LipoproteinsMetabolism

Lipid compounds are relatively water insoluble. Therefore, they are

transported in plasma (aqueous) as lipoproteins

Introduction

Lipoproteins and Related Clinical Problems

• Atherosclerosis

• Hypertension

• Coronary heart diseases

• Lipoproteinemias (hypo- and hyper-)

• Fatty liver

Lipoprotein Structure

Protein part:• Apoproteins or apolipoproteins• Apoproteins proteins may be structural or transferred

Lipid part:• Each lipoprotein contains different types of lipids in

various combinations• Type of lipids in a lipoprotein is governed according to

the type of lipoprotein

Lipoprotein Structure

Spherical molecules of lipids and proteins (apoproteins) = amphipathic molecules

Outer coat: Proteins - Apoproteins

Lipids (amphipathic) - Phospholipids (PL) - free Cholesterol

Inner core: Lipids (hydrophobic) - Triglycerides (TG) - Cholesterol ester (CE)

Apolipoproteins (Apoproteins)

• Five major classes (A-E) divided by structure & function

• Each class has subclasses as Apo A, Apo CII

Functions:• Some are required as structural proteins (i.e. they

are essential structural components of the lipoprotein particles & can not be produced without them)

• Some are activators for enzymes of lipoprotein metabolism

• Some are recognition sites for cell-surface receptors

Types of Lipoproteins

• Types of lipoproteins are different in lipid & protein composition & therefore, they differ in:- Size & density- Electrophoretic mobility

Types andComposition

ofLipoproteins

Chylomicrons

Very low densityLipoprotein (VLDL)

Low densityLipoprotein (LDL)

High density Lipoprotein (HDL)

Size & Density of

Lipoproteins

Lipoprotein Electrophoresis

Plasma Lipoproteins

For triacylglycerol transport (TG-rich):

- Chylomicrons: TG of dietary origin- VLDL: TG of endogenous (hepatic)

synthesis

For cholesterol transport (cholesterol-rich):

- LDL: Mainly free cholesterol - HDL: Mainly esterified cholesterol

Chylomicrons

• Synthesis: in intestinal mucosal cells• Function: Transport dietary lipids from GIT to tissues (& liver). Responsible for physiological milky appearance of plasma (up to

2 hours after meal)

• Structure: Lowest density Largest size Highest % of lipids and lowest % proteins Highest triacylglycerol (dietary origin)

Apo E mediates uptake

Type I hyperlipoprotemia

Chylomicrons metabolism

Lipoprotein Lipase• Extracellular enzyme anchored by heparan sulphate to the capillary walls of most tissue especially those of adipose tissue,

cardiac & skeletal muscles

BUT: Adult liver does not have this enzyme

• Its synthesis & transfer to luminal surface of the capillary is stimulated by insulin (in fed state)

• Activated by apoC-II

Function of lipoprotein lipase

• Lipoprotein lipase hydrolyses circulating TG in chylomicrons to fatty acids & glycerol

• Fatty acids are stored (in adipose) or used for energy (in muscles)

• Glycerol is transferred to the liver (to be used for glycolysis, gluconeogenesis or lipid synthesis)

Deficiency of lipoprotein lipase (or apo CII) :

causes type 1 hyperlipoproteinemia (familial lipoprotein lipase deficiency)

accumulation of chylomicrons in plasma (hypertriglyceridemia)

Very Low Density Lipoproteins (VLDL)

- Synthesis: in the liver- Structure: composed predominantly of triglycerides (TG) - Function : is to carry lipids (mainly TG) from the liver to tissues. In peripheral tissues, TG are degraded by lipoprotein lipase to FA & glycerol.

Fatty liver (hepatic steatosis)Occurs when TG synthesis in liver is more than VLDL secretionAs in cases of: - Obesity - Uncontrolled DM- Chronic ethanol ingestion

Metabolism of VLDL

Low Density Lipoproteins (LDL)

LDL is produced in the circulation as the end product of VLDLs

Compared to VLDLs:It contains only apo B-100Smaller size & more dense (less lipids)Lipid contents:

Less triglycerides (TG) More cholesterol (C) & cholesterol ester (CE)

Function of LDLLDL transport cholesterol from liver to peripheral tissuesUptake of LDL at tissue level by LDL receptor-mediated endocytosis recognized by apo B-100

Receptor-Mediated Endocytosis

1- LDL (through apo 100), binds to LDL receptors in peripheral tissues forming

a

complex

2- Internalization of the complex by endocytosis to inside cells.

3- Release of cholesterol inside the cells for:

Utilization, storage (as cholesterol ester) or excretion

4- Degradation of LDL: into amino acids, PL & FAs

5- Degradation or recycling of receptor

Deficiency of functional LDL receptors:Causes elevation of LDL in blood (& therefore blood cholesterol is elevated)

Type II hyperlipidemia (familial hypercholesterolemia)

LDL: Receptor-mediated endocytosis

LDL Receptor-Mediated Endocytosis: Regulation

Cholesterol derived from LDL causes:1- Decrease de novo synthesis of cholesterol (by inhibition of HMG CoA reductase)

2- Inhibition of LDL receptor synthesis at gene level thus, limiting further entry of LDL cholesterol into cells.

3- In case cholesterol is not used immediately: Cholesterol is esterified to cholesterol esters (CE) by: acyl CoA: cholesterol acyltransferace (ACAT). Cholesterol esters can be stored in cells. ACAT is enhanced in cases of increased intracellular cholesterol.

LDL-C = Total cholesterol – [ HDL-C + TG/2.2 ]in case of mmol/L or 5 in case of mg/dL

Low Density Lipoprotein Cholesterol (LDL-C)calculation

Coronary Heart Disease Risk Factors

Positive Risk Factors: Age ≥ 45 y for men , ≥55 y for females or premature

menopause Family history of premature CHD Current cigarette smoking Hypertension ( BP≥ 140/90 or taking antihypertensive

drugs HDL-C concentration < 40 mg/dL (< 1.0 mmol/L) Diabetes mellitus = CHD risk equivalent Metabolic syndrome (multiple metabolic risk factors)

Negative Risk Factors: HDL-C concentration ≥ 60 mg/ dL (≥ 1.6 mmol/L) ; its

presence removes one risk factor from the total count

Categories of Risk for LDL Cholesterol GoalsLDL goal mg/dL

< 100

<130

<160

Risk Category

CHD & CHD risk equivalents

Multiple (2+) risk factors

0-1 risk factor

For cholesterol the molar concentration can be changed to mass concentration by the formula: mg/dL =mmol/L x 38.7

High Density Lipoproteins (HDL)

• Synthesis: by intestine and liver

Nascent HDL: Disk-shapedContains apo A-I, C-II and EContains primarily phospholipid (PC)

Mature HDL (HDL2):First, the HDL3 collects cholesterol (C) from peripheral tissues & other lipoproteins. Then, Cholesterol is converted to CE (by PCAT) to form HDL2.

CE is transported to liver by HDL2.

HDL Metabolism

Composition of LDL and HDL

High density lipoprotein (HDL)Mostly cholesterol esterMore % proteinMore % phospholipids

Low density lipoprotein (LDL) Mostly free cholesterol

Functions of HDL

• Reservoir of apoproteinse.g. Apo C-II and E to VLDL

• Uptake of cholesterol:From peripheral tissue (& other lipoproteins)

• Esterification of cholesterol:Enzyme: PCAT/LCATActivator: Apo A-I Substrate: Cholesterol, Co-substrate: PCProduct: Cholesterol ester (& Lyso-PC)

• Reverse cholesterol transport transports cholesterol from peripheral tissues to liver

VLDL

HDL

PL ,TAGCE

Cholesteryl Ester Transfer Protein

Why Is HDL a Good Cholesterol carrier?

• Inverse relation between plasma HDL levels and atherosclerosis …. How?

• Reverse cholesterol transport involves:Efflux of cholesterol from peripheral tissues and other lipoproteins to HDL3

Esterification of cholesterol & binding of HDL2 to liver (and steroidogenic cells) by scavenger receptor class B (SR-B1)

Selective transfer of cholesterol ester into these cells

Release of lipid-depleted HDL3

Lp (a)

• Simulates LDL but apo(a) covalently linked to apo B-100• Competes with plasminogen to plasminogen activator • Genetical element• Estrogen decreases it while trans fats increases it

Hyperlipoprotenemias1- Type I hyperlipoproteinemia:

Familial lipoprotein lipase deficiency - Due deficiency of lipoprotein lipase or apo C-II

- Slow clearance of TG–rich lipoproteins in plasma (chylomicrons & VLDL)

- Hypertriacylglyceremia (increased TG in blood)

- Treated by reducing fat in diet

2- Type II hyperlipoproteinemia :

Familial hypercholesterolemia - Due to deficiency of functional LDL receptors

- Reduced clearance of LDL

- Elevation of plasma cholesterol (but plasma TG remains normal)

- Predispose to atherosclerosis & CHD

Abnormalities in lipoprotein metabolism

3- Type III hyperlipoproteinemia familial dysbetalipoproteinemia or broad B disease - Due to abnormal apo E (on chylomicrons) - Reduction of clearance of chylomicron remnants by liver - Accumulation of chylomicron remnants in plasma. - Hyperchloesterolemia - Predispose to atherosclerosis & CHD

4- Type IV hyperlipoproteinemia Familial hypertriacylglycerolemia - Increased production of VLDL - Commonly associated with type II DM & obesity - Elevated blood TG & cholesterol - Predispose to atherosclerosis & CHD.

Abnormalities in lipoprotein metabolism cont.

Hypolipoproteinemia

1- Abetalipoproteinemia - defect in triacylglycerol transfer protein (MTP) responsible for loading of apo-100 with lipid with no chylomicrons & no VLDL synthesis - No chylomicrons synthesis in intestine ↓ blood TG - No VLDL synthesis in liver ↑ TG in liver - No VLDL synthesis no LDL ↓ blood cholesterol

2- Familial hypobetalipoproteinanemia - ↓ apo B-100 synthesis - ↓ VLDL ↓ blood TG & ↑ TG in liver - ↓ LDL ↓ blood cholesterol

Abnormalities in lipoprotein metabolism cont.