single bonds – improves shelf life and increases stability – increases the melting temperature – converts some cis double bonds to trans double bonds Dietary intake of trans fatty acids is linked to a higher incidence of cardiovascular disease – Trans fatty acids: raise the level of triacylglycerols in the blood raise the level of LDL (“bad”) cholesterol in the blood lower the level of HDL (“good”) cholesterol increase the body’s inflammatory response  Principle Membrane lipids are composed of hydrophobic tails attached to polar head groups. Cellular membranes are composed of a variety of lipids, including glycerophospholipids and sterols. These lipids are used for structuring membranes as well as for displaying molecules on the membrane surfaces for signaling and molecular recognition.  Biological Membranes Biological membranes = double layer of lipids that acts as a barrier to polar molecules and ions Membrane lipids: – amphipathic = one end of the molecule is hydrophobic, the other hydrophilic hydrophobic regions associate with each other hydrophilic regions associate with water General types of membrane lipids:  phospholipids = have hydrophobic regions composed of two fatty acids joined to glycerol or sphingosine  glycolipids = contain a simple sugar or a complex oligosaccharide at the polar ends  sterols = compounds characterized by a rigid system of four fused hydrocarbon rings  Structural lipids in membranes (polar)  Contain polar head groups and nonpolar tails (usually attached fatty acids)  Diversification can come from: modifying a different backbone changing the fatty acids modifying the head groups  The properties of head groups determine the surface properties of membranes  Different organisms and different tissues have different membrane lipid head group compositions 14  Phospholipids: Glycerophospholipids Membrane lipids in which two fatty acids are attached in ester linkage to the first and second carbons of glycerol, and a highly polar or charged group is attached through a phosphodiester linkage to the third carbon Derivatives of phosphatidic acid 15  Some Glycerophospholipids Have Ether‐Linked Fatty Acids ether lipids = one of the two acyl chains is attached to glycerol in ether, rather than ester, linkage Platelet‐activating factor = an ether lipid that serves as a potent molecular signal released from leukocytes called basophils stimulates platelet aggregation and serotonin release plays a role in inflammation and the allergic response  Sphingolipids Sphingolipids = large class of membrane phospholipids and glycolipids – have a polar head group and two nonpolar tails – contain no glycerol – contain one molecule of the long‐ chain amino alcohol sphingosine or one of its derivatives – C‐1, C‐2, and C‐3 of sphingosine are structurally analogous of the three carbons of glycerol in glycerophospholipids Ceramide = compound resulting when a fatty acid is attached in amide linkage to the –NH2 on C‐2 structurally similar to a diacylglycerol 17  Glycosphingolipids  Glycosphingolipids = have head groups with 1+ sugars connected directly to the –OH at C‐1 of the ceramide moiety  do not contain phosphate  occur largely in the outer face of plasma membranes  Main families:  cerebrosides  gangliosides  globosides  Blood groups are determined in part by the type of sugar located on the head groups in glycosphingolipids.  The type of that sugar is determined by the expression of specific glycosyltransferases  Individuals with no active glycosyltransferase will have the O antigen  Individuals with a glycosyltransferase that transfers an N‐acetylgalactosamine group have A blood group  Individuals with a glycosyltransferase that transfers a galactose group have B blood group 18  Phospholipids and Sphingolipids Are Degraded in Lysosomes Phospholipases of the A type remove one of the two fatty acids Lysophospholipases remove the remaining fatty acid Lysosomal enzymes catalyze the stepwise removal of sugar units of gangliosides  Abnormal Accumulations of Membrane Lipids Genetic defects in any of these hydrolytic enzymes leads to the accumulation of gangliosides in the cell  Sterols and Cholesterol  Cholesterol and related sterols are present in the membranes of most eukaryotic cells Modulate fluidity and permeability Thicken the plasma membrane  Mammals obtain cholesterol from food or synthesize it de novo in the liver Synthesis inhibited by statins (inhibitors of HMGCoA Reductase)  Many hormones are derivatives of sterols 21  Cholesteryl esters  More non‐polar than cholesterol  Contain a fatty acid esterified to the oxygen  Come from a fatty acyl‐CoA  Make cholesterol more hydrophobic, unable to enter membranes  Transported in lipoproteins to other tissues or stored in liver 22  Principle Lipids have uses in the cell beyond energy storage and membranes construction. Many lipids are present in the cell at smaller amounts than those making up membranes or being stored as fat. These lipids can function as cellular messengers, hormones, electron carriers, or pigments.  Signalling Lipids: Eicosanoids  Enzymatic oxidation of arachidonic acid yields: Prostaglandins (inflammation and fever) Thromboxanes (formation of blood clots) Leukotrienes (smooth muscle contraction in lungs) Lipoxins (potent anti‐inflammatory agents) 24  Principle Lipids are the principal form of stored energy in most higher organisms, as well as the major constituents of membranes. However, due to their hydrophobicity, they cannot be transported free in solution in the bloodstream, plasma lipoproteins are required. Dietary Fats Are Absorbed in the Small Intestine  Lipids are transported in the blood as plasma lipoproteins  Spherical particles  Surface is made of proteins (called apolipoproteins) and a lipid monolayer  Contains cholesterol, TAGs, cholesteryl esters (in the interior) 27  Human plasma lipoproteins Table 21-1 Major Classes of Human Plasma Lipoproteins: Some Properties Lipoprotein Density (g/mL) Protein Phospholipids Composition Composition Triacylglycerols (wt %): Free (wt %): cholesterol Cholesteryl esters Chylomicrons