Lipoprotein metabolism,

LIPOPROTEIN METABOLISM

Dr ANKITA MISHRAJNMCH

AMU,ALIGARH

LIPOPROTEIN

• Macromolecular assembly that contain lipids and proteins.

E

CLASSIFICATION

APOPROTEINS• Surface proteins present on lipoproteins.• Functions• Provides structural stability to lipoproteins.• Ligands in lipoprotein-receptor interactions.• Cofactors in enzymatic processes that regulate

lipoprotein metabolism. • 2 types• Integral proteins- Peripheral proteins- Apo A & B Apo C & E

Apo A1- L,I HDL,LCAT cofactor,ABCA1 ligand Apo A2- L inhibits apoE binding to R Apo A5- L activates LPL, inhibit VLDL TAG Apo B100-L struc. Pr. ,LDL R ligand Apo B48- I struc. Pr. CM Apo C1- L LCAT activator,R binding -remnant

Apo C2- L LPL cofactor Apo C3- L R binding of remnant Apo E- L,B,G,S ligand LDL R,remnant R Apo (a)- L modulator of fibrinolysis

LIPOPROTEIN METABOLISM

1.Transport of exogenous (dietary)lipids (chylomicron processing)

2.Transport of endogenous lipids Apo B-100 lipoprotein guided system Apo A1 governed lipoprotein system

TRANSPORT OF EXOGENOUS LIPIDS

• ABSORPTION OF DIETARY LIPIDS

• NASCENT CHYLOMICRON

• CHYLOMICRON

• CHYLOMICRON REMNANTS

ABSORPTION OF DIETARY LIPID• In order for the dietary lipids to be absorbed1. large aggregate,must be broken down physically

and held in suspension-emulsification2. TAG –enzymatically digested to yield - MAG & Fatty acids- easily diffuse in to the enterocytes.

• 2 key players in this transformation-Bile acid & Pancreatic lipase

ABSORPTION OF DIETARY LIPID lumen

• Dietary fats are emulsified in the SI- action of bile acid.

• Lipids and bile salts interact to form micelles[4-8 nanometer] -contain FA, monoglycerides & C in their

hydrophobic centers.• Micelles solubilizes the lipids and provides a

mechanism for their transport to the enterocytes.

Lumen-enterocyte TAG-Pancreatic lipase acts on TAG in micelle-- MAG & FFA- taken up byenterocyte

-Short chain& medium chain FFA are absorbed directly in to the enterocytes and then toportal circulation.

CHOLESTEROL-NPC1L1mediatesabsorptionof intest. C,plant sterol.-C taken up by enterocytes in micellar form.-Plant sterols are notabsorbed.-ABCG5&8 transporters -channel plant sterol back in to the lumen.

enterocyte• TAG-DAG transferase converts FFA+MAG again

in to TAG(occurs in SER)• MTP facilitates transfer of TAG to the site –

apoB48• CHOLESTEROL- is converted to CE by ACAT-

2(I&L).[ACAT1 in macrophage]• NASCENT CHYLOMICRON-TAG is combined

with PL, CE,apoB48- exocytosed-lacteals-thoracic duct-systemic circulation

Micelles,C

Niemann Pick C1 like Protein(NPC1 LP)

Triglycerides

Microsomal Transfer Protein

(MTP)ER

Apo B-48

Chylomicron

Cholesterol Cholesterol Esters

ACAT-2(Acyl Coenzyme A:

Cholesterol Acyl Transferase)

Enterocyte

DIET

TAG, CHOLESTEROL , FAT SOL. VITAMIN FA+GLYCEROL TAG + CE + APO B48,A1 + PL

NASCENT CHYLOMICRON

ACAT2DAG

LIPASE

CHYLOMICRON• NASCENT CM reaches the plasma-rapidly

modified- receive apo E and C. • The source of these apolipoproteins is

circulating HDL • This leads to formation of mature

CHYLOMICRON.

NASCENT CHYLOMICRON

THORACIC DUCT

SYSTEMIC CIRCULATION

APO E,C(HDL)

CHYLOMICRONApo-A

CHYLOMICRON REMNANT• CM- metabolized at capillary luminal surface - LPL [ adipose tissue, skel. &cardiac m,

breast tissue -lactating women].

• TAG -hydrolyzed by LPL(apoC2-cofactor)-FFA utilized by adjacent tissues. Glycerol-in liver(glycolysis,gluconeogenesis)

• CM remnants- still contain dietary C- detach from the capillary.

• Remnants - sequestered by the interaction of apoE -heparan sulfate proteoglycans - surface of hepatocytes & processed by hepatic lipase, further reducing the remnant TAG content.

• ApoE mediates remnant uptake by interacting with the hepatic LDL receptor or LRP.• LRP - backup R- uptake of apoE-enriched remnants of CM and VLDL. HSP, facilitate

the interaction of apoE-containing remnant LP with the LRP.

• Initial hydrolysis of CM - apoA-I and PL shed from the surface of CM in the plasma-(nascent HDL)

CHYLOMICRON

CHYLOMICRON REMNANT

TGLPL

FFA+GLYCEROL

Apo-A,C(HDL)

Cholesterol biosynthesis

Acetyl CoA Acetoacetyl CoA

HMG- CoAHydorxy Methyl Glutarate

HMG- CoA ReductaseMevalonate

Presqualena Pyrophosphate

SqualeneSqualene synthase

Cholesterol

TRANSPORT OF ENDOGENOUS LIPIDS

VLDL• VLDL are produced in the liver when TAG

production is stimulated by an increased flux of FFA / increased de novo synthesis of FA by the liver.

• ApoB-100 , synthesized in liver -incorporated into VLDL . Small amounts of apoE & C are incorporated into nascent VLDL (TAG approx 60% )within liver before secretion.

• most of the apoE & C are acquired from plasma HDL after VLDL are secreted by the liver

FFA

TAG

NASCENT VLDL

APO B100,,E,C

VLDL

APO E,C(HDL)

LIVER

PLASMA

APOB100

APO-E

APO-C

LDL• TAG in plasma VLDL- hydrolysed by LPL in capillary

endothelium- IDL [<30% TAG]

• ApoB-100 containing small VLDL and IDL (VLDL remnants), 2 potential fates

• 40-60%- cleared from the plasma by liver via interaction with LDL receptors & LRP.

• LPL and HL convert remainder of IDL to [TG<10%]LDL . The apo E,C, redistribute to HDL.

VLDL

IDL

TG FFALPL

LPL

LDL

TG

APO C,E(HDL)

APO-B100

CHOLESTEROL

CELL MEMBRANEVIT D

MYELIN SHEATHSTEROID HORMONE

REGULATION OF CHOLESTEROL SYNTH.• Liver expresses a large complement of LDL R &

removes 75% of LDL from plasma- manipulation of hepatic LDL R gene expression is most effective way to modulate plasma LDL-C levels.

• Regulation of LDL receptor expression- part of complex process by which cells regulate their free C content.- transcription factors - sterol regulatory element binding proteins (SREBPs) and SREBP cleavage activating protein (Scap) .

• Scap- a sensor of C content in ER & an escort of SREBPs from ER to Golgi apparatus.

• In Golgi - SREBPs undergo proteolytic cleavage-nucleus- it activates expression of the LDL R gene & of genes encoding enzymes involved in C biosynthesis.

• ER C content binds Scap, precluding Scap from escorting SREBP to the Golgi A for processing & ultimately from reaching the nucleus.

ROLE OF LDL IN ATHEROGENESIS

HDL• FUNCTIONS• Serves as a circulating reservoir for apo-C and

apo-E.• Delivering-chol. esters to liver for uptake by

SR-B1(reverse cholesterol transport).• Protective effect - anti-inflammatory, anti-

oxidative, platelet anti-aggregatory, anticoagulant, and profibrinolytic activities

HDL METABOLISM • The precursor HDL is a discoidal particle containing

apoA-I &PL called preβ-1 HDL .

• Synthesized by liver &intestine, & also arise when surface PL & apoA-I of CM and VLDL are lost as the TAG of these LP are hydrolyzed.

• Discoidal pre-β1 HDL - acquire free C from tissues, macrophages. ABCA1 and ABCG1, promote the efflux of C from macrophages .

• The membrane transporter ABCA1 facilitates the transfer of free C from cells to HDL .

• Free C esterified by LCAT.---Esterified &nonpolar C moves into the core of the discoidal HDL.

Contd.• As the CE content increases, the HDL particle becomes spherical -HDL3

• further enlarge by accepting more free C which is in turn esterified by LCAT -HDL2

• As the CE content of the HDL2 increases, the CE of these particles begin to be exchanged for TAG derived from any of the TAG containing LP . This exchange is mediated by the CETP .

• The transferred C -metabolized as part of the lipoprot

• SR-B1 in liver facilitates uptake of CE from HDL.

• HDL2 ,TAG is hydrolyzed by HL-regenerates - HDL3 - recirculate & acquire additional free C from tissues containing excess C.

LIPOPROTEIN (A)

• Lp(a) is composed of an LDL particle that has a second apoprotein in addition to apoB-100

• Apo(a), is attached to apoB-100 by at least one disulfide bond

• does not function as a lipid-binding apoprotein.• Apo(a) of Lp(a) is structurally related to plasminogen • Atherogenic - interferes with fibrinolysis of thrombi on

the surfaces of plaques

THANK YOU

CLASSIFICATION OF HYPERLIPIDEMIA

LPL

hypolipoproteinemia

METABOLIC SYNDROME

LIPIDS• Heterogenous gp. of compounds related to

fatty acids,insoluble in water & are stored in the body as source of energy. 3 types

• Simple lipids-SSFAs,MUFAs,PUFAs,TFAs

• Compound lipids-sulfolipids,phospholipids

• Neutral lipids-TGs,CH,CE

Lipoproteins Lipoprotein Apoproteins Function

Chylomicron apoB-48, apoC, apoE Transport TGs form intestine to liver/ other tissues

VLDL apoB-100, apoC, apoE Transport TGs from liver to adipose/ muscles.

IDL apoB-48, apoC, apoE Intermediary between VLDL and LDL

LDL apoB-48 Transport cholesterol to peripheral tissues.

HDL apoA, apoC, apoE, apoD

•Absorb cholesterol form peripheral tissues and transport it to liver•Reservoir for exchange of lipoproteins in VLDL and Chylomicron metabolism

INTRODUCTION

• Lipoprotein• Apoprotein• Lipoprotein metabolism• Dyslipidaemia• Metabolic syndrome

REVERSE CHOLESTEROL TRANSPORT

NASCENT CHYLOMICRON• CM are assembled in intestinal mucosal cells and carry

dietary TAG,cholesterol, fat-sol. vit, and CE [TAGs 90%]• • Apolipoprotein B-48 is unique to chylomicrons. Its synthesis

begins on the RER.

• The enzymes involved in TAG, cholesterol, and PL synthesis are located in the SER. Assembly of the apo and lipid into CM requires MTP.

• The particle released by the intestinal mucosal cell is called a “nascent” chylomicron because it is functionally incomplete.

CHYLOMICRON REMNANT• TAG in CM core - degraded by LPL , the particle decreases

in size and increases in density. • The apo C (but not apo E) are returned to HDL. The

remaining particle, called a “remnant,” is rapidly removed from the circulation by the liver, whose cell membranes contain lipoprotein receptors that recognize apo E.

• Chylomicron remnants are taken into the hepatocytes by endocytosis. The endocytosed vesicle fuses with a lysosome, and apo, C,E, and other components of the remnant are degraded, releasing amino acids, free cholesterol, and fatty acids.

METABOLISM OF HDL• Nascent HDL are discoidal phospholipid layer containing apo-A,C,E and free cholesterol.

HDL is synthesized and secreted by both liver and intestine.

LCAT binds to the discoidal HDL and converts the free cholesterol in to cholesteryl ester.

The nonpolar cholesteryl ester move in to the hydrophobic core-as cholesteryl esters accumulate it becomes spherical HDL3 .

CONTD.• HDL2 is synthesized when more cholesterol is accepted by

HDL3 from peripheral tissue.

• CETP moves some of the CE from HDL to TAG containing lipoprotein and accepts TAG from them.

• HDL3 then reforms either after selective delivery of CE to liver by SRB1 or by hydrolysis of TAG & PL by HL.This interchange of HDL2 & HDL3 is called HDL cycle.

• Free apoA1 is released by these processes and form pre β HDL(nascent) after attaching with min. amt of PL and cholesterol.

Present in chylomicron,HDL;atheroprotective;

activates hep.lipase