Lipids Pt 1.docx

Lipids: General Info Lipids are soluble in non-polar substances such as ether, benzene, chloroform, or other lipids. Body lipids are generally compartmentalized. Lipids are stored in adipocytes and are a major source of energy for the body. Lipid functions include: Providing hydrophobic barriers whi...

Lipids: General Info Lipids are soluble in non-polar substances such as ether, benzene, chloroform, or other lipids. Body lipids are generally compartmentalized. Lipids are stored in adipocytes and are a major source of energy for the body. Lipid functions include: Providing hydrophobic barriers which allow for compartmentalization. Protection against physical trauma by providing cushioning action. Acting as a structural component for biological membranes Controlling homeostasis by being a component of prostaglandin and steroid hormones Being thermal and electrical insulators Being metabolic regulators. Ex: associated with liposoluble vitamins regulating enzymes Hydrophilic molecules are water loving and considered to be polar. Hydrophobic molecules are water fearing and considered to be non-polar. If a molecule is amphipathic, they are both water fearing and water loving. An example of an amphipathic molecule is a phospholipid. Common Lipids Examples of simple lipids includes: Saturated and unsaturated fatty acids Neutral fats (such as waxes and ceramides) Mono-, di-, triacylglycerol (TAG) Examples of complex lipids include: Glycolipids Sphingolipids/ sphingoglycolipids Phospholipids Lipoproteins Examples of derived lipids include: Steroids (such as cortisol, aldosterone, sex hormones) Eicosanoids (such as prostaglandin, thromboxane, leukotrienes) Ketones (which are modified fatty acids) Fat soluble vitamins (such as A, D, E, K) Fatty Acids: General Info Fatty acids are used as the building block for lipids. Fatty acids are in the body as fatty acid esters or are free in the body (in small amounts). Fatty acid esters are fatty acids combined with an alcohol (such as glycerol). During a period of fasting, TAG’s are released from adipocytes and utilized as an energy source for cells within tissues. The travel to the tissue cells bound to plasma albumin. Beta oxidation is a form of getting energy from fatty acids and is commonly utilized in the liver and muscles. Fatty acid structural components include phospholipids and glycolipids in the plasma membrane. Fatty acids are the precursor for the prostaglandin hormone. Fatty acids are stored for energy in white adipose tissue as TAGs. Fatty acids must be bound to a protein for plasma circulation, such as albumin or a lipoprotein. Fatty Acids: Structure Fatty acids are made of a hydrophobic hydrocarbon chain with a terminal hydroxyl group (COOH). At physiological pH, the hydroxyl group is ionized to COO^- (and becomes polar). This anionic group is hydrophilic and gives fatty acids their amphipathic nature. In long chain (length) fatty acids (LCFA), majority of it is a hydrophobic portion, causing them to be very water insoluble. Over 90% of fatty acids circulating in blood plasma are in an esterified form (such as a phospholipid, TAG, cholesteryl ester) contained in lipoprotein particles. Fatty Acid: Saturation Saturated fatty acids means that they are saturated in hydrogen bonds and lack double bonds. Saturated fatty acids have a higher melting point than unsaturated fatty acids. Unsaturated fatty acids means that they have double bonds. Cis double bonds cause kinks within the fatty acid. 2 or more double bonds are always spaced in 3 carbon intervals. Fatty Acid: Nomenclature When numbering a carbon chain, the 1st carbon (aka: carbon 1) is called the carbonyl carbon. When describing the structure of molecule it may be in the format “#:#(#)”. #:#(#) is equivalent to- number of carbons: number of double bonds (position of each double bond). For example, 18:2(9,12) means that there are 18 total carbons in the chain, there are 2 double bonds in the chain, and there is a double bond at carbons 9 and 12. When numbering a carbon chain, the 2nd carbon is attached to the carbonyl carbon and is referred to as the “alpha (a) carbon”. When numbering a carbon chain, the 3rd carbon is attached to the alpha carbon and is referred to as the “beta (B) carbon”. When numbering a carbon chain, the 4th carbon is attached to the beta carbon and is referred to as the “gamma (Y) carbon”. When numbering a carbon chain, the carbon furthest from the carbonyl carbon (at the end of the carbon chain), is referred to as the “omega (w) carbon” and is a methyl group. Double bonds can be identified using the omega carbon as reference, by counting backwards on the carbon chain and staring at the omega end. This double bond is identified by counting the amount of carbons from the omega carbon to the double bond. If there are 6 carbons from the omega carbon to the double bond, it would be referred to as omega-6 fatty acid. Essential fatty acids have 18 carbons total in their carbon chain. Short chain fatty acids (SCFA) have 2-5carbons. Shorter chain fatty acids are the easiest to digest. Medium chain fatty acids (MCFA) have 6-12carbons. Long chain fatty acids (LCFA) have 13-21 carbons. Very long chain fatty acids (VLCFA) have 22+ carbons. VLCFA are typically found within the brain. Essential Fatty Acids Essential fatty acids are essential for metabolism but cannot be synthesized by the body so it must be absorbed from the diet. Different species will have different essential fatty acid requirements, however, most require 5:1 to 10:1 (omega-6:omega-3). Sources for essential fatty acids include: nuts, algae, fish oil, seeds, vegetable oil. Linolenic acid (omega-6 fatty acid) is a precursor for arachidonic acid which is a substrate used for eicosanoid synthesis. Alpha linolenic acid (omega-3 fatty acid) is essential for growth and development. It is also used in eicosanoid synthesis. Phospholipids: Structure Phospholipids are lipid compounds that are composed of a polar phosphate head group, and 2 non-polar fatty acid tails that are joined by a glycerol backbone. The phosphate head group can link with other polar heads such as serine and choline. This causes the whole head group to be polar. Serine is a polar amino acid with an alcohol function. The hydrophobic tail will contain either a fatty acid or a fatty acid derived hydrocarbon. Overall the phospholipid structure looks like: 2 fatty acid tails + glycerol back bone + phosphate + alcohol (acting as the polar head group). Phospholipids: General Info In membranes, the hydrophobic part of the phospholipid is connected to the non-polar parts of other membrane molecules such as glycolipids, cholesterol, and proteins. The hydrophilic polar head of the phospholipid will be facing the external aqueous environment. Membrane phospholipids can store intracellular messenger molecules or act as anchors. Nonmembrane phospholipids are important components of lung surfactant and detergent-like molecules (bile). Phospholipids are the main lipids within the cellular membrane. In aqueous environments, the phospholipids can orient themselves into a lipid bilayer or into a liposome, depending on which is more energetically favorable. Phospholipid: Classes Glycerophospholipids have glycerol as their backbone. They make up majority of phospholipids within the cell membrane and are the most prevalent phospholipid, in general. Phosphatidic acid (PA) is the precursor for glycerophospholipids, and is esterified to different alcohols (polar heads). Examples of glycerophospholipids include: Phosphatidylcholine (choline + PA) Major component of lecithin which is present in lung surfactant Phosphatidylserine (serine + PA) Phosphatidylethanolamine (ethanolamine + PA) Cephalin Phosphatidylinositol (inositol + PA) Important to regulate intracellular signals, lipid transport, and vesicular trafficking. Phosphatidylglycerol (glycerol + PA) Present in lung surfactant. Sphingophospholipids have sphingosine as their backbone. Sphingosine is a derivative of serene and palmitate. Attached to it is an unsaturated LCFA with a long hydrocarbon tail. Sphingomyelin is the main type of sphingophospholipid and is an essential component of the myelin sheath of nerve fibers. Sphingolipid structure looks like: fatty acid + sphingosine backbone + phosphate + choline. Note that glycerophospholipids will have an alcohol attached to their phosphate group, while sphingophospholipid will have a choline attached to their phosphate group. Phospholipids with Physiological Relevance Cardiolipin is a component found within the inner mitochondrial membrane (where it is relevant for the maintenance of the ETC) and is used for blood clotting. Platelet activating factors (PAF) is involved in the activation of inflammatory cells, platelet aggregation (for blood clotting), and is involved in hypersensitivity and anaphylactic reactions. Phospholipid: Synthesis (General Steps) Essentially all cells except for erythrocytes can synthesize phospholipids. Glycerophospholipids are synthesized from cell cytosolic precursors such as fatty acyl CoA and glyceral-3-phosphate (which is obtained via glycolysis). Step 1: In the sER, phospholipids are synthesized. Step 2: In the Golgi apparatus, the phospholipids are modified. Step 3: The phospholipids are either secretes into vesicles or will compose the membranes of organelles. Phospholipid: Synthesis of Glycerophospholipids Step 1: 2 fatty acids linked to CoA are joined to glyceral-3-phosphate, forming phosphatidic acid. Step 2: Phosphatase converts phosphatidic acids into diacylglycerol. Step 3: The diacylglycerol has different polar head groups attached to it, resulting in a variety of possible formations. Examples include: phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine. Phospholipid: Degradation Phospholipase is used to degrade phospholipids and is found in all tissues and within pancreatic juice. Phospholipases are found in many venoms, such as snake and bee venom. Many pathogenic bacteria can secrete this enzyme to facilitate entry into cell membranes via dissolving it, to further spread infection. Glycolipids and Glycosphingolipids Glycolipids are composed of carbohydrate and lipid components. The main function of glycolipids is to maintain the stability of the cell membrane and aid in cellular recognition. Glycosphingolipids are a subgroup of glycolipids. They contain a carbohydrate (sugar) group and a ceremide derivative (in which a LCFA is attached to an amino alcohol sphingosine- acting as the backbone that will be attached to the carb). They are attached together via an O-glycosidic bond. Unlike phospholipids, glycosphingolipids do not contain a phosphate group. Instead, the polar head group function is provided by a mono- or oligosaccharide. Glycosphingolipids are found in high concentrations within nerve tissue and can be found in the outer part of the cell membrane where they interact with the extracellular environment and have an antigenic recognition function. Glycosphingolipids are for regulation of cellular interactions, growth, and development. Glycosphingolipids and Blood Group Antigens Each blood type molecule has a glycosphingolipid that is attached to a Glu, Gal, GalNAc, Gal, and Fuc chain. Blood types differ based on what is on the terminal sugar group. Blood group O lacks both GalNAc and Gal on their terminal sugar group. Blood group A has GalNAc on that terminal sugar. Blood group B has Gal on that terminal sugar. Blood group AB has both Gal and GalNAc on the terminal sugar. Each blood group is also referred to as an antigen. Example: Blood group B is equivalent to B-Antigen. Lipids: Eicosanoids Eicosanoids are signaling molecules that are lipid derivatives. They are very potent and have a wide range of effects. Eicosanoid effects include physiologic (inflammatory response) and pathologic (hypersensitivity). Eicosanoids are produced in very small amounts and act locally within tissues. Eicosanoids are classified as local hormones. Eicosanoids are not stored and have very short half-lives. Examples of eicosanoids include prostaglandin (PG), thromboxane (TX), and leukotrienes (LT). These are all derived from omega 3 and omega 6 polyunsaturated fatty acids with 20 carbons (eicosa=20). Eicosanoids: Arachidonic Acid Arachidonic acid is the main immediate precursor for eicosanoids. Arachidonic acid is part of the membrane phospholipids. It is not an essential fatty acid but can be limited (since it is derived from essential fatty acids. Some mammals (like cats) lack or have very limited availability to synthesize arachidonic acid. Therefore, arachidonic acid would be an essential fatty acid for cats. Types of Eicosanoids Prostaglandin (PG) PG is responsible for pain and fever response. PG actions can impact the reproductive and GI tract. PG actions can also impact bronchopulmonary tone and vascular smooth muscle tone (mostly vasodilation). PG is also involved in the regulation of hormones, calcium movement, and inflammation. Thromboxane (TX) Thromboxane is synthesized in platelets (thrombocytes). TX promote platelet homeostasis by inhibiting or promoting blood clot formation. Leukotriene (LT) LT is synthesized in leukocytes such as macrophages, mast cells, neutrophils, and eosinophils. LT synthesis is not inhibited by NSAIDs. LT acts as a mediator for allergic response and inflammation. Lipids: Cholesteryl Ester (CE) CE is the esterified version of cholesterol. Esterification makes the molecule even more hydrophobic. CE must be associated with a lipoprotein for transport. CE is present in low levels, associated with lipoproteins. CE are not found within membranes. Lipids: Cholesterol Cholesterol is a very hydrophobic compound that is composed of 4 fused hydrocarbon rings (A-D) which are referred to as the “steroid nucleus”. Cholesterol can be brought into the body via diet, or it can be synthesized via “cholesterol de novo synthesis” by the liver and extrahepatic tissue. Cholesterol is part of the cell membrane, aiding it in fluidity modulation, where it plays a structural role. Cholesterol also plays a structural role in lipoproteins. Cholesterol is a precursor to bile acids (bile salts), steroid hormones, and vitamin D. Cholesterol is biosynthesized by all animal cells. Disturbance in balance can lead to cholesterol deposition within tissue and dangerous plaque formations. The liver is essential in the control of cholesterol homeostasis. Lipids: Steroid Hormones Cholesterol is the precursor to all steroid hormones such as: Glucocorticoids (cortisol) Sex hormones (progestins, estrogens, androgens) Mineralocorticoids (aldosterone) Hormones are transported in the blood from site of synthesis (adrenal glands) to their target organs. Steroid hormones are hydrophobic and must travel bound to plasma proteins like albumin. Lipids: Plasma Lipoproteins Plasma lipoproteins are spherical macromolecular complexes of lipids and proteins (apolipoproteins). Plasma lipoprotein types include: Chylomicrons Majority of it’s composition is TAG. VLDL (very low density lipoprotein) Majority of it’s composition is TAG. LDL (low density lipoprotein) Majority of it’s composition is cholesterol and cholesteryl esters. HDL (high density lipoprotein) Majority of it’s composition is proteins. Plasma lipoproteins differ in protein and lipid composition, size, density, and site of origin. Plasma lipoprotein function to keep their lipid components soluble of transport in plasma and provide effective transport of lipids to and from tissues. Humans and other animals can experience gradual depositions of lipids (specifically cholesterol) in tissue and blood vessels. Abnormalities of lipoprotein metabolism generally occur at their site of production or site of utilization.