Lipid Transport and Storage Dr.S.Chakravarty ,MD

Specific Learning Objectives At the end of this lecture a student will be able to – Describe the composition of various lipoproteins and list the key Apo proteins Describe the various pathways of lipoprotein metabolism in detail List the enzymes and receptors involved in lipoprotein metabolism and their deficiency states 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

Apolipoproteins Provide structure to lipoproteins Enzyme co-factors – C2 for lipoprotein lipase A1 for Lecithin cholesterol acyl transferase Ligands for receptors – Apo B100 and APO E – LDL receptor Apo A1 – Srb1 and ABCA 1 receptor Enzyme inhibitors: C1 – cholesterol ester transfer protein.

SEPARATION OF LIPOPROTEINS -ve CHYLOMICRON CHYLOMICRON LDL VLDL IDL IDL VLDL LDL HDL HDL FFA-Alb FFA +ve DENSITY Electrophoresis

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 : HDL: 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

Lipoprotein Metabolism Exogenous pathway - (dietary fat / chylomicrons) Endogenous pathway - (Lipids synthesized by the liver / VLDL) HDL metabolism - (apolipoprotein transfer, cholesteryl ester transfer, reverse cholesterol transport

CHOLESTEROL DIGESTION CHOLESTEROL CHOLESTEROL ESTER POLAR NON –POLAR

CHOLESTEROL DIGESTION G I tract Cholesterol + Cholesterol esters lntestinal cells Chylomicrion Bile, Pancreatic esterase CE + TG + PL + APO B 48 Lymph & Thoracic duct CE + TG PL Cholesterol + FA Reesterification by ACAT (acyl cholesterol acyl transferase) Hydrolysis , emulsification & absorption

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

Summary of Chylomicrons and VLDL INSULIN + POLAR + Kaplan USMLE step 1 Lecture Notes

= OH group of cholesterol c Apo A Cell membrane LDL C c c TG, C CE HDL LCAT = OH group of cholesterol c Apo A Apo A LCAT = esterification of cholesterol to CE Once esterified Cholesterol is trapped inside as it becomes Non-Polar

Fate of Cholesterol LDL receptor defectType II a Hypercholesterolemia or Familial Hypercholesterolemia No cholesterol can come insideMore endogenous synthesis !! Loss of receptors Kaplan USMLE step 1 Lecture Notes

HDL

Ox-LDL (B-100 donates an electron ) NOT DOWNREGULATED BY CHOLESTEROL -ve Vitamin E ( role in preventing atherosclerosis DOUBTFUL) FREE RADICALS Ox-LDL (B-100 donates an electron ) NOT DOWNREGULATED BY CHOLESTEROL Scavenger Receptor SR -A SR –B1 Smooth Muscle Proliferation HDL , LDL AND ATHEROGENESIS Kaplan USMLE step 1 Lecture Notes

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

Abetalipoproteinemia Autosomal recessive – mutation in gene (MTP) Absent Chylomicrons, VLDL, IDL Very low cholesterol, TGs, Apo B48 and Apo B100 Parents are normal. Early childhood – diarrhoea, failure to thrive. Fat malabsorption, spinocerebellar ataxia, pigmented retinopathy. Defect : decreased absorption of fat-soluble vitamins. Treatment : low fat, high calorie, vitamin enriched diet.

Fredrickson classification of hyperlipoproteinemias Synonyms Defect Increased lipoprotein Main symptoms Treatment Serum appearance Estimated prevalence Type I a Buerger-Gruetz syndrome, or Familial hyperchylomicronemia Decreased lipoprotein lipase (LPL) Chylomicrons (= 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 II Familial hypercholesterolemia LDL receptor deficiency LDL Xanthelasma, arcus senilis, tendon xanthomas Bile acid sequestrants, statins, niacin Clear 1 in 500 for heterozygotes Familial combined hyperlipidemia Decreased LDL receptor and increased ApoB LDL and VLDL Statins, niacin, fibrate 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 hypertriglyceridemia Increased VLDL production and Decreased elimination VLDL Can cause pancreatitis at high triglyceride levels Fibrate, niacin, statins Type V Increased VLDL production and Decreased LPL VLDL and Chylomicrons Niacin, fibrate Creamy top layer & turbid bottom

USMLE FAVOURITES!! I Familial lipoprotein lipase (rare ) 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 xanthomas Fatty liver Acute pancreatitis Abdominal pain after fatty meal IIa LDL receptor defect! AUTOSOMAL DOMINANT CHOLSETSROL LDL High risk of atherosclerosis and CAD Homozygous condition , death usually by <20 years Xanthomas of the Achilles tendon Tuberous Xanthomas on elbows Xanthelasmas Corneal Arcus

Tuberous Xanthomas Xanthelasma Corneal Arcus

Lipoprotein Lipase deficiency (Type I) FFA Liver HL x LPL Exogenous Pathway Chylo Remnant Chylomicron Peripheral Cells Free Cholesterol ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Intestine HL Steroidogenic Cells LCAT Nascent HDL HDL3 HDL2 LDL Liver ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol CETP PLTP Tg Endogenous Pathway CE Liver 3 x LPL HL VLDL IDL TG ++ , Low HDL and LDL FFA

Lipoprotein Metabolism LDL-R defect FFA Liver HL LPL Exogenous Pathway Chylo Remnant Chylomicron Peripheral Cells Free Cholesterol ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Intestine X HL Steroidogenic Cells LCAT Nascent HDL HDL3 HDL2 LDL Liver X ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol CETP PLTP Tg Endogenous Pathway CE Liver 3 VLDL LPL HL IDL FFA

Lp(a) excess Lp(a) has Structural homology with Plasminogen 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 :-

HDL Risk <40 Increased risk 40-59 Medium risk >60 protective TGs Risk <150 Normal 150-199 Borderline 200-499 High >500 Very high LDL Risk <100 Reduced 100-129 Near optimal 130-159 Borderline 160-189 High >190 Very high Lp(a) Risk <14 Desirable 14-30 Borderline 31-50 High risk >50 Very high

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 ? CHYLOMICRONS HDL IDL LDL VLDL

Which of the following lipoproteins increase in Familial hypercholesterolemia Type 1 . Chylomicrons LDL VLDL D. Total cholesterol E. IDL

Thank you