Lipids and Lipoproteins PDF

Lipids and lipoproteins Metabolism and associated disorders  Intro to Lipids Unlike the other major biomolecules that are defined by their chemical properties, lipids are defined by their physical properties Lipids are soluble in organic solvents but are nearly insoluble in w...

Lipids and lipoproteins Metabolism and associated disorders  Intro to Lipids Unlike the other major biomolecules that are defined by their chemical properties, lipids are defined by their physical properties Lipids are soluble in organic solvents but are nearly insoluble in water Primarily contain nonpolar carbon-hydrogen (C-H) bonds and yield fatty acids and/or complex alcohols after hydrolysis  Intro to lipids They are found throughout the body as structural components, hormones, and nerve insulators The clinical significance of lipids is their link to coronary heart disease (atherosclerosis), cardiovascular disease, and lipoprotein disorders Broadly subdivided 1) Cholesterol 2) Fatty acids 3) Acylglycerols 4) Sphingolipids 5) Prostaglandins 6) Terpenes  Cholesterol 12 17 11 13 D 16 C 14 15 1 9 2 10 A B 8 3 5 4 6 7 HO Found almost exclusively in animals Key membrane component of cells, and a precursor in the synthesis of bile acids and steroid hormones A,B,C,D = Cyclopentanoperhydrophenanthrene (steroid alcohol) Cholesterol Absorption Derived from animal and dairy products in our diet Only ~30% to 60% is absorbed Acted upon by cholesterol esterases secreted from the pancreas and small intestine Delivered to the liver and peripheral tissues by chylomicrons (more on those later) Cholesterol Synthesis Made by all cells in the body, but particularly by the liver and intestine. Occurs in 3 stages, beginning with acetyl CoA, to produce the 27- carbon molecule https://epomedicine.com/medical-students/cholesterol-synthesis-mnemonic/ Cholesterol synthesis (basic steps) Acetyl CoA mevalonic acid (mevalonate) squalene (structure before rings close) Lanosterol (rings close) cholesterol bile salts steroid hormones Vitamin D production Cholesterol synthesis (Complex steps) Acetyl-CoA 3-Hydroxy-3-methylglutaryl-CoA HMG-CoA reductase Squalene Mevalonate Cholesterol + Cholesterol Lecithin ester “Statin” drugs inhibit this enzyme Cholesterol Esterification Esterified to a fatty acid to form cholesteryl ester by 2 different enzymes In cells, esterified by acylcholesterol acyltranferase (ACAT) then stored in intracellular lipid drops In plasma, lecithin cholesterol acyltranferase (LCAT) will esterify cholesterol Cholesterol esters account for ~70% of total cholesterol in plasma In this form, cholesterol loses its free hydroxyl group and becomes more hydrophobic Cholesterol Catabolism Majority of catabolism occurs in the liver Remainder is used to synthesize steroid hormones by specialized endocrine cells ~1/3 of daily production is converted into bile acids Much of the rest is re-secreted into circulation on lipoproteins, with the remainder excreted into bile unchanged. When amount of cholesterol exceeds capacity, it is possible for it to precipitate and form gall stones  Fatty acids RCOOH is the general formula Classified by chain length as well as degree of saturation Saturated FA’s have no double bonds (C=C) between carbon atoms Monounsaturated contain one double bond Polyunsaturated contain multiple double bonds Most FAs are synthesized by the body except essential FAs  FA catabolism Catabolized in the mitochondria Produce energy by a series of reactions known as ß- oxidation Process is repeated to shorten the FA chain by 2 carbon atoms at a time Ex. A 16 carbon FA is converted into 8 molecules of a 2- carbon sugar, Acetyl CoA Acetyl CoA will condense with oxaloacetate to yield citrate and enter the Krebs cycle Acylglycerols (Glycerol Esters) Glycerol is a 3-carbon alcohol Class of acylglycerol is determined by the number of fatty acyl groups present: One fatty acid- monoacylglycerols Two FA- diacylglycerol Three FA- triacylglycerol a.k.a triglycerides  Triglycerides (triacylglycerol) Constitute 95% of tissue storage fat Predominant form of glycerol esters found in plasma Generally, triglycerides from plant sources tend to be enriched in unsaturated FAs and are liquids at room temp Those from animals tend to have saturated FAs and are solids at room temp  Sphingolipids Derived from the amino alcohol sphingosine It is an intermediate structure in the formation of: Sphingomyelin Galactosylceramide Glucosylceramide Involved in the recognition of cells as self and in recognition of blood group antigens Also used to form complex globosides and gangliosides, the latter of which is abundant in the membranes of grey matter of the brain  Prostaglandins Represents about 20 different tissue hormones These hormones are synthesized at the sight of reaction and have a short life (rapidly catabolized) Involved with smooth muscle contractions, glandular secretion Made from arachidonic acid (a 20 – carbon unsaturated fatty acid)  Terpene s Made from 5 –carbon isoprene units to make other fat-soluble vitamins (vitamins A, E, K). Used to make carotenoids - red, yellow, orange plant pigments. Beta-carotene Blood Lipids – Lipoproteins Chylomicrons VLDL IDL LDL HDL Lipoprotein (a)- LP(a) Lipoproteins are spherical micelle-like particles with nonpolar neutral lipids (triglycerides and cholesterol esters) in their core and more polar amphipathic lipids at their surface. They also contain one or more specific proteins, called apolipoproteins, on their surface Classification Have different physical and chemical properties because they contain different proportions of lipids and proteins Traditionally categorized based on differences in their densities In general, the larger lipoproteins contain more core lipids in their core (triglycerides and cholesterol esters) and hence are lighter in density Relative Sizes of Lipoproteins VLDL (50%) Relative sizes of the Chylomicron four main types of LDL lipoproteins and their (85%) (10%) relative triglyceride content. HDL (4%) Composition of Chylomicrons Chylomicron (% by mass) 7% triglycerides 2% phospholipids 3% protein cholesterol esters 2% 86% cholesterol Composition of VLDLs VLDL (% by mass) 3% 7% 12% triglycerides phospholipids 50% protein 10% cholesterol esters cholesterol other 18% Composition of ldls LDL (% by mass) 8% 10% 20% triglycerides phospholipids protein 38% cholesterol esters cholesterol 24% Composition of hdls HDL (% by mass) 2 % 4% 15% 24% triglycerides phospholipids protein cholesterol esters cholesterol 55% Lipoproteins Chylomicron: Transports lipids from the intestinal mucosa to the tissues via the lymph system and circulatory system In the blood stream, triglycerides are hydrolyzed to monoglycerides and fatty acids which are absorbed by the tissues. The remnants carry cholesterol to the liver. Very Low-Density Lipoprotein (VLDL): Transports triglycerides from the liver to the tissues. In the blood stream, triglycerides are hydrolyzed to monoglycerides and fatty acids which are absorbed by the tissues. The remnants are LDL and some IDL (intermediate density lipoprotein) Lipoproteins Low Density Lipoprotein (LDL): Transports cholesterol and cholesterol esters to the tissues. LDL is absorbed through receptor-mediated endocytosis where the cell hydrolyzes the cholesterol esters, any remaining triglycerides, and the protein. High Density Lipoprotein (HDL): HDL removes excess cholesterol in the form of cholesterol esters from tissues and transports it to the liver. It is sometimes called the “good cholesterol”, because it helps to impede the accumulation of artheroscleotic plaque on blood vessel walls. Lipoprotein (a)- LP(a) Distinct class of lipoprotein that is structurally related to LDL but contains a carbohydrate protein apo(a) Plasma levels are mostly genetically determined Lp(a) is particularly proatherogenic and has been associated with aortic stenosis Currently no adequate drug or dietary therapy for lowering levels APOLIPOPROTEINS The protein composition differs from one lipoprotein class to another, and the protein constituents are called Apolipoprotein Functions of apolipoproteins Activate enzymes involved in lipid metabolism Maintain structural integrity of lipid/protein complex Delivery of lipids to cells via recognition of cell surface receptors (APO B) Apolipoprotein content of LPs Lipoprotein Apolipoprotein(s) Chylomicron AI, B-48, CI, CII, CIII VLDL B-100, CI, CII, CIII, E IDL B-100, E LDL B-100 HDL AI, AII Metabolism of lipoproteins Exogenous Pathway In mouth = nothing happens Stomach = emulsification begins by churning action, and gastric lipases which produce some diacylglycerols and fatty acids Small Intestine = 1. Emulsification by bile salts (from bile duct) which act like a soap causing large droplets to become small droplets. This creates more surface area for lipase contact. This is NOT a chemical reaction. Absorption of Lipids 2. Hydrolysis reaction by pancreatic lipase and some intestinal mucosal lipases. Triglycerides become mono and di glycerides; cholesterol esters become free cholesterol; phospholipids become lysophospholipids The breakdown products of fats form large aggregates with bile acids called micelles. Absorption occurs when the micelles encounter the microvilli of the intestinal cells The micelles are re-esterified in intestinal cells (golgi apparatus) to form triglycerides and cholesteryl  These fats are packaged into chylomicrons, which are large micelles containing a core of the fats surrounded by a shell of phospholipids, apolipoproteins, and free cholesterol. This outer shell is polar in structure, which helps for Chylomicrons Leave mucosal cells to enter lacteals (lymph capillaries), which are more porous, where they are carried in lymph to the thoracic duct, which empties into the blood stream (at the left subclavian/jugular vein junction). Subclavian from the arm Jugular from the neck Junction is at the collar bone The chylomicrons make their way to the liver, adipose tissue, and other organs as needed.  Exogenous Pathway After entering circulation, chylomicrons interact with proteoglycans Proteoglycans promote the binding of LPL (lipoprotein lipase) which hydrolyzes triglycerides Triglycerides are hydrolyzed back into FAs and glycerol so they can be used as an energy source for cells Excess FAs are re-esterified into triglycerides for long- term energy storage in adipocytes Endogenous Pathway Function is to transfer hepatically derived lipids (synthesized by the liver, or dietary lipids that were transferred) to peripheral cells for energy metabolism Mediated by the apo B-100 containing lipoproteins VLDL is the molecule responsible for more of the transport of lipids from the liver to the cells Upon reaching the cells, LPL (lipoprotein lipase) will breakdown the VLDL to release the lipids for energy usage Intracellular-cholesterol transport pathway Represents the mechanisms that cells use to maintain cholesterol balance- excess cholesterol is toxic to cells All cells receive cholesterol via uptake of extracellular lipoproteins Cholesterol delivered to the cells is 1) Used for membrane biogenesis 2) Stored in intracellular lipid drops 3) Carried from the cell via reverse-cholesterol transport pathway Reverse-cholesterol transport pathway Purpose is to remove excess cellular cholesterol from peripheral cells and return it to the liver for excretion Largely mediated by HDL → secreted from the liver as crescent-shaped molecules containing mostly phospholipids and apo A-I Gain their spherical shape in the extracellular space Control of Lipids in the Body  Lipid metabolism is a constant state of dynamic equilibrium; some lipids are constantly being oxidized to meet energy needs, while others are being synthesized and stored. A delicate balance between two antagonistic processes adjusts body fat storage: lipogenesis produces fat stores and lipolysis mobilizes fat Fat Mobilization Pulling lipids out of storage Making new fats Opposite from digestion Lipolysis: hydrolysis of lipids Triglycerides + water lipase> glycerol + 3 fatty acids Glycerol (gluconeogenesis) Glycerol glycerol-3-phosphate DHAP PGAL glucose DHAP = dihydroxy acetone phosphate PGAL = phosphoglyceraldehyde  Fatty Acid – Beta oxidation ß-oxidation is a 4-step biochemical pathway Fatty acids are chopped 2 carbons at a time resulting in production of acetyl CoA for Kreb’s cycle and electron transport chain i.e., 16 carbons will result in 8 acetyl CoA’s  Step 1: Oxidation and FADH2 is produced Step 2: Hydration Step 3: Oxidation and NADH produced Step 4: Carbon-carbon bond broken – shortens chain by two carbons and produces Acetyl CoA  Ketogenesi s Too much beta oxidation of fat. Occurs when body needs energy, but no carbs are stored so excess Acetyl CoAs are produced 2 Acetyl CoAs condense into ketone bodies, since they can’t enter the Kreb’s cycle fast enough Result: ketoacidosis and drop with blood pH Energy Yield: Fat vs. Carbohydrate Per carbon, fat yields more energy than sugar, carbons are more reduced (saturated) therefore more oxidation steps are possible Fat Metabolism OR Lipogenesis Making lipids from: 1.AcetylCoA fatty acids Where? Not in the mitochondria, but in the Endoplasmic Reticulum. The reducing agent isn’t NADH or FADH, but NADPH from the HMP shunt. Very different pathway (not an exact reversal of beta- oxidation). Reverse reactions such as reduction and dehydration. Why? Don’t want to utilize a pathway where NADH/FADH are used, as they would then be Making lipids from: 2. DHAP glycerol 3-phosphate glycerol How? DHAP is a product of fructose split from PGAL. Why? Glycerol now available to bind with 3 fatty acids to produce a new triglyceride