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 circulationLipids 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)

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  H

OH

O

O

R

HOHO

O

R

HOHO

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

PhospholipidTriglyceride

Cholesteryl esterApolipoprotein

Major lipoprotein classes

Chylomicrons (derived from diet) density <<1.006 g/cm3

diameter 80 - 500 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/cm3

diameter 30 - 80nm 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

VLD

L

meta

bolis

m

Major lipoprotein classes

IDL (intermediate density lipoproteins) density: 1.006 - 1.019 diameter: 25 - 35nm cholesteryl esters and triglycerides apoB-100, apoE, apoC-II/C-III slow pre-beta

Major lipoprotein classes

LDL (low density lipoproteins) density: 1.019 - 1.063 diameter: 18-25nm cholesteryl esters apoB-100 beta (electrophoresis) < 130 LDL cholesterol is desirable, 130-

159 is borderline high and >160 is high

Major lipoprotein classes

HDL (high density lipoproteins) density: 1.063-1.210 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 HDL3

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 HDL3 to HDL2a (an HDL

with a high apoE and cholesterol ester content) cholesterol ester-rich HDL2a is then converted to

triglyceride-rich HDL2b by concomitant transfer of HDL cholesterol esters to VLDL and VLDL triglycerides to HDL

H

DL

meta

bolism

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