Hyperlipidaemia

History  Hypercholestrolemia is an inherited condition and for several years scientists have studied the effects of high cholesterol on the circulatory system.  In one study of young men without known heart disease.  cholesterol levels were measured and participants were observed for 6 years.

CONT…  Researchers found that the deaths of those participants who had high cholesterol levels were typically linked to heart disease.  It was concluded that the risk for a fatal heart attack is about 5 times higher in those with a cholesterol level of 300 mg/dL or more, than in those with a cholesterol level below 200 mg/dL

CONT…  The Framingham Heart Study is probably the most famous ongoing heart study in the world.  Cholesterol levels, smoking habits, heart attack rates, and deaths in the population of an entire town have been recorded for over 40 years.

Cont…  After 30 years, over 85% of people with cholesterol levels of 180 mg/dL or less were still alive.  almost 33% of those with cholesterol levels greater than 260 mg/dL had died.

Introduction  Fats are triacylglycerols containing saturated fatty acids - solid at room temp - usually from animal source (however, coconut & palm oil are saturated).  Oils are triacylglycerols containing mono- or polyunsaturated fatty acids - liquid at room temp - usually from plant sources (however, fish oils are polyunsaturated).  Phospholipids are triacylglycerols that have had a FA replaced with a phosphate linked FA group.  The major dietary sterol is cholesterol.

LIPID DIGESTION  Stomach - lingual lipase and gastric lipase attack triacylglycerols and hydrolyse a limited number of FA.  Small Intestine - acid chyme (stomach contents) stimulates mucosa cells to release hormone (choleocystokinin).

Cont…  This stimulates gall bladder and pancreas to release bile and digestive enzymes respectively (bile acids help emulsify fat droplets thus increasing their surface area).  Other mucosa cells release secretin which causes pancreas to release bicarbonate rich fluid to neutralise chyme.

Enzymic digestion of lipids in small intestine

Cont…  Enzymic digestion generates more polar products that form mixed micelles of free fatty acids, 2-monoacylglycerol, cholesterol & bile salts that are adsorbed (except bile salts which pass through to ileum.  Once adsorbed fatty acids and 2-monoacylglycerol are recombined to form triacylglycerol.  Triacylglycerol + cholesterol + phospholipid + proteins form a lipoprotein complex called a chylomicron which transports the lipids in the circulation.

Lipid transport in the circulation Lipids are insoluble in plasma. In order to be transported they are combined with specific proteins to form lipoproteins: Non polar lipids in core (TAG and cholesterol esters)cholesterol esters Proteins (apoproteins) Cholesterol Apoproteins are only weakly associated with a particular lipoprotein and are easily transferred to another lipoprotein of a different class. Apoproteins have various functions including: Structural role Binding sites for receptors Activators or co-enzymes for enzymes involved with lipid metabolism

DYSLIPIDEMIA Dyslipidemia (elevated blood lipid and lipoproteins has several forms:  Hyperlipidemia: elevated blood TG & cholesterol  Hypertriglyceridemia: elevated TG only  Hypercholesterolemia: only elevated blood cholesterol concentrations  Hyperlipoproteinemia: elevated lipoprotein concentrations

Hyperlipidemia  What is Cholesterol?  A soft, waxy substance found among the lipids (fats) in the bloodstream  Used to form cell membranes and some hormones  High levels in the blood are a major risk factor for coronary heart disease  Fats can not dissolve in the blood and must be transported by lipoprotiens

Hyperlipidemia  What is HDL Cholesterol?  High-density lipoprotien  “Good” cholesterol  Carries cholesterol away from the arteries and back to the liver  May remove excess cholesterol from fatty plaques and slow their growth  High levels of HDL appear to protect against heart attack  Low HDL indicates a greater risk for heart attack

Hyperlipidemia  What is LDL Cholesterol?  Low-density lipoprotien  “Bad” cholesterol  Major cholesterol carrier in the blood  High levels cause slow build up of plaques in the walls of the arteries  A blood clot may form in the area of a plaque and block the flow of blood causing a heart attack or stroke

Lipoproteins  particles found in plasma that transport lipids including cholesterol  lipoprotein classes  chylomicrons: take lipids from small intestine through lymph cells  very low density lipoproteins (VLDL)  intermediate density lipoproteins (IDL)  low density lipoproteins (LDL)  high density lipoproteins (HDL)

LIPOPROTEINS  Pathophysiology of lipoproteins  Micelle structures with apolipoprotiens surrounding a lipid core  Core contains TG, phospholipids & cholesterol  4 classes of lipoproteins  Chylomicrons – intestinal absorption of dietary TG  VLDL – primary transport for TG  LDL – principle carrier of cholesterol  HDL – reverse transport of cholesterol

Structure of Lipoproteins Free cholesterol Phospholipid Triglyceride Cholesteryl ester Apolipoprotein

Major lipoprotein classes  Chylomicrons (derived from diet)  density <<1.006 g/cm 3  diameter nm  dietary triglycerides  apoB-48, apoA-I, apoA-II, apoA-IV, apoC-II/C-III, apoE  remains at origin in electrophoretic field

Chylomicron  formed through extrusion of resynthesized triglycerides from the mucosal cells into the intestinal lacteals  flow through the thoracic ducts into the suclavian veins  degraded to remnants by the action of lipoprotein lipase (LpL) which is located on capillary endothelial cell surface  remnants are taken up by liver parenchymal cells due to apoE-III and apoE-IV isoform recognition sites

Major lipoprotein classes  VLDL  density >1.006 g/cm 3  diameter nm  endogenous triglycerides  apoB-100, apoE, apoC-II/C-III  prebeta in electrophoresis  formed in the liver as nascent VLDL (contains only triglycerides, apoE and apoB)

VLDL  nascent VLDLs then interact with HDL to generate mature VLDLs (with added cholesterol, apoC-II and apoC-III)  mature VLDLs are acted upon by LpL to generate VLDL remnants (IDL)  IDL are further degraded by hepatic triglyceride lipase (HTGL) to generate LDLs

VLDL metabolism

Major lipoprotein classes  IDL (intermediate density lipoproteins)  density:  diameter: nm  cholesteryl esters and triglycerides  apoB-100, apoE, apoC-II/C-III  slow pre-beta

Major lipoprotein classes  LDL (low density lipoproteins)  density:  diameter: 18-25nm  cholesteryl esters  apoB-100  beta (electrophoresis)  160 is high

Major lipoprotein classes  HDL (high density lipoproteins)  density:  diameter: 5-12nm  cholesteryl esters and phospholipids  apoA-I, apoA-II, apoC-II/C-III and apoE  alpha (electrophoresis)

HDLs  Several subfamilies exist  Discoidal HDL :  contains cholesterol, phospholipid, apoA-I, apoA-II, apoE and is disc shaped;  it is formed in liver and intestine  It interacts with chylomicra remnants and lecithin- cholesterol acyl transferase (LCAT) to form HDL 3

HDLs  HDL3  composed of cholesterol, cholesterol ester, phospholipid and apoA and apoE  interacts with the cell plasma membranes to remove free cholesterol  reaction with LCAT converts HDL 3 to HDL 2a (an HDL with a high apoE and cholesterol ester content)  cholesterol ester-rich HDL 2a is then converted to triglyceride- rich HDL 2b by concomitant transfer of HDL cholesterol esters to VLDL and VLDL triglycerides to HDL

HDL metabolism

Functions of HDL  transfers proteins to other lipoproteins  picks up lipids from other lipoproteins  picks up cholesterol from cell membranes  converts cholesterol to cholesterol esters via the LCAT reaction  transfers cholesterol esters to other lipoproteins, which transport them to the liver (referred to as “reverse cholesterol transport)

Lipoproteins (a)- Lp(a)  another atherogenic family of lipoproteins (at least 19 different alleles)  they consist of LDL and a protein designated as (a)  the apoA is covalently linked to apoB- 100 by a disulfide linkage  high risk association with premature coronary artery disease and stroke