Plasma Lipids, lipoprotein & Apolipoprotein Proteins

8/14/2019 Plasma Lipids, lipoprotein & Apolipoprotein Proteins

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Plasma Lipids, Lipoproteins, ApolipoproteinsLecture Outline

Plasma lipids function, biochemistry, groups Cholesterol, fatty acids, triglycerides, phospholipids

Lipoproteins Classification of lipoproteins Apolipoproteins

Low density lipoprotein Control of LDL/cholesterol Factors influencing plasma levels of LDL Lipoprotein receptors - LDL receptor Exogenous lipid pathway

Endogenous lipid pathway Very low density lipoprotein Reverse cholesterol transport High density lipoprotein Enzymes involved in lipid metabolism

Looking at the pathways and lipoproteins


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Lipids Endogenous: synthesized by the body

Exogenous: derived from food Lipids needs to be transported from one organ to

another

Lipids are insoluble in water

Circulated in body fluids as soluble proteincomplexes


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Lipids - Functions

Metabolic fuel

Hormones & hormone precursors

Sex hormones

Glucorticoids

Mineralocorticoids

Aiding in digestion bile lipids

Energy storage

Functional and structural components of cellmembranes

Forming membrane

Allow nerve conduction

Fat-soluble vitamins


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Lipid Biochemistry

Insoluble in H2O

Soluble in organic solvent Chemically, lipids are either:

Components that yield fatty acids on hydrolysis,

or Complex alcohols that combine with fatty acids to

form ester

Some contain non-lipid groups such as sialic,phosphoryl, amino or sulfate groups Increase solubility


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Plasma Lipids

Divided into groups based on chemicalstructure:

1. Cholesterol

2. Fatty acids

3. Triglycerides

4. Phospholipids


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Cholesterol

Steroid precursor to bile acids, steroid hormones Cholesterol level in body = 150 200 mg/dl

Sources

Diet: 400 700 mg/day

On average 30 60% absorbed De novo synthesis

Synthesis in intestines and liver

The liver

HDL, VLDL Free cholesterol in bile

Conversion bile salts

Excretion = 1 g/day as bile acids


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Fatty Acids

Straight chain carbon compounds

CH3(CH2)nCOOH


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Fatty Acids

Esterified with glycerol triglycerides

Non-esterified (NEFA) or free (FFA)

Oxidised for production of energy in mitochondria by

oxidation During prolonged starvation excessive degradation of

fatty acids by oxidation in liver causes an acetyl CoAexcess

Acetyl CoA acetoacetic acid

hydroxybutanic acid acetones are produced

(ketone bodies)

Excess production of ketone bodies ketosis


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Plasma Fatty Acids

In plasma free fatty acids are carried bound to

albumin Free fatty acids: immediate source of energy yield

large quantities of ATP


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Triglycerides

Fatty acid esters of glycerol containing 3 different fattyacids

Transported as lipoproteins from gut and liver to

tissues

After hydrolysis fatty acids taken up, re-esterifiedand stored as triglycerides


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Phospholipids

Complex lipids that resemble triglycerides but contain

phosphate + 1 nitrogen base in place of one fatty acid

Important components of cell membranes andlipoproteins maintain solubility of non-polar lipids

and cholesterol


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Lipoproteins

Lipids + proteins

Synthesis: liver and intestines

Modified after secretion by enzyme-catalysed reactions Remnants are taken up by receptors on cell surfaces

Modification and uptake of remnants regulated byapolipoproteins ~ the protein component

Lipoproteins are classified by density, which in turnreflects their size

The more lipid a complex contains, the greater thelipid/protein ratio the larger it is, and the lower thedensity


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Classification of Lipoproteins

Transient intermediate formed duringconversion of VLDL LDL, undetectable innormal plasma

Cholesterol + triglycerides

IDL(intermediate density

lipoproteins)

Transport of cholesterol from cells to liverHDL

(high density

lipoproteins)

Formed from VLDL

Transport cholesterol to cells

Contains mostly cholesterol

LDL

(low densitylipoproteins)

Transport endogenous lipids from liver to cells

Large, triglyceride rich

VLDL

(very low density

lipoproteins)

Transport exogenous lipids from intestines to all

cells, large, triglyceride rich

Chylomicrons

RoleLipoproteins


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Lipoproteins - chylomicrons

Dietary fat fatty acids + cholesterol

+ cholesterol (from bile)

Re-esterification (in intestinal mucosal cells) tryiglycerides + cholesteryl esters

+ phospholipids + apoA + apoB chylomicrons

Chylomicron secretion from cells into lymphatic system

depends on presence of apoB + apoC + apoE in lymphatic system and in plasma


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Tissue of origin and function of plasma lipoproteins

Origin FunctionsChylomicrons Intestines Absorption of dietary

fat

Chylo. remnants Plasma Deliver dietary fat to

liverVLDL Liver Deliver triglycerides from

liver to other tissues

IDL Plasma Initial product of VLDL catabolism

LDL Plasma Cholesterol transport

HDL Liver, Removal of excessintestines cholesterol from

tissues and lipoprotein


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Apolipoproteins

Lipid-binding protein constituents of plasmalipoproteins

Transport dietary lipids from intestines to liver, andendogenously synthesized lipids from liver tostorage tissues

Apolipoproteins control: Normal lipid secretion

Activation of enzymes concerned with lipidmetabolism

Receptor recognition of lipoproteins


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Apolipoproteins

Apoliproteins are designated by letters, e.g. apoA

If each class has more than one member, then

Roman numerals are used:apoA-I, apoA-II, apoB-48, apoB-100,

apoC-I, apoC-II


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Apolipoproteins

A-I, A-II, C-II, EHDL

B-100,LDL

B-100, E, C-IIILDL

B-100, E, C-I, C-IIVLDL

B-48, A-1, A-IV, C-II, EChylomicrons

ApolipoproteinsLipoproteins


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Apolipoproteins - Functions

Binding of IDL and chylomicron

remnant particles to receptor

E

Cofactor for lipoprotein lipaseC-II

Secretion of chylomicrons and VLDL

Binding of LDL to receptor

B

Cofactor for the enzyme LCAT

(lecithin-cholesterol acyltransferase)

A-I

FunctionApolipoproteins


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LDL

Small, cholesterol-rich lipoprotein containing onlyapoB

Longer life than its precursors (VLDL and IDL)

70% of total cholesterol in plasma Taken up by specific receptors on cell surfaces LDL

receptors or apoB/E receptors

LDL receptors present on all cells and most abundantin liver

After entering cells LDL broken down by lysosomes cholesterol released


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Control of LDL / Cholesterol level

Most cells can synthesise cholesterol but cholesteroltaken up by receptors inhibit intracellular cholesterolsynthesis and prevents further uptake

One way to control uptake of LDL by cells is to reducesynthesis of LDL receptors

Most plasma LDL is removed by LDL receptors

If plasma LDL level is high, some LDL may enter cellsby a passive unregulated route possible because ofits small size


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Factors influencing plasma level of LDL

Plasma level of LDL and cholesterol determined by the

rate of uptake by LDL receptors

Liver has the central role: Contains the most of the LDL receptor in the body

Synthesizes most of the endogenous cholesterol

Receives cholesterol from the diet and from

lipoproteins Is the only organ that can excrete cholesterol from

the body


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LDL receptor

Down regulated when sufficient cholesterol is available

Up regulated when cells require additional cholesterol

Regulation is controlled either by:

Extent to which existing receptors are recycled to the

cell surface after endocytosis, or

The amount of new receptors that are synthesized

Concentration of LDL receptors on hepatic cell surface

depends on the amount of cholesterol in cells

Increase in intracellular cholesterol reduction innumber of receptors

Factors that increase cholesterol in liver will increase

plasma LDL concentration because number of receptors

is reduced


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LDL receptor

Best characterised

Present in liver and some tissues

Contained in coated pits

160,000 Dalton glycoprotein Recognises apoB-100 and apoE

Through binding of apoB-100 mediates clearance ofIDL

VLDL contains both apoB-100 and apoE but cannotbind because VLDL also contains apo C-III

Expression is regulated by the need of the cell forcholesterol


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Lipoprotein receptors

Receptor Recognition LP Tissue

LDL apoB-100 LDL Liver apoE IDL Other

Chylomicron apoE Chylomicron Liverremnants remnants

IDL Unknown HDL Liver

Scavenger Chemically Modified Endotheliummodified or damaged macrophagesapoB-100 LDL


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Lipoprotein receptors

Receptor Role

LDL Removal of IDL, LDL from circulationMediate delivery of cholesterol from plasmato tissue

Chylomicron Uptake of dietary fat by the liverremnants Also called the apoE receptor

IDL HDL binding to cells

Existence is questionable

Scavenger Removal of chemically altered LDLPoorly defined


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Overview of lipoprotein function

Dietary fat transportsystem

Intestine

Extrahepatic Liver

tissues

Triglyceride secretion

system

Liver

Extrahepatic

tissues

Reverse cholesterol

transport

Extrahepatictissues

Liver

VLDL

IDL

LDL

HDL

LDL

Chylomicrons

Chylo

remnants


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Lipoproteins

When a lipoprotein reaches its destination: Chylomicron and VLDL carry triglycerides/cholesterol Lipoprotein docks via apoC-II Activates lipoprotein lipase Releases fatty acids absorbed by cells Some will complex to serum albumin for further

transport Remainder of VLDL is now IDL and returned to liver,

or IDL is further degraded by lipase to LDL

LDL returns to liver for endocytosis or endocytized byperipheral cells (must have LDL receptor) Remainder of chylomicron-chylomicron remnant is

returned to liver Degraded by lysosomes


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Exogenous Lipid Pathway

Exogenous lipids lipids released by digestion of dietaryfat (fatty acids, cholesterol) and cholesterol released bybile

Digestion: not much in the stomach

Lipids broken into FFA and acyl-glycerols Transported across the intestinal walls

Triglycerides are reassembled before enteringbloodstream and associated with proteins before being

transported complexes called chylomicrons Upon reaching their destinations triglycerides are:

Broken down to provide energy

Stored in adipose tissues


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Endogenous Lipid Pathway

Lipids synthesized and released by the liver

Triglycerides from glycerols and fatty acids from fat

stores or synthesized from glucose Hepatic cholesterols are either synthesized locally or

derived from lipoproteins e.g. from chylomicron remnants

Transported from the liver in VLDL


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VLDL

Large, triglyceride-rich

Incorporates apoB, apoC, ApoE and after secretion,

incorporates more apoC from HDL

In peripheral tissues hydrolysis by lipoprotein lipase release triglycerides

After hydrolysis IDL

IDL contains triglycerides + cholesterol + apoB + apoE

IDL either: Taken up by liver

Loses remaining tryiglycerides and apoE LDL


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Reverse cholesterol transport

Cells produce cholesterol needed for cellular

homeostasis

The liver: the only organ that is capable of degrading

cholesterol Cholesterol must be transported through blood to the

liver for processing, degradation, secretion and excretion

into bile

Since the liver is the center of cholesterol homeostasis inthe body, cholesterol that moves from peripheral tissues

to the liver is considered to be moving in the reverse

direction


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Reverse cholesterol transport

HDL: the only particle capable of receiving cholesterolfrom peripheral cells

HDL responsible for most of the reverse cholesteroltransport

ApoA-I is the major apolipoprotein in HDL and theprimary acceptor for un-esterified cholesterol fromperipheral cells

Level of plasma apoA-I is lower in smokers than in non-

smokers Exercise training increases plasma level of apoA-I

Inverse relationship between coronary disease and theplasma apoA-I level


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Reverse Cholesterol Transport

Extrahepatic Tissues

C

HDL3

C+FA

CE

TG VLDLHDL2

Liver

Bile

Faeces

CE CE

LCAT

C

C


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HDL

Synthesized de novo in liver and small intestines

Protein-rich disc shaped particles, containing

phospholipid, free cholesterol, apoA, apoB Primary apolipoproteins are apoA-I, apoC-I, apoC-II

and apoE

One major function of HDL is to act as circulatingstores of apoC-I, apoC-II and apoE


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HDL

HDL converted to spherical lipoproteins withaccumulation of cholesterol esters

This addition of cholesterol esters convert nascentHDLs to HDL2 and HDL3

Cholesterol-rich HDLs return to liver where they areendocytosed

Hepatic uptake of HDL (reverse cholesterol transport)may be mediated by SR B-I receptor or through lipid-

lipid interaction Macrophages also take up HDL through apoA-I

receptor interaction


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HDL

Since macrophages take up HDL through apoA-I

receptor interaction - HDL can then acquire cholesterol

and apoE from macrophages

Enriched HDLs are then secreted from the

macrophages

The added apoE in these HDL lead to an increase in

their uptake and catabolism by the liver

HDL also acquire cholesterol by extracting it from cell

surface membranes causing cholesterol storedintracellularly as cholesteryl esters to be mobilized to

replace the cholesterol removed by HDL

As a result, intracellular cholesterol level is lowered


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Enzymes involved in lipid metabolismLipoprotein Lipase

Hydrolyse triglycerides contained in circulatingchylomicrons and VLDL monoglycerides and fatty acids Acts on surface of capillary endothelial cells activated by

apoC-II (present in VLDL and chylomicron) Present in many tissues adipose tissue, mammary

glands, heart Activity increased by insulin, when insulted is administered Enzyme formed within the tissue and then secreted to the

surface of endothelial cells Binds firmly to the glycoprotein present on the surface of

endothelial cells Acts on triglycerides while firmly bound to endothelial

surface Monoglycerides are then transported to the liver where

they are degraded by a hepatic monoglycerate lipase


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Enzymes involved in lipid metabolism

Hepatic Lipase Similar in properties to lipoprotein lipase

Present in liver sinusoids

A lipid hydrolase

Acts on IDL and HDL2

Acts on triglycerides and also on phosphoglycerides

present on surface coats

Probably is responsible for the conversion of IDL toLDL or for processing of IDL for uptake by the liver

Also may be responsible for HDL2 processing: either

for uptake by liver or for conversion back to HDL3


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Acid Lipase Acts intracellularly after lipoprotein is removed from

circulation by receptor-mediated endocytosis

Contained in lysosomes

Member of a family of enzymes called lysosomal

acid hydrolases

Hydrolyses triglycerides and cholesterol esters

remaining in lipoproteins

releasing fatty acids and

cholesterol for utilisation in cells


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LCATlecithin-cholesterol acyltransferase

Mediates cholesterol esterification in plasma

Intracellularly acyl-cholesterol acyl-transferase

(ACAT)

Re-esterify excess cholesterol for intracellularstorage

Activity is enhanced by presence of intracellular

cholesterol

C + FA CE

LCAT


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Enzymes involved in lipid metabolismCETP

Cholesteryl estertransferprotein

Glycoprotein Synthesized mainly in the liver

In plasma, CEPT is predominantly bound to the HDLcontaining apoA-I only particles

Mediates the exchange of HDL cholesteryl esters withtriglycerides of Apo B containing lipoproteins

Plays a central role in reverse cholesterol transport


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Plasma Lipids, lipoprotein & Apolipoprotein Proteins

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