Lipids and lipoproteins Lecture 7

Lipid chemistry and cardiovascular profile Main lipids in the blood are the triglycerides and cholesterol Insoluble in the water. Transport in the blood is via lipoproteins

Triglycerides Glycerol with 3 attached fatty acids Exogenous source : Dietary Endogenous : Liver and tissue storage 95 % of body fat is triglycerides Energy source when plasma glucose is decreased Triglyceride catabolism is regulated by lipase, epinephrine and cortisol Triglycerides are transported by Chylomicrons ( exogeneous ) and VLDL very low density lipoprotein ( endogenous )

Chylomicrons (from the Greek chylo, meaning juice or milky fluid, and micron, meaning small particle) are lipoprotein particles that consist of triglycerides (85–92%), phospholipids (6–12%), cholesterol (1–3%), and proteins (1–2%). They transport dietary lipids from the intestines to other locations in the body. VLDL stands for very low density lipoprotein. Lipoproteins are made up of cholesterol, triglycerides, and proteins. They move cholesterol, triglycerides, and other lipids (fats) to around the body. VLDL is one of the three main types of lipoproteins. VLDL contains the highest amount of triglycerides.

Cholesterol Transported by HDL and LDL Found only in animals Important component of membranes, steroid hormones, bile and Vitamin D Exogeneous cholesterol comes from diet Endogeneous cholesterol is synthesized by the liver 70 % of cholesterol associated with cellular components 30 % is in the plasma ( ⅓ free form , ⅔ esterified) Transported by HDL and LDL

Dietary intake supplies only about 20 – 25% of the cholesterol needed everyday. Functions of Cholesterol in the body to build cell membranes, synthesize bile acids/salts synthesize hormones of the adrenal glands (aldosterone, cortisol) • and synthesize the sex hormones. The other 75 – 80% of our daily need for cholesterol is synthesized in the liver.

Esterification reaction between a glycerol molecule and a fatty acid. glycerol is a three carbon chain with three OH groups attached. a fatty acid is a long hydrocarbon chain with an acid group at one end of the chain. these two molecules react by a condensation reaction (water is removed). the OH in the acid group of the fatty acid reacts with one of the OH groups on the glycerol molecules. an H is removed from one of the OH groups and the OH group is completely removed from the other. this leaves a carbon molecule bonded to an oxygen molecule which is the bonded to another carbon molecule. this is called an ester or peptide bond hence the esterification of a fatty acid with glycerol.

Ester bond can takes place 3 times with the same glycerol molecule but with different fatty acids. this molecule is then called a triglyceride. this is used as an energy storage in fat cells. but its most important use as far as biology is concerned is a phospholipid. instead of bonding three fatty acid chains to the glycerol molecule a phosphate group could be bonded on. this is makes up all cell membranes.

Fatty acids are short to long carbon chained molecules Saturated fatty acids Unsaturated fatty acids Phospholipids Important components of cell membranes Lecithin and sphingomyelin are utilized to determine fetal lung maturity from amniotic fluid ( L / S Ratio ) Glycolipids Lipids with a carbohydrate component ABO antigen are glycolipids

lecithin–sphingomyelin ratio The lecithin–sphingomyelin ratio is a marker of fetal lung maturity. The outward flow of pulmonary secretions from the fetal lungs into the amniotic fluid maintains the level of lecithin and sphingomyelin equally until 32–33 weeks gestation, when the lecithin concentration begins to increase significantly while sphingomyelin remains nearly the same. As such, if a sample of amniotic fluid has a higher ratio, it indicates that there is more surfactant in the lungs and the baby will have less difficulty breathing at birth. An L–S ratio of 2 or more indicates fetal lung maturity and a relatively low risk of infant respiratory distress syndrome, and an L/S ratio of less than 1.5 is associated with a high risk of infant respiratory distress syndrome. If preterm delivery is necessary (as evaluated by a biophysical profile or other tests) and the L–S ratio is low, the mother may need to receive steroids such as betamethasone to hasten the fetus' surfactant production in the lungs. Procedure: An amniotic fluid sample is collected via amniocentesis and the sample is spun down in a centrifuge at 1000 rpm for 3–5 minutes. Thin layer chromatography (TLC) is performed on the supernatant, which separates out the components. Lecithin and sphingomyelin are relatively easy to identify on TLC and the predictive value of the test is good.

lipoproteins Lipoprotein is a complex spherical structure that has a hydrophobic core wrapped in hydrophilic coating OR A lipoprotein is a biochemical assembly that contains both proteins and lipids, bound to the proteins, which allow fats to move through the water inside and outside cells. The proteins serve to emulsify the lipid molecules. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins. Examples include the plasma lipoprotein particles classified under high-density (HDL) and low-density (LDL) lipoproteins, which enable fats to be carried in the blood stream, the transmembrane proteins of the mitochondrion and the chloroplast, and bacterial lipoproteins.[1] 4 major classes of lipoproteins Chylomicrons Very low density lipoproteins (VLDL) Low density lipoproteins (LDL) High density lipoproteins (HDL)

lipoproteins

Lipoproteins compositions

Composition of lipoproteins Class Diameter (nm)  % protein  % cholesterol  % phospholipid  % triacylglycerol & cholesterol ester HDL 5–15 33 30 29 4 LDL 18–28 25 50 21 8 IDL 25–50 18 22 31 VLDL 30–80 10 Chylomicrons 100-1000 <2 7 84

Chylomicron structure

LDL Most core lipid in LDL is cholesterol ester. Major cholesterol carrying lipoprotein 2/3 - 3/4 of serum cholesterol is carried by LDL 50% of mass is cholesterol Produced as a product of VLDL metabolism Delivers cholesterol to peripheral tissues for biosynthesis and steroid hormone production Most core lipid in LDL is cholesterol ester. ApoB100 is only apolipoprotein in the surface.

LDL receptor Also named as apoB-100/apoE receptors LDL receptors exist in the liver and in most peripheral tissues The complexes of LDL and receptor are taken into the cells by endocytosis, where LDL is degraded but the receptors are recycled Number and function of the receptor shows LDL levels. LDL cholesterol levels are positively related to risk of cardiovascular disease Therefore, cholesterol in LDL has been called “bad cholesterol”

Apoliproproteins Outer protein “shell” of the lipoprotein molecule The protein – lipid interaction allows the water insoluble lipid to become soluble in plasma

Classes of apolipoproteins A, B, C, D, E are major classes Subclasses: apo A-1, apo C-II function of all apolipoproteins are not yet known Act as structural components of lipoproteins Recognize the lipoprotein receptors on cell membrane surface as ligand Activate/inhibit enzymes involved in lipoprotein metabolism

METABOLISM Exogenous Endogenous Lipoprotein lipase release FFA and glycerol from chylomicron and VLDL Lecithin Cholesterol acyl transferase (LCAT) Forms cholesteryl esters from free cholesterol and fatty acids

Atherogenesis and LDL Formation of fatty streaks

HDL –a good cholesterol • Nascent HDL takes CH from Foam cells and periphery. • CH is converted into CE by LCAT (lecithin cholesterol acyl transferase). • The CE of HDL is transported to VLDL, LDL, IDL by CETP (cholesteryl ester transfer protein) which further goes to liver via LD Rreceptor: Reverse cholesterol transfer.

Lipid and Lipoprotein Population Distributions Serum lipoprotein concentrations differ between adult men and women, Primarily as a result of differences in sex hormone levels, Women having, on average, higher HDL cholesterol levels and lower total cholesterol and triglyceride levels than men. The difference in total cholesterol, however, disappears after menopause as estrogen decreases

Hypercholesterolemia Familial hypercholesterolemia (FH) (7.5- 12 mmol/L) Primarily LDL elevations Synthesis may be normal but decrease or lack LDL receptors due to mutation in LDL receptor gene. Therefore LDL builds-up in serum Since cells cannot acquire from LDL therefore increase internal synthesis of cholesterol. Tendon xanthomatas (is a deposition of yellowish cholesterol-rich material that can appear anywhere in the body in various disease states) Early occurrence of coronary artery disease M. Zaharna Clin. Chem. 2009

Hypertriglyceridemia Triglycerides Borderline = 150-200 mg/ dl High 200-500 mg/dl Very High > 500 mg/dl Familial hypertriglyceridemia Genetic Secondary hypertriglyceridemia Hormonal imbalances Imbalance between synthesis and clearance of VLDL M. Zaharna Clin. Chem. 2009

Hypertriglyceridemia Generally caused by deficiency of LPL or LPL cofactor. (LPL hydrolyzes triglycerides in chylomicrons and VLDL) Deficiency prevents processing and clearing of triglycerides Elevated even with fasting

Familial Combined Hyperlipidemia Presence of elevated levels of serum total cholesterol and triglycerides Hepatic overproduction of apo B Increased VLDL and LDL M. Zaharna Clin. Chem. 2009

Familial hyperchylomicronemia Genetic mutation of LPL or apo C-II gene Recurrent abdominal pain Pancreatitis Clinical disorders of lipid metabolism Primary Secondary

hyperlipidemias Ethiopathosis is the cause / subsequent development of an abnormal condition or of a disease.

secondary Disease Lipid abnormality DM TG Alcohol CRF Drugs thiazide Hypothyroidism Cholesterol Nephrotic syndrome