Learning Objectives The structure and composition of lipoproteins Exogenous dietary fat transport vs endogenous fat transport systems Key enzymes involved in lipoprotein metabolism Key cholesterol transporting lipoproteins and the relationship between their concentrations and the incidence ID: 935136
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Lipids III:Plasma Lipoproteins
Slide2Learning Objectives
The structure and composition of lipoproteins
Exogenous dietary fat transport vs. endogenous fat transport systems
Key enzymes involved in lipoprotein metabolism
Key cholesterol transporting lipoproteins and the relationship between their concentrations and the incidence of cardiovascular diseases
Hypercholesterolemia vs. hypocholesterolemia and the treatment or prevention of cardiovascular diseases
Slide3Structure and Composition
Apolipoproteins in their outer shell & a hydrophobic core of TG and cholesteryl esters
Most LPs are spherical except newly secreted HDLs (discoidal)
become spherical by the action of LCAT in plasma
Apoproteins share a common structure in the form of amphipathic helix
All of the LPs except apo B can change their LP associations
Chylomicrons & VLDL: the principal TG carriers
LDLs & HDLs: most cholesterol transport
Apo B-48 from intestine & B-100 from liver: RNA editing, deamination of C changes to U, introduce stop codon (CAA UAA)
Slide4Generalized structure of a lipoprotein
Slide5Properties of Human Apolipoproteins
Slide6Physical Data for the Major Types of Lipoprotein
Slide7Comparison of different lipoproteins in plasma
Slide8Composition of Lipoproteins (Percent of Mass)
Slide9Metabolism
Lipoprotein lipase (LPL): a serine esterase, include hepatic & pancreatic lipases, concentrated in muscle & adipose tissue, contain binding sites for GAG & apo CII
required for activation, major E in the processing of chylomicrons & VLDL, apo CIII inhibits the activation of LPL, [insulin] modulate activity
Hepatic lipase: liver E, localized on memb. surf.-heparan sulfate, continues the lipolysis of VLDL & IDL LDL, hydrolyze phospholipids & HDL-TG, respond + to androgens, - to
levels of estrogen
LCAT: circulate with HDL, LDL, apo D, CETP, activated by apo A-I, transfer of LCFA from PLs to cholesterol cholesterol esters for storage & transport, HDL interacting with all LP
ACAT: esterifies free cholesterol by linking it to a FA, an intracellular enzyme
prepare for storage as in liver parenchymal cells
Slide10Chylomicrons
Assembled in Mucosal enterocyte
golgi
/ER of SI
Acquire Apo B-48, A-I, A-II, & A-IV at the junction of RER & SER, secreted into the lymph, enter the blood circulation at the thoracic duct
Synthesis/secretion linked to the rate of dietary fat absorption
In the circulation, undergo a number of changes, acquiring apo C & E from HDL in exchange for PL, hydrolysis of TG by LPL
The core TG depleted & substantial portion of PL, apo A & C transferred to HDL
CM remnant rich in cholesteryl ester & apo B-48 and E
removed by liver parenchymal cells through apo E R
lysosomal lipases & proteases complete degradation
Slide11Steps involved in the metabolism of chylomicrons – the exogenous pathway of lipid transport
Slide12Produced by parenchymal cells of the liver
TGs derived from FAs from adipose tissue, conversion of CHOs to FAs in the liver, and hydrolysis of LP TGs on capillary endothelia & in the liver, Apo B-100 required
New VLDL undergoes changes in plasma, acquires apo C & E from HDL, core TGs are removed, apo C is lost, ≈ half of the VLDL is removed by the liver via apo B-100-E receptor pathway, the rest remains in circulation as VLDL remnants
some are called IDL, analogous to CM remnants, further catabolism by hepatic lipase, lose apo E
LDL with apo B-100, accounts for all LDL present
serves as a source of cholesterol for most tissues of the body
Although most cells can synthesize cholesterol under normal conditions, most endogenous production occurs in the liver and intestine, distributed by LDL
provide efficient balance b/w dietary intake and endogenous production of cholesterol
Very-Low-Density Lipoproteins
Slide13Conversion of very low-density lipoproteins (VLDLs) to low-density lipoproteins (LDLs), via intermediate density lipoproteins (IDLs) (the endogenous pathway of lipid transport)
Slide14Low-Density Lipoproteins
Distribution of cholesterol to peripheral tissues
LDL receptor
Glycoprotein, 839a.a., 5 distinct domains, apo B & E binding through electrostatic interactions
# of LDL receptors on membrane depends on the degree of accumulation of intracellular cholesterol
down regulates R gene expression
Released free cholesterol into liver cells
Incorporate into plasma membrane
Inhibit new LDL receptor synthesis
Inhibit cholesterol synthesis
Microsomal ACAT activity stimulation
Increased activity of 7
-hydroxylase in bile acid synthesis
About 75% of high-affinity LDL uptake occurs in the liver
Bulk phase pinocytosis
Slide15Cellular uptake and metabolism of LDL
Slide16High-Density Lipoproteins
Secreted by hepatocytes & enterocytes in small intestine
Discoidal, nascent HDL
spherical, mature HDL by acquiring free cholesterol, peripheral cholesterol removal
inverse relationship b/w plasma [HDL] & CHD
Esterification of surface cholesterol by LCAT, activated by apo A-I
increases the gradient of free cholesterol b/w cellular plasma membrane & HDL particles
Cholesteryl esters also transferred to VLDL & LDL via apo D &, the cholesteryl ester transfer protein
ABC1 transporter:
Tangier
disease, CF, EOMD, SSL, ALD, Zellweger syndrome, PFIC
Modifications of HDL size by Es, LCAT, CETP, or hepatic & LP lipases
Apo A-II present on larger HDL particles
increase hydrolysis of HDL-TG & PL by hepatic lipase
HDL binding sites in tissues, mediated by apo A-I
The liver & kidney: principal organs for HDL catabolism
Slide17Sources of HDL
Slide18Reverse cholesterol transport (RCT) mediated by HDL
Slide19Hyperlipoproteinemia
Slide20Inherited Defects Causing Familial Hypercholesterolemias
Slide21Defects in the LDL receptor
result in decreased uptake of LDL & increased production of
IDL that is converted to LDL
Hypercholesterolemias
Slide22Cross-sectional view of an artery
Slide23Cholesterol level and CHD risk
Epidemiological studies: reduction in plasma [total cholesterol]
reduced CHD risk
Statins in patients with CAD & elevated [cholesterol]
reduces both fatal & nonfatal heart attacks
The relationship b/w premature CHD development & LDL cholesterol and inverse correlation b/w HDL cholesterol & premature CHD
well established
Lowered HDL cholesterol independent risk factor for premature CHD
Potential mechanisms of antiatherogenic effects of HDL cholesterol
Inhibition of LDL to
oxLDL
conversion
Prevention of adhesion of monocytes to endothelium
The prolongation of the half-life of prostacyclin produced by endothelial cells to promote vasodilatory effects
Slide24Evaluation of plasma cholesterol level
The measurement of LDL and HDL cholesterol, determined by measurement of plasma TG & cholesterol after a 12- to 14- hour fast
LDL cholesterol= total cholesterol- (VLDL cholesterol + HDL cholesterol) or
LDL cholesterol= total cholesterol - (
TG/5
+
HDL cholesterol
)
In the absence of chylomicrons & remnant lipoproteins, VLDL cholesterol= TG/5
HDL cholesterol is estimated in the supernatant obtained from precipitation of non-HDL lipoproteins by haparin-Mn
2+
, dextran sulfate 500, or phosphotungstate-Mg
2+
Direct LDL & HDL measurement by
immunoseparation
, antibodies against apo A-I & E, remove HDL & VLDL fractions
allowing LDL cholesterol measurement
Measurement of apo A-I, apo B, & apo E
equally useful for the assessment of CHD
Slide25CHD Risk Assessment Using Lipoprotein-Associated Cholesterol and Total Cholesterol (mg/dL)
Slide26Examples of Secondary Causes That Can Alter Plasma Lipoprotein Levels
Slide27Lipid-Lowering Methods
Reduce dietary intake of cholesterol & saturated fats
Drug therapy: decrease production or enhance removal of lipoprotein from plasma
Cholestyramine & colestipol: nonabsorbable resins, interrupt enterohepatic circulation of bile acids
Nicotinic acid: reduce VLDL & LDL by inhibiting hepatic secretion of VLDL & by suppressing mobilization of FA
Clofibrate & gemfibrozil: promote rapid turnover of VLDL by activating lipoprotein lipase, gemfibrozil inhibit VLDL secretion
Probucol: reduce plasma cholesterol level but no effect on TG, act via blockage of intestinal cholesterol transport, HDL cholesterol levels are reduced by this drug
Statins: inhibit the regulatory step in biosynthesis of cholesterol, lower serum cholesterol & LDL cholesterol by inhibition of hepatic cholesterol synthesis, by up-regulating LDL receptor activity
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