Lecture 9: Cholestrol Flashcards
Define cholestrol
important aspect of cell membranes, has a rigid ring system and a short branched hydrocarbon tail.
Cholesterol is largely hydrophobic.
But it has one polar group, a hydroxyl, making it amphipathic
How is cholestrol incoperated into cell membrane?
Cholesterol inserts into bilayer membranes with its hydroxyl group oriented toward the aqueous phase & its hydrophobic ring system adjacent to fatty acid chains of phospholipids.
The OH group of cholesterol forms hydrogen bonds with polar phospholipid head groups.
Two strategies by which phase changes of membrane lipids are avoided:
Cholesterol: In the absence of cholesterol, such membranes would crystallize at physiological temperatures.
The inner mitochondrial membrane lacks cholesterol but includes many phospholipids whose fatty acids have one or more double bonds, which lower the melting point to
below physiological temperature.
Defien triglyceride
are esters of long chain fatty acids and glycerol sometimes called triacylglycerol.
Define Lipoprotein
particles found in plasma that transport lipids including cholesterol
Lipoprotein classes
chylomicrons: take lipids from small
intestine through lymph cells
very low density lipoproteins (VLDL)
intermediate density lipoproteins (IDL)
low density lipoproteins (LDL)
high density lipoproteins (HDL)
Draw the structure of a plasma lipoprotein
Lecture Slide
Apolipoproteins purpose
major components of lipoproteins
responsible for recognition of particle by receptors
Lipoprotein brief description (shape, Apolipoproteins present and classification)
spherical particles with a hydrophobic core
apolipoproteins on the surface
Large: apoB (b-48 and B-100)
smaller: apoA-I, apoC-II, apoE
classified on the basis of density and electrophoretic mobility
Apoproteins of human lipoproteins
A-I (28,300)
- principal protein in HDL
- activate LCAT
A-II (8,700)
- occurs as dimer mainly in HDL
- enhance hepatic activity
B-48 (240,000)
– found only in chylomicron
B-100 (500,000)
– principal protein in LDL
- binds to LDL receptor
C-I (7,000)
– found in chylomicron, VLDL, HDL
-activate LCAT
C-II (8,800)
- found in chylomicron, VLDL, HDL
- activate lipoprotein lipase
C-III (8,800)
- found in chylomicron, VLDL, IDL, HDL
- inhibits lipoprotein lipase
D (32,500)
- found in HDL
E (34,100)
- found in chylomicron, VLDL, IDL HDL
- Binds to LDL receptor
H (50,000)
– found in chylomicron
Apolipoprotein versus lipoprotein
lipoprotein is an assembly of molecules whose function is to transport hydrophobic lipids in watery media including water and extracellular fluid whereas apolipoprotein is a protein bound to lipids in order to form lipoproteins.
Lipoproteins on gel electrophoresis
Lecture slide
Major lipoprotein classes: Chylomicron
formed through extrusion of resynthesized triglycerides from the mucosal cells into the intestinal lacteals
flow through the thoracic ducts into the suclavian veins
degraded to remnants by the action of lipoprotein lipase (LpL) which is located on capillary endothelial cell surface
remnants are taken up by liver parenchymal cells due to apoE-III and apoE-IV isoform recognition sites
VLDL Lipoprotein: Density Diameter: Type apolipoproteins present: Electrophoresis stage Formed?
density >1.006 diameter 30 - 80nm endogenous triglycerides apoB-100, apoE, apoC-II/C-III prebeta in electrophoresis
formed in the liver as nascent VLDL (contains only triglycerides, apoE and apoB)
nascent VLDLs then interact with HDL to generate mature VLDLs (with added cholesterol, apoC-II and apoC-III)
mature VLDLs are acted upon by LpL to generate VLDL remnants (IDL)
IDL are further degraded by hepatic triglyceride lipase (HTGL) to generate LDLs
IDL Lipoprotein Density Diameter: Type apolipoproteins present: Electrophoresis stage
density: 1.006 - 1.019
diameter: 25 - 35nm
cholesteryl esters and triglycerides
apoB-100, apoE, apoC-II/C-III
slow pre-beta
LDL Lipoprotein Density Diameter: Type apolipoproteins present: Electrophoresis stage Favourable amount?
density: 1.019 - 1.063
diameter: 18-25nm
cholesteryl esters
apoB-100
beta (electrophoresis)
< 130 LDL cholesterol is desirable, 130-159 is borderline high and >160 is high
HDL Lipoprotein Density Diameter: Type apolipoproteins present: Electrophoresis stage
density: 1.063-1.210
diameter: 5-12nm
cholesteryl esters and phospholipids
apoA-I, apoA-II, apoC-II/C-III and apoE
alpha (electrophoresis)
Discoidal HDL
contains cholesterol, phospholipid, apoA-I, apoA-II, apoE and is disc shaped;
it is formed in liver and intestine
Functions of HDL
transfers proteins to other lipoproteins
picks up lipids from other lipoproteins
picks up cholesterol from cell membranes
converts cholesterol to cholesterol esters via the LCAT reaction
transfers cholesterol esters to other lipoproteins, which transport them to the liver (referred to as “reverse cholesterol transport)
Lipoproteins (a)- Lp(a)
they consist of LDL and a protein designated as (a)
the apoA is covalently linked to apoB- 100 by a disulfide linkage
high risk association with premature coronary artery disease and stroke
Exogenous pathway
Dietary TGs are digested in the stomach and duodenum into monoglycerides (MGs) and FFAs by gastric lipase, emulsification from vigorous stomach peristalsis, and pancreatic lipase.
Once absorbed into enterocytes, they are reassembled into TGs and packaged with cholesterol into chylomicrons, the largest lipoproteins
Chylomicrons transport dietary TGs and cholesterol from within enterocytes through lymphatics into the circulation.
In the capillaries of adipose and muscle tissue, apoprotein C-II (apo C-II) on the chylomicron activates endothelial lipoprotein lipase (LPL) to convert 90% of chylomicron triglyceride to fatty acids and glycerol, which are taken up by adipocytes and muscle cells for energy use or storage.
Endogenous pathway
the liver assembles and secretes triglyceride-rich very low-density lipoprotein (VLDL) particles, which transport triglycerides from the liver to peripheral tissues.
hydrolysis of the triglycerides by LPL, the VLDL particles are reduced to intermediate-density lipoproteins (IDL), which can be taken up by the liver or can be further hydrolysed to LDL particles.
LDL transports cholesterol primarily to hepatocytes but also to peripheral tissues. ApoB-100 is responsible for the recognition and uptake of LDL by the LDL receptor
High-density lipoprotein (HDL) plays an important role in reverse cholesterol transport, which shuttles cholesterol from peripheral cells to the liver
Draw a diagram of the exo and endogenous pathways combined
Lecture Slide
3 types of abnormal lipid metabolism and brief description
Dyslipidemia: abnormal lipid levels
causes: defective synthesis/transport/catabo lism of lipoproteins
hyperlipoproteinemia: elevated lipoprotein levels
- hypercholesterolemia
- hypertriglyceridemia
- combined hyperlipidemia
hypolipoproteinemia: decreased lipoprotein levels
Hypercholesterolemia 4 types and cause
isolated high plasma cholesterol concentration
- Common hypercholesterolaemia
- most frequent dyslipidemia, multifactorial - Familial hypercholesterolemia
- LDL receptor gene mutations - Familial defective apoB- 100
- apo B-100 gene mutations = defective LDL receptor binding - Autosomal recessive hypercholesterolemia
- mutations = defective LDL receptor-mediated endocytosis
Describe Familial hypercholesterolemia
monogenic disorder, autosomal dominant, rare
LDL receptor gene mutations
very high plasma cholesterol & LDL-C levels
lipid deposits at eyelids, tendon, hand, cornea
heterozygotes: also symptomatic
Hypertriglyceridemia
isolated high plasma TG concentration
borderline high: 150-200 mg/dL
high: 200-500 mg/dL very high: >500 mg/dL
genetic abnormalities or secondary causes
(e.g. some hormonal abnormalities)
imbalance between VLDL synthesis vs clearance
Hypertriglyceridemia: Familial chylomiconemia
very rare; LPL or apo C-II deficiency
- chylomicron & VLDL accumulation à very high TG
- fasting chylomicronaemia
Hypertriglyceridemia: Familial hypertriglyceridemia
relatively common
- isolated VLDL elevation
- excess VLDL production
- polygenic
