LIPIDS and lipoproteins introduction.docx

**Introduction to lipids and lipoproteins** **Prof AB OKESINA,** **DEPT. CHEMICAL PATHOLOGY AND IMMUNOLOGY** **Cardiovascular risk factors** Discussion of lipid metabolism is essential because it is an important risk factor for cardiovascular disease. Many factors are associated with or cause i...

**Introduction to lipids and lipoproteins** **Prof AB OKESINA,** **DEPT. CHEMICAL PATHOLOGY AND IMMUNOLOGY** **Cardiovascular risk factors** Discussion of lipid metabolism is essential because it is an important risk factor for cardiovascular disease. Many factors are associated with or cause increased cardiovascular risk. These can be divided into those which cannot be influenced and those which can be influenced. Those that cannot be influenced include: a family history of premature vascular disease,age and pre‐existing vascular disease. Those whose modification has an established role include: cigarette smoking, hypertension, diabetes and the hyperlipidaemias, especially hypercholesterolaemia. **Lipids** Lipids in plasma include: cholesterol, triglycerides, fatty acids and phospholipids. They act as energy stores (triglycerides) and as important structural components of cells (cholesterol and phospholipids). They also have specialised functions (e.g. as adrenal and sex hormones). The main lipidsare insoluble in water and are therefore transported in plasma as particulate complexes with proteins, the lipoproteins. **Cholesterol** This is a steroid that is present in the diet, but it is mainly synthesised in the liver and small intestine, the rate‐limiting step being catalysed by HMG‐CoA reductase. HMG‐CoA reductase inhibitors, commonly referred to as statins, are effective cholesterol‐ lowering drugs. Cholesterol is a major component of cell membranes, and acts as the substrate for steroid hormones formation in the adrenals and the gonads. It is present in plasma mainly esterified with fatty acids. The body cannot break down the sterol nucleus, so cholesterol is either excreted unchanged in bile or converted to bile acids and then excreted. Cholesterol and bile acids both undergo an enterohepatic circulation. It exists as either free cholesterol or esterified cholesterol. Cholesterol synthesis involves the initial conversion of acetate to mevalonic acid. The rate-limiting step is catalyzed by the enzyme β-hydroxyl-β methyl glutaryl coenzyme A reductase (HMG COA reductase). The enzyme activity is controlled by a negative feedback mechanism instituted by the intracellular cholesterol concentration. About two-thirds of the plasma cholesterol is esterified with fatty acid to form cholesterol esters. Laboratories measure plasma total cholesterol concentration and do not distinguish between the esterified and unesterified forms. Plasma concentration of cholesterol does not rise after a meal like triglycerides. Acetate (2 carbon units) Aceto acetyl COA 3hydroxyl-3methyl glutaryl COA (HMG-COA) HMG-COA reductase Mevalonic acid Iso pre noids Squalene Lanosterol Cholesterol **Triglycerides** These are fatty acid esters of glycerol, and are the main lipids in the diet. They are broken down in the small intestine to a mixture of monoglycerides, fatty acids and glycerol. These products are absorbed, and triglycerides are resynthesised from them in the mucosal cell. Most of these **exogenous** triglycerides pass into plasma as chylomicrons. **Endogenous** triglyceride synthesis occurs in the liver from fatty acids and glycerol. The triglycerides synthesised in this way are transported as very low density lipoproteins (VLDL). Plasma triglycerides rise after a fatty meal and remain increased for several hours. **Fatty acids** They are mainly derived from dietary or tissue triglyceride, but the body can also synthesise most of them, apart from certain polyunsaturated (essential) fatty acids. Fatty acids act as an alternative or additional energy source to glucose. These are straight-chain carbon compounds of varying length. They may contain no double bonds -- saturated fatty acids or they may be mono or polyunsaturated. **Examples of Fatty Acids** **Double Bond** **Name** **Chain Length** **Source** ------------------ ----------------- ------------------ ------------------ Saturated Myristic C14 Coconut oil Palmitic C16 Animal/plant fat Stearic C18 Animal/plant fat Mono unsaturated Palmitoleic C16 Fat Oleic C18 Natural fat Poly unsaturated Linoleic C18 Plant oils Linolenic C18 Plant oils Arachidonic C20 Plant oils Eicosapentanoic C20 Fish oils Fatty acids may be esterified with glycerol to form triacylglycerol or be non-esterified (NEFA) or free (FFA). Plasma free fatty acids (FFA) liberated from adipose tissue are transported, mainly bound to albumin, to the liver and muscle where they are metabolized. They provide a significant proportion of the energy requirements of the body. **Phospholipids** These have a structure similar to triglycerides, but a polar group (e.g. phosphorylcholine) replaces one of the three fatty acid components. The presence of both polar and nonpolar (fatty acid) groups gives the phospholipids their characteristic detergent properties. Phospholipids are mainly synthesised in the liver and small intestine; they are important constituents of cell membranes. **Lipoproteins** Cholesterol and its esters, triglycerides and phospholipids are all transported in plasma as lipoprotein. Fatty acids are transported bound to albumin. Lipoprotein particles comprise a peripheral envelope, consisting mainly of phospholipids and free cholesterol (which each have both water‐soluble polar and lipid‐soluble nonpolar groups) with some apolipoproteins, and a central nonpolar core (mostly triglyceride and esterified cholesterol). The molecules in the envelope are distributed in a single layer in such a way that the polar groups face out towards the surrounding plasma, while the nonpolar groups face inwards towards the lipid core in which the insoluble lipids are carried. Most lipoproteins are assembled in the liver or small intestine. Five main types of lipoprotein particle can be recognised: **Chylomicrons** are the principal form in which dietary triglycerides are carried to the tissues. **Very Low Density Lipoproteins** (**VLDLs)** are triglyceride‐rich particles that form the major route whereby endogenous triglycerides are carried to the tissues from the liver and, to a lesser extent, from the small intestine. **Intermediate‐density lipoproteins** (**IDLs or 'VLDL remnants'**) are particles formed by the removal of triglycerides from VLDLs during the transition from VLDLs to LDLs. **Low Density Lipoproteins** (**LDLs)** are cholesterol‐rich particles, formed from IDLs by the removal of more triglyceride and apolipoprotein. Increased plasma LDL cholesterol, and hence plasma total cholesterol, is positively correlated with the incidence of ischaemic heart disease. **High Density Lipoprotiens (HDLs)** act as a means whereby cholesterol can be transported from peripheral cells to the liver, prior to excretion. Increased plasma HDL cholesterol is negatively correlated with the incidence of ischaemic heart disease, presumably explained by  its role in transporting cholesterol from the periphery. **A sixth type of lipoprotein particle,Lp(a)**, is synthesised in the liver and has approximately the same lipid composition as LDL (see further on). The physiological role of Lp(a) is not known, but its concentration is highly heritable. Plasma Lp(a) concentration is positively associated with the incidence of ischaemic heart disease, independently of other lipoprotein fractions. The effect may be due to competition between Lp(a) and plasminogen for endothelial cell receptors, thereby inhibiting thrombolysis. +-----------------+-----------------+-----------------+-----------------+ | **LIPOPROTEIN** | **SOURCE** | **APOLIPOPROTEI | **ELECTROPHORET | | | | N** | IC** | | | | | | | | | | **MOBILITY** | +=================+=================+=================+=================+ | Chylomicrons | Gut | A,B,C,E | Origin | +-----------------+-----------------+-----------------+-----------------+ | VLDL | Liver | B,C,E | Pre-β | +-----------------+-----------------+-----------------+-----------------+ | IDL | Plasma | B,E | Broad β | +-----------------+-----------------+-----------------+-----------------+ | LDL | VLDL via IDL | B | Β | +-----------------+-----------------+-----------------+-----------------+ | HDL | Gut/liver | A,C,E | Α | +-----------------+-----------------+-----------------+-----------------+ **The apolipoproteins** The protein components of the lipoproteins, the apolipoproteins, are a complex family of polypeptides that promote and control lipid transport through the circulation and lipid uptake into tissues. They are separable into four main groups (apoA, B, C and E), some of which may be subdivided. **ApoA** is synthesised in the liver and intestine. It is initially present in chylomicrons in lymph, but rapidly transfers to HDL. **ApoB** is present in plasma in two forms, apoB100 and apoB48. ApoB100 is the protein component of LDL, and is also present in chylomicrons, VLDL and IDL. ApoB48 (the N‐terminal half of apoB100) is only found in chylomicrons. ApoB100 is recognised by specific receptors in peripheral tissues. **ApoC**. This family of three proteins (apoC‐I, apoC‐ II and apoC‐III) is synthesised in the liver and incorporated into HDL. **ApoE** is synthesised in the liver, incorporated into HDL and transferred in the circulation to chylomicrons and VLDL. There are three major isoforms (apoE2, apoE3 and apoE4) at a single genetic locus, giving rise to several genotypes (E3/3, E2/3, E2/4, etc.). ApoE is probably mainly involved in the hepatic uptake of chylomicron remnants and IDL; it binds to apoB receptors in the tissues. Apo(a) is present in equimolar amounts to apoB100 in Lp(a). It has a high carbohydrate content and has a similar amino acid sequence to plasminogen. It varies in size due to a polymorphism causing variable numbers of repeats of part of its structure, resulting in a number of isoforms. There is an inverse correlation between the size of the isoform and the plasma Lp(a) concentration. **Functions of Apolipoproteins** **APO LIPOPROTEIN** **Associated lipoprotein** **Function** --------------------- ------------------------------ --------------------------------------------- A~1~ Chylomicrons & HDL LCAT activator A~2~ Chylomicrons &HDL LCAT activator B~48~ Chylomicrons & VLDL Secretion of chylomicrons /VLDL B~100~ IDL, VLDL, LDL LDL receptor binding C~2~ Chylomicrons, HDL, VLDL, IDL Lipoprotein lipase activator C~3~ Chylomicrons, HDL, VLDL, IDL Lipoprotein lipase activator E Chylomicrons, HDL, VLDL, IDL IDL and remnant particles receptor binding. **Enzymes involved in lipid transport** Four enzymes of relevance to clinical disorders are: **Lecithin cholesterol acyltransferase (LCAT)** transfers an acyl group (fatty acid residue) from lecithin to cholesterol, forming a cholesterol ester. In plasma, this reaction probably takes place exclusively on HDL, and may be stimulated by apoA‐I. ** Lipoprotein lipase** is attached to tissue capillary endothelium and splits triglycerides (present in chylomicrons and VLDLs) into glycerol and free fatty acids. Its activity increases after a meal, partly as a result of activation by apoC‐II, which is present on the surface of triglyceride‐bearing lipoproteins. ** Hepatic lipase** has an action similar to that of lipoprotein lipase. ** Mobilising lipase**, present in adipose tissue cells, controls the release of fatty acids from adipose tissue into plasma. It is activated by catecholamines, GH and glucocorticoids (e.g. cortisol), and inhibited by glucose and by insulin.