Lipid Transport and Storage

Dr.S.Chakravarty ,MD

Specific Learning Objectives • At the end of this lecture a student will be able to –

1. Describe the composition of various lipoproteins and list the key Apo proteins

2. Describe the various pathways of lipoprotein metabolism in detail

3. List the enzymes and receptors involved in lipoprotein metabolism and their deficiency states

4. Classify Lipoproteinemias and describe the clinical features of various lipoproteinemias

5. Describe the pathogenesis of atherosclerosis

6. List the drugs used to treat hyperlipoproteinemias and its mechanism of action

What are lipoproteins?

• Transport of lipids from various tissues for storage and utilization – water soluble.

• Lipoproteins - large mostly spherical complexes

• Hydrophobic core – TGs and cholesterol esters

• Hydrophilic surface – phospholipids, unesterified Cholesterol and Apoproteins.

Structure of Lipoprotein

Harper 28th

Apolipoproteins1) Provide structure to lipoproteins

2) Enzyme co-factors – – C2 for lipoprotein lipase– A1 for Lecithin cholesterol acyl transferase

3) Ligands for receptors – – Apo B100 and APO E – LDL receptor– Apo A1 – Srb1 and ABCA 1 receptor

4) Enzyme inhibitors: – C1 – cholesterol ester transfer protein.

SEPARATION OF LIPOPROTEINS

CHYLOMICRON

VLDL

HDL

LDL

IDL

FFA

CHYLOMICRON

VLDL

HDL

LDL

IDL

FFA-Alb

-ve

+ve

Electrophoresis

DENSITY

Separation based on ultracentrifugation /density:

Key Apoproteins to identify various lipoproteins

• APO A1 – HDL• APO B48 – Chylomicrons• APO -B100 – VLDL, IDL, LDL• APO C and E – present in all particles(with

exceptions ) predominantly donated by HDL to other molecules

Types of lipoproteins:Chylomicrons :

– derived from intestinal absorption of TGs and other lipids

– Exogenous triglycerides – Highest triglyceride content – Major APO protein – APO-B48

VLDL :– Derived from liver and helps in transport of TGs to

peripheral tissues.– Endogenous triglycerides– Major APO protein – APO-B100

LDL :– Derived from catabolism of VLDL– APO proteins same as VLDL– Highest cholesterol content– Formation of modified / oxidized LDL - Atherosclerosis

HDL:– Reverse cholesterol transport– Extracts cholesterol from the tissues and brings it to liver– Provides Apoproteins to VLDL and Chylomicrons for maturation– Major APO protein – APO A-1

CHOLESTEROL DIGESTION

• CHOLESTEROL CHOLESTEROL ESTER

NON –POLAR POLAR

Cholesterol

+ Cholesterol esters

Bile, Pancreatic esterase

Cholesterol + FA

CE+TG+PL

Reesterification by ACAT(acyl cholesterol acyl transferase)

G I tract

lntestinal cells

CE + TG + PL +

APO B 48

Chylomicrion

Lymph & Thoracic duct

Hydrolysis , emulsification & absorption

CHOLESTEROL DIGESTION

Cholesterol absorption

Glucose

Kaplan USMLE step 1

Structure of Lipoprotein

Harper

Chylomicrons

TG, CE

TG, CE

TG, CE

+

Harper

VLDL,IDL AND LDL

TG, C

TG, C

TG, C

TG,C

+

Harper

CHYLOMICRONS AND VLDL

SIMILARITIES DIFFERENCES

Apo B , C & E Apo B 48 VS Apo B 100

Huge CARRIES – CE in Chylomicrons VS mainly C in VLDL

Both carry TG SYNTHESIS - Intestine vs Liver

Lymph vs Blood

LPL – lipoprotein lipase • Activated by Insulin

• Requires cofactor apo C-II protein

• Present in endothelium of capillaries – mainly in heart, adipose tissue and skeletal muscle

• LPL of heart has low Km compared to adipose tissue.

• Heparin LPL is released from tissues Clears Lipemia

INSULIN

+

POLAR +

Kaplan USMLE step 1 Lecture Notes

Summary of Chylomicrons and VLDL

Cell

mem

bran

e

LDL

HDL

CE

TG, C

Apo A LCAT = esterification of cholesterol to CE

Once esterified Cholesterol is trapped inside as it becomes Non-Polar

cc

C

c = OH group of cholesterol Apo A

LCAT

Fate of Cholesterol

Kaplan USMLE step 1 Lecture Notes

LDL receptor defectType II a Hypercholesterolemia or Familial Hypercholesterolemia

No cholesterol can come insideMore endogenous synthesis !!

Loss of receptors

HDL

Ox-LDL (B-100 donates an electron )Scavenger Receptor

SR -A NOT DOWNREGULATED

BY CHOLESTEROL

FREE RADICALS

LDL

HDL , LDL AND ATHEROGENESIS Kaplan USMLE step 1 Lecture Notes

SR –B1

Smooth Muscle Proliferation

-ve Vitamin E( role in preventingatherosclerosis DOUBTFUL)

The Narrowing of the arteries

Note :- The growing atheroma does not encroach upon the arterial lumen until the burden of atherosclerotic plaque exceeds ~40% of the area encompassed by the internal elastic lamina. Thus, during much of its life history, an atheroma will not cause stenosis that can limit tissue perfusion.

Hypolipoproteinemias • Abetalipoproteinemia :- No chylomicrons , VLDL, LDL

– Rare ; blood acyl glycerols low; intestine and liver accumulate acylglycerols ;Intestinal malabsorption .

– Fat malabsorption, spinocerebellar ataxia, pigmented retinopathy– Early death avoidable by administration of large doses of fat-soluble

vitamin E.

• Familial alpha –lipoprotein deficiency – Tangier’s disease(ABCA1 transporter deficiency)– Fish-eye disease (partial LCAT deficiency)– Apo A-I deficiency

• LOW or NEAR Absence of HDL Tendency toward hypertriacylglycerolemia as a result of absence of apo C-II.Low LDL

Fredrickson classification of hyperlipoproteinemiasHyperlipo-proteinemia Synonyms Defect Increased

lipoprotein Main symptoms TreatmentSerum appearance

Estimated prevalence

Type I

a Buerger-Gruetz syndrome, or Familial hyperchylomicronemia

Decreased lipoprotein lipase (LPL) Chylomic

rons

(= Increased

TG)

Abdominal pain (from pancreatitis), lipemia retinalis, eruptive skin xanthomas, hepatosplenomegaly

Diet control Creamy top layer 1 in 1,000,000

b

Familial apoprotein CII deficiency

Altered ApoC2

Type IIa Familial hypercholesterolemia LDL receptor

deficiencyLDL Xanthelasma, arcus

senilis, tendon xanthomas

Bile acid sequestrants, statins, niacin

Clear 1 in 500 for heterozygotes

b Familial combined hyperlipidemia

Decreased LDL receptor and increased ApoB

LDL and VLDL

Statins, niacin, fibrate Clear 1 in 100

Type III Familial dysbetalipoproteinemia

Defect in Apo E 2 synthesis IDL

Tubo-Eruptive Xanthomas & Palmar Xanthomas

Fibrate, statins Turbid 1 in 10,000

Type IV Familial hypertriglyceridemiaIncreased VLDL production and Decreased elimination

VLDLCan cause pancreatitis at high triglyceride levels

Fibrate, niacin, statins Turbid 1 in 100

Type VIncreased VLDL production and Decreased LPL

VLDL and Chylomicrons

Niacin, fibrateCreamy top layer & turbid bottom

Type

DEFICIENCY iNHERITANCE LIPID elevated in Blood

Lipoprotein elevated in Blood

Comments

I Familial lipoprotein lipase (rare )Apo C-II (rare )

Autosomal recessive

TG CHYLOMICRONS (after a high carb diet )

VLDL

Red orange eruptive xanthomasFatty liverAcute pancreatitis Abdominal pain after fatty meal

IIa LDL receptor defect! AUTOSOMAL DOMINANT

CHOLSETSROL LDL High risk of atherosclerosis and CADHomozygous condition , death usually by <20 yearsXanthomas of the Achilles tendonTuberous Xanthomas on elbowsXanthelasmasCorneal Arcus

USMLE FAVOURITES!!

Tuberous Xanthomas

Corneal Arcus Xanthelasma

Lp(a) excess

Normally Plasminogen activated to Plasmin Plasmin binds Fibrin Fibrin is lysed.

• Lp(a) has Structural homology with Plasminogen

• Lp(a) excess Binds to fibrin Inactivates Plasminogen activation Fibrin is not lysed

• Normal levels <15mg/dl• >30mg/dl = increased risk of Coronary artery disease

Acquired Lipoproteinemias

• Diabetes Mellitus • Nephrotic Syndrome• Hypothyroidism• Obstructive Jaundice• Metabolic syndrome

Metabolic Syndrome

ANY THREE OUT OF :-

Drugs used in Hyperlipoproteinemia• Statins - HMG-CoA reductase inhibitors

• Bile acid sequestrants- Basic ion exchange resin

• Fibrates – (+) Lipoprotein lipase • Nicotinic acid (-) TGs in liver and (+) LPL

Drugs

• Orlistat – (-) pancreatic lipase• Ezetimibe – (-) cholesterol and bile salt from

gut.

• A lipoprotein synthesized in liver , containing high concentration of TG and mainly cleared from circulation by adipose tissue and muscle ?

A. CHYLOMICRONSB. HDLC. IDLD. LDLE. VLDL

• Which of the following lipoproteins increase in Familial hypercholesterolemia Type 1 .

A. Chylomicrons B. LDLC. VLDLD. Total cholesterolE. IDL

Thank you