Cholesterol Metabolism Flashcards
(40 cards)
What is Cholesterol and where is it found?
- it is not found in plants (major animal sterol)
- it is synthesized in tissues containing mitochondria
What is Hyper-cholestrolemia?
- elevated plasma cholesterol
- increased risk for atherosclerosis and CHD
- weak correlation between dietary and plasma cholesterol
Xanthoma
cholesterol deposit under skin, joints, tendon
Xanthelasma
smaller cholesterol deposit often around eyelids
Cholesterol Structure
- 27-C
- steroid nucleus
- 8C branched chain
- Hydroxyl group (-OH) at C3
- double bond
Functions of cholesterol
- structural component of cell membranes
- stabilizes membrane fluidity (decreased fluidity at higher temperatures)
- precursor for bile acid, steroid hormones, vitamin D
Sources of Liver Cholesterol (Influx)
- dietary cholesterol (chylomicron remnants)
- from extra-hepatic tissues (HDL)
- de novo synthesis in the liver
- return of hepatic cholesterol by LDL
Sources of Liver Cholesterol (Efflux)
- free cholesterol secreted into the bile
- secretion of VLDL
- conversion to bile acids/salts
Where does De Novo synthesis of cholesterol occur?
- all cells with mitochondria (liver, intestine, adrenal cortex, reproductive tissues)
- acetyl CoA provides all 27 carbons transported from mitochondria by citrate shuttle
- Synthesis of Mevalonate from Acetyl-CoA
.Synthesis of Mevalonate from Acetyl-CoA is
2 molecules of Acetyl-CoA (2C) condense
to form Acetoacetyl CoA (4C)
▪ Enzyme: Thiolase
Another Acetyl-CoA is added to make β-
Hydroxy β-methylglutaryl-CoA (HMG-CoA)
(6C)
▪ Enzyme: HMG-CoA Synthase
Cleavage of CoA thioester and reduction
to mevalonate (6C)
▪ Enzyme: HMG-CoA Reductase
▪ Rate limiting and key regulated step!
▪ Inhibited by statins
What is Rate Limiting Step of Cholesterol synthesis?
- cleavage of HMG-CoA (6C) to Mevalonate (6C) with enzyme HMG-CoA Reductase
What enzyme is mainly inhibited by statins?
HMG-CoA Reductase
(makes Mevalonate from HMG-CoA)
- Synthesis of Farnesyl Pyrophosphate
- Mevalonate (6C) is
decarboxylated to activated
isoprenoid precursor units IPP
and DMAPP (5C) - Fusion of IPP (5C) and DMAPP
(5C) into Geranyl-PP (10C) - Addition of another IPP to generate Farnesyl-PP (15C)
- Synthesis of 7-dehydrocholesterol
- 2 Farnesyl-PP fuse making
Squalene (30C) - Squalene undergoes
cyclization to generate the
first steroid: Lanosterol
(30C) - Lanosterol is converted to
7-Dehydrocholesterol
What is 7-Dehydrocholesterol converted to?
In the skin, converted to Cholecalciferol (vitamin
D3) in a photochemical reaction using
energy from UV light
- Formation of Cholesterol
7-Dehydrocholesterol is reduced to
Cholesterol by 7-dehydrocholesterol
reductase enzyme
Smith-Lemli-Opitz Syndrome (SLOS)
Most common in Caucasians
▪ Central Europe (Czech, Slovakia)
* Autosomal Recessive
* Mutations in DHCR7 gene encoding 7-Dehydrocholesterol
reductase (The final step in de novo cholesterol synthesis)
Clinical Presentation
* Congenital abnormalities
▪ Microcephaly
▪ Distinctive facies
▪ Malformations of the heart, lungs, kidneys, gastrointestinal tract, and
genitalia are also common
* Intellectual disability
* Learning/Behavioral problems
Pathogenesis
* Cholesterol precursors accumulate in the cells
* Cholesterol is necessary for embryonic development
How do cells increase intracellular cholesterol
levels?
- De novo synthesis
- LDL import via the LDL receptor
How does Intracellular cholesterol regulate
its own levels by 3 mechanisms?
- Inhibition of de novo synthesis
(HMG-CoA reductase) - Activation of storage as esters
(ACAT) - Inhibition of LDL-receptor gene
expression
Hormonal Regulation of HMG-CoA Reductase
Insulin signaling
▪ Dephosphorylation activates HMG-CoA
Reductase
active inactive
Glucagon signaling
▪ Phosphorylation inactivates HMG-CoA
Reductase
Glucagon
So, cholesterol is synthesized in the
well-fed state when energy is
abundant, but not in the fasting state
Fates of Hepatic Cholesterol
When intracellular cholesterol levels
are high:
* No catabolic pathway!
- Conversion to cholesterol esters by
ACAT
▪ Since very hydrophobic - packaged in
lipoprotein cores (VLDL)
▪ Distributed to tissues
* Membranes, steroids, vitamin D - Conversion to Bile Acids/Salts
▪ Storage in gallbladder or transferred to
duodenum - Biliary cholesterol
▪ Free cholesterol solubilized in the bile
▪ Excretion in feces
What is the role of Statins?
Used in the treatment of hypercholesterolemia
▪ Reduce plasma cholesterol (LDL) levels
* Competitive inhibitors of HMG-CoA Reductase
▪ Inhibit de novo cholesterol synthesis
▪ Structural analogues of HMG-CoA
How do statins lower plasma LDL?
- Inhibit HMG-CoA reductase and intracellular de novo cholesterol
synthesis - Intracellular cholesterol levels decrease
- Expression of the LDL-Receptor increases
(Elevated LDL-Receptors internalize/clear more LDL from the plasma)
What does Cholesterol Synthesis Require?
- High energy state (216 ATP per molecule of
cholesterol) - Abundant Acetyl-CoA
