Ray Hreiche updated slides from Mohana Ratnapalan amp Anna Sher THANK YOU Learning Objectives Explain the physiological functions of cholesterol in membrane stability Outline the synthesis of cholesterol from acetate ID: 910682
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Slide1
Cholesterol and Lipid Transport
Ray Hreiche(updated slides from Mohana Ratnapalan & Anna Sher)(THANK YOU!!!)
Slide2Learning Objectives
Explain the physiological functions of cholesterol in membrane stability.Outline the synthesis of cholesterol from acetate.Outline the synthesis of bile acids and steroid hormones from cholesterol.
Describe the mechanism of transport of cholesterol around the body and its uptake into cells.
Draw a diagram of low density lipoprotein (LDL).
Explain why disturbances in cholesterol homeostasis cause disease.
Give an example of how a selective enzyme inhibitor can be used as a pharmacological agent controlling cholesterol metabolism
Slide3Learning Objectives
Explain the physiological functions of cholesterol in membrane stability.
Outline the synthesis of cholesterol from acetate.
Outline the synthesis of bile acids and steroid hormones from cholesterol.
Describe the mechanism of transport of cholesterol around the body and its uptake into cells.
Draw a diagram of low density lipoprotein (LDL).
Explain why disturbances in cholesterol homeostasis cause disease.Give an example of how a selective enzyme inhibitor can be used as a pharmacological agent controlling cholesterol metabolism
Already discussed in Rachel’s presentation!
Slide4Overview
Cholesterol, Lipids, Bilayer
Slide5Cholesterol is one component of the lipid
bilayer
Slide6Structure of the lipid bilayer
Slide7Structure of Cholesterol
Derivative of saturated tetracyclic hydrocarbon
All cyclohexane rings are in the chair conformation
Planar, rigid structure
Storage form
= acylated at position 3
Slide8physiological functions of cholesterol in membrane stability
Objective 1:
Explain the physiological functions of cholesterol in membrane stability.
Slide9Function of Cholesterol
In membranes high cholesterol leads to reduced fluidity due to:reducing phase transitions of lipidsreducing lateral motility of polar lipidsAs a precursor of steroid hormonesAs a precursor of bile salts
Other roles: signalling molecule
Slide10Cholesterol Synthesis
Slide11STEP 1 – Formation of Mevalonate
1.1
1.2
1.3
HMGCoA Reductase as the regulated step in cholesterol synthesis
CHOLESTEROL BIOSYNTHESIS
Slide12STEP 2 – Mevalonate to Squalene (Isoprenoid metabolism)
2.1. Mevalonate to C5 units (isoprene units) 2.2.Head-to-tail condensations of isoprene units2.3 Branched pathway at farnesyl pyrophosphate
C5
C10
C15
C30
Slide13STEP 3 - Squalene to cholesterol
Cyclization reaction
Slide14Cholesterol Derivatives
Slide15METABOLISM OF CHOLESTEROL: SYNTHESIS OF STEROID HORMONES
Levels of hormone controlled by the rate of synthesis
Cholesterol desmolase generates pregnenolone the precursor of all steroid hormones
5 Classes:
Progestins
Glucocorticoids
MineralocorticoidsAndrogensEstrogens
Slide16METABOLISM OF CHOLESTEROL: SYNTHESIS OF BILE ACIDS
Conjugated bile acids
This pathway represents the major route for elimination of cholesterol via the GI tract
Enterohepatic circulation of bile acids
Regulated step:
Chol 7a
-hydroxylase,
a cytochrome P450 monooxygenase
Slide17FUNCTION OF BILE SALTS
Emulsification of dietary fats
Slide18Transport and Cellular uptake
Slide19Fat Absorption in GI tract
Slide20Fat Absorption in GI tract
Slide21Fat Absorption in GI tract
Question: How to transport
liphophilic
(hydrophobic) fatty acids/glycerol/cholesterol in the blood (hydrophilic)???
Slide22Fat Absorption in GI tract
Lipoproteins
Slide23LIPOPROTEINS
Slide24LIPIDS ARE PACKAGED AS LIPOPROTEINS
Generalised structure of a plasma lipoprotein.
Cholesteryl esters and triacylglycerol are found in the core and free cholesterol, phospholipids and proteins are in the surface layer.
Slide25Slide26SEPARATION, IDENTIFICATION AND COMPOSITION OF LIPOPROTEINS
Separated by:
ultracentrifugation
or
electrophoresis
Slide27CIRCULATION OF LIPOPROTEINS
Slide28ROLE OF APOPROTEINS
Slide29CIRCULATION OF LIPOPROTEINS
Slide30TRAFFICKING OF THE LDL RECEPTOR
Slide31Slide32Homeostasis and Disease
Slide33Homeostasis and Disease
Xanthelasma
Xanthoma
Slide34FAMILIAL HYPERCHOLESTEROLAEMIA (FH)
Slide35BIOCHEMICAL DEFECT IN FH CELLS
LDL RECEPTOR ACTIVITY
LDL RECEPTOR CLEARANCE
Slide36PATHOGENESIS OF FH
Slide37Pharmacology
Slide38Pharmacology
Slide39CHOLESTEROL BALANCE
Slide40CONTROL OF
HYPERCHOLESTEROLAEMIA
Dietary
restriction
Increased
Excretion:
resins
Inhibition of
cholesterol synthesis:
HMGCoA Reductase
inhibitors
Slide41?