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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Enzymes involved in lipid metabolism
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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Enzymes involved in lipid metabolism
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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