Lipids Key Points

a lipid disorder characterised by an abnormal lipid profile, it refers to an imbalance in the levels or composition of lipids in the bloodstream. It is a broad term that encompasses various abnormalities in lipids, including triglycerides and cholesterol

Elevated total cholesterol/Hyperlipidaemia Hypertriglyceridemia - Chylomicron syndromw Familial hypercholesterolemia - FT IIa Type III Hyperlipoproteinemia

condition characterised by elevated levels of cholesterol (particularly LDL) which leads to cholesterol deposits along the walls of blood vessels. This causes strain on the heart which puts an individual at major risk of coronary heart disease. Cholesterol plaques may also rupture and form clots which impedes blood flow, tissue is starved of oxygen and angina or heart attack can occur

Also called Chylomicron syndrome or Fredrickson Type 1. Caused by a deficiency in either lipoprotein lipase (LPL) or apolipoprotein CII (which activates LPL). The patient cannot clear TAG rich chylomicrons from their circulation and thus have a profound hypertriglyceridemia. This hypertriglyceridemia will lead to eruptive xanthomata which must be treated with a low fat diet or a plasma infusion for ApoCII deficient cases.

Fredrickkson Type IIa Caused by a deficient LDL-receptor function, usually a mutation in the receptor but there can also be deficits in cytoplasmic adaptor proteins. This mutation prevents LDL from being internalised i.e. LDL remains in plasma which elevated cholesterol levels and minor changes to TAGs. Tendon xanthoma and corneal arci are common symptoms of this. LDL-R can be upregulated with drugs in heterozygous patients to increase clearance of LDL from blood, homozygous patients may need plasma apheresis to remove LDL.

associated with the E2 variant of ApoE. It results in impaired catabolism of IDL which results in accumulation of VLDL remants

Predominant hypercholesterolaemia – caused by cholestasis and primary hypothyroidism Predominant hypertriglyceridaemia – caused by obesity, diabetes and metabolic syndrome

Dyslipidaemias can be treated with therapies and diet. Diet is essential for hypertriglycerideamia, patient must cut out saturated fats and use plant stanol esters. Therapies are essential to stop cholesterol synthesis in hypercholesterolaemia. Statin class drugs such as Lipitor competitively inhibit cholesterol synthesis, Eztimibe blocks cholesterol absorption by acting as a bile acid binding resin

Cholesterol – CHOD-PAP method of detection is used, Cholesterol oxidase peroxidase aminoantipyrine method. It is a coupled assay which generates a coloured product, quinoneimine. Cholesteryl esterase acts on cholesteryl esters to form free cholesterol, cholesterol oxidase acts on the cholesterol to form H2O2, peroxidase acts on H2O2 to form quinoneimine. We can measure this red chromogen at 500nm. The Lieberman-Burchard Reaction or Amplex Red assay can be used to measure cholesterol. LBR utilises reagents which are difficult and dangerous to use while Amplex red is a more sensitive assay. Amplex red works by measuring fluorescent resorufin. There are some variables in cholesterol testing including: age and gender, within day variation of 2-3%, seasonal variation of 3-5%, venous stasis and trauma.

Cholesteryl esterase acts on cholesteryl esters to form free cholesterol, cholesterol oxidase acts on the cholesterol to form H2O2, peroxidase acts on H2O2 to form quinoneimine.

age and gender, within day variation of 2-3%, seasonal variation of 3-5%, venous stasis and trauma

HDL cholesterol is measured in fasting samples through the use of reagents which cause LDL cholesterol to precipitate. If the patient was fasting only HDL cholesterol should remain in plasma. Can thus measure cholesterol as normal to determine the HDL cholesterol. The LDL cholesterol can then be determined by calculation using the Friedewald Formula

complex coupled assay consisting of four enzyme reactions which measures the concentration of free glycerol via generation of quinoneimine. Lipase converts TAGs into Glycerol + FAs, Glycerol kinase converts glycerol into glycerol-3-phosphate, Glycerol-P-Oxidase converts G3P into H2O2, peroxidase converts H2O2 into quinoemimine

Lipid rich food is ingested and broken down by the stomach. Lipids are absorbed by enterocytes whereby they are packed into chylomicrons. Chylomicrons structure consists of mostly TAGs and ApoA1 and ApoB48. Chylomicrons then pass into lymph where they will enter circulation in the thoracic duct. In circulation chylomicrons donate ApoA1 to HDL and pick up ApoC-II and Apo-E. ApoC-II is an activator of lipoprotein lipase, it works by promoting the binding of lipoproteins to LPL which enhances its enzymatic activity. Activation of lipoprotein lipase breaks down TAGs in chylomicrons to form MAG and fatty acids. The fatty acids will be taken up by albumin and transported to cells in need of energy. The TAG-less chylomicron is called a chylomicron remnant which is taken up by the liver through receptor-mediated endocytosis via Apo-E. ApoC-II is donated to HDL. The chylomicron remnants are broken down by lysosomal degradation and their apolipoproteins and components are recycled. Any remaining cholesterol or TAGs are hydrolysed into free fatty acids, glycerol and cholesterol. The recycled apolipoproteins are incorporated into new lipoprotein particles which are involved in the endogenous pathway of lipoprotein metabolism e.g. VLDL

The synthesis of TAGs in the presence of excess carbohydrates. Liver produces TAGs but cannot store them so they are secreted in the form of lipoproteins e.g. VLDL. VLDL contains ApoB100. ApoE and ApoCII. VLDL delivers TAGs to tissues in need of energy and works by lipoprotein lipase activity. As VLDL delivers TAGs it’s relative cholesterol content increases and a VLDL remnant particle is produced. This VLDL remnant is also called intermediate density lipoprotein and it contains only 10% of the TAG contained by the VLDL. IDL lacks ApoCII therefore it cannot activate lipoprotein lipase. IDL is taken up by the liver which is mediated by ApoE binding to LDLR or LRP1. In the liver IDL is further modified by hepatic lipase to become low density lipoprotein. LDL is rich in cholesterol and contains ApoB100 and can be taken up by cells expressing the LDLR. LDL is taken up by receptor mediated endocytosis and the LDLR is recycled to the surface following internalisation. LDL can then be broken down into amino acids and cholesterol by cells. Reverse cholesterol transport is another aspect of endogenous lipoprotein metabolism which is mediated by HDL. This is initiated when lipid poor ApoA1 is synthesised in the periphery. This ApoA1 is then loaded with cholesterol to form Nascent HDL/B-HDL. LCAT then drives the conversion of B-HDL to larger a-HDL. Cholesterol content is then delivered to the liver via the HDL through receptor SRB1. Liver can again recycle this HDL to produce apolipoproteins or bile.

HDL Chlyomicrons

Chylomicrons

VLDL LDL

VLDL HDL

VLDL IDL

Activates LCAT

Lecithin cholesterol acyltransferase in the blood catalyses the formation of cholesteryl esters from free cholesterol and fatty acids

Its an LRP receptor ligand

Activates lipoprotein lipase