Lipoproteins and Dyslipidemias

Lipoproteins & Dyslipidemias

• This lecture aims to enable students to distinguish between lipoprotein complexes such as Chylomicrons, VLDL, IDL, LDL, and HDL.
• Understanding the makeup of each complex, including associated apolipoproteins and fat content, is crucial.
• Identifying the tissue where each complex forms and explaining each complex's primary role in fat transport, including hormonal controls, is part of the learning objectives.
• It is important to describe different hyperlipoprotenemias.

Lipids in Plasma

• Lipids are insoluble in aqueous plasma, necessitating association with proteins for solubility and transportation in plasma.

Lipoprotein Structure

• Lipoproteins are primarily spherical molecules made of lipids and proteins, known as apoproteins.
• Newly secreted HDL (nascent) is an exception, having a discoidal shape.
• The outer coat is hydrophilic, containing apoproteins, phospholipids, and cholesterol, whereas the inner core is hydrophobic, consisting of TAG and cholesterol ester.
• Phospholipids are amphipathic, having both polar and nonpolar regions.

Apolipoproteins' Role

• Lipoproteins differ in function, composition, size, density, site of origin, and apolipoprotein type.

Five Types of Plasma Lipoproteins

• There are five types of plasma lipoproteins: Chylomicrons (CM), Very low-density lipoproteins (VLDL), Intermediate density lipoprotein (IDL), Low-density lipoproteins (LDL), and High-density lipoproteins (HDL).
• Integral apoproteins include Apo B-48, found in the small intestine, and Apo B-100, found in the liver.
• Peripheral apoproteins include Apo A I, II, IV; Apo C I, II, III; Apo D; and Apo E.
• CM consists of Apo B-48 and is synthesized in the intestine from Apo B-100 mRNA, with a stop signal introduced via RNA editing, allowing translation of 48% of Apo B-100.
• Lipoproteins can be separated by ultracentrifugation or electrophoresis.

Lipoprotein Function

• Lipoproteins transport exogenous lipids from diet or those endogenously synthesized.
• Chylomicrons transport TAG of dietary origin
• VLDL transports TAG of endogenous hepatic synthesis.
• LDL carries cholesterol from the liver to extrahepatic tissues and HDL carries cholesterol from peripheral tissues to the liver.
• Additional functions include transporting fat-soluble vitamins and drugs, and delivering cholesterol to steroid hormone-producing tissues.

Lipoprotein Metabolism

• The exogenous pathway involves dietary fat, while the endogenous pathway involves lipids synthesized by the liver.

Chylomicrons

• Chylomicrons assemble in intestinal mucosal cells and are characterized by their low density and large size.
• They have the highest percentage of lipids, mainly triacylglycerol of dietary origin representing close to 90% of the lipids in a chylomicron, and the lowest percentage of proteins.
• Chylomicrons transport these dietary lipids to peripheral tissues.
• Nascent Chylomicrons contain Apo B-48 initially, and mature into containing Apo B-48 plus Apo C-II and Apo E, acquired from HDL.
• Mature chylomicrons enter the lymphatic system and then the blood, accounting for the physiological milky appearance of plasma up to 2 hours after a meal.
• Lipoprotein lipase is essential to degrade TAG into glycerol and fatty acids, serving as the clearing factor.
• As chylomicrons circulate, they degrade triacylglycerol.
• The remaining particle, the chylomicron remnant, decreases, and increases in density.
• CII apoproteins return to HDL and the remnant is removed from circulation as lipoprotein receptors in the liver recognize apo E.

Lipoprotein Lipase

• Lipoprotein lipase hydrolyzes TAG of CM & VLDL releasing fatty acids and glycerol.
• It is an extracellular enzyme anchored to the capillary walls of cardiac muscles, skeletal muscles, adipose tissue and lactating mammary glands.
• Phospholipids and Apo CII are cofactors for LPL, and its synthesis is enhanced by Insulin in adipocytes.
• Fatty acids stores in adipose tissue/used for energy by the heart and muscle, while glycerol is taken by the liver.

Very Low-Density Lipoproteins (VLDLs)

• Assembled and secreted by the liver

• Composed of endogenous triacylglycerol produced by the liver, accounting for 60% of their content.

• They transport lipids from the liver to peripheral tissues.

• Nascent VLDL contains Apo B-100, and mature VLDL contain Apo B-100, Apo C-II, and Apo E gained from HDL.

• ApoC-II activates lipoprotein lipase.

• Lipoprotein lipase is required to degrade TAG into glycerol and fatty acids.

• As this degradation happens, VLDLs become smaller and denser, turning into intermediate density lipoprotein

• Surface components, including the apo C and some apo E, are returned to HDL, with the remaining particles retaining apo B-100, thus forming LDL.

LDL Metabolism

• LDL is formed from IDL, contains less TAG, and has more cholesterol and cholesterol esters than VLDL.
• LDL deposits cholesterol into cells and arterial vessel walls and is removed from the blood via apo B-100, in Receptor-Mediated Endocytosis.
• In Receptor-Mediated Endocytosis, if the cholesterol isn't needed urgently, it will be esterified by acyl CoA, cholesterol acyl transferase (ACAT) whose activity is enhanced if cholesterol levels are high, used in steroid hormone synthesis, or will enter the membrane structure.
• High intracellular cholesterol content can decrease further uptake of LDL via down-regulation of LDL receptors /degradation, while low intracellular cholesterol triggers the converse.
• Scavenger receptors A exist in endothelium and macrophages.
• Receptors bind and endocytose modified LDL, unlike LDL receptors.
• Macrophages using these receptors accumulate cholesterol, which transforms the material into "foam" cells, this participates in the formation of atherosclerotic plaque.

Lipoprotein (a) and Heart Disease

• Lipoprotein (a) functions as an atherogenic lipoprotein that is retained longer in the blood than LDL.
• Large amounts are associated with increased risk of coronary heart disease, while Estrogen reduces expression of apo(a).
• Similarity between apo (a) and plasminogen means they interfere with plasminogen activation which provokes an acute thrombosis.

HDL Metabolism

• HDL is the primary carrier of cholesterol from peripheral tissues to the liver for excretion via bile in reverse cholesterol transport where a higher concentration is inversely related to likelihood of myocardial infarction
• HDLs form in the blood through the addition of lipids to apo A-1, which is made by the liver and intestine, accounting for 70% of HDL's apoproteins.
• Major functions include it's role as reservoir for apolipoproteins (apo C-II/ apo E), uptake of unesterified cholesterol, esterification of cholesterol, and reverse cholesterol transport.

Reverse Cholesterol Transport

• This process involves the selective transfer of cholesterol from peripheral cells to HDL, esterification of cholesterol, by lecithin: cholesterol acyltransferase (LCAT).
• Accumulation of cholesteryl esters with the liver for utilization.
• Nascent HDL turns spherical before CE to HDL3 and then HDL2 and becomes antiatherogenic via decreased cholesterol levels.
• LCAT transfers fatty acid from carbon point 2, of phosphatidylcholine, to cholesterol, forming hydrophobic cholesteryl ester / lyso-phosphatidylcholine maintaining cholesterol concentration gradient.
• HDL exchanges cholesteryl ester for TAG with VLDL, the cholesterol ester transfer protein (CTEP) (Apo D) relieves inhibition of LCAT by CE.
• Hepatic lipase is a lipolytic enzyme synthesized by hepatocytes transferring lipids to the surface/endothelial cells.
• Hepatic lipase hydrolyzes triacylglycerol and phospholipids in chylomicron remnants (IDL / HDL).

Scavenger Receptors

• Scavenger receptor class B (SR-B) is found primarily in the liver, binds HDL, and selectively uptakes CE.
• Scavenger receptor class is found on macrophage in blood; uptake ox LDL which causes the formation of foam cells/ atherosclerotic plaques.

Hyperlipoproteinemia

• Hyperlipidemia, hyperlipoproteinemia or dyslipidemia involves high or abnormal levels of lipids and/or lipoproteins, forming primary and secondary versions.
• Primary involves with single gene/polygenic affection, as secondary relates to obesity, jaundice, diabetes, hypothyroidism
• Type I Hyperlipoproteinemia is caused by lipoprotein lipase (LPL) or its activator apolipoprotein, results in higher than usual plasma TAG, and often causes acute abdomen and/or pancreatitis.
• Type IIa hyperlipoproteinemia (Familial hypercholesterolaemia) includes a mutation, results in a high plasma LDL level, premature atherosclerosis and onset ischemic heart diseases.

Metabolism Syndrome

• Syndrome entails risk factors for issues like diabetes and stroke, having at least three issues is a requirement.
• Risk factors: abdominal obesity, triglycerides, low HDL cholesterol, high blood pressure, and high fasting blood sugar.

Biochemical Basis of Atherosclerosis

• This involves modified LDL (oxidized) due to oxidative stress.
• This leads to uptake of oxLDL by macrophage scavenger receptor which results in the plaque forming, the following can be the cause of hypercholesteremia; diabetes, familial, hypothyroidism

Heart Disease

• High blood pressure, coffee and cigarettes, plus diabetes can be causes and triggers.

Methods of prevention

• Consuming less sugars , plus more fruits, while eating healthy is part of forming new habits.

Atherosclerosis prevention

• It is important to stop smoking and engage in physical activity, plus stress control.
• Drug use involves statins, resins.
• Increased lipolysis, oxidized LDLs, cholesterol contribute to the disease.
• Having a heart history or increase in age also adds one to the risk.