‫‪Regulation of cholesterol‬‬

‫‪synthesis‬‬

‫پوهاند شمس الرحیم"رحیم"‬

‫دیپارتمنت بیوشیمی‬
Regulation of cholesterol synthesis
HMG-CoA Reductase, the rate-limiting step on
the pathway for synthesis of cholesterol, is a major
control point.
HO
CH3
C
H2C
CH2 C SCoA
C
 O
O O
HMG-CoA
2NADPH
HMG-CoA
2NADP+ Reductase
+ HSCoA
HO
CH3
C
H2C H2
CH2 C OH
C
 mevalonate
O O
 Regulation of HMG-CoA Reductase

As rate-limiting step, it is the principal site of

regulation in cholesterol synthesis
• 1) Phosphorylation by cAMP-dependent
kinases inactivates the reductase
• 2) Degradation of HMG-CoA reductase - half-
life is 3 hrs and depends on cholesterol level
• 3) Gene expression (mRNA production) is
controlled by cholesterol levels
Short-term regulation:
HMG-CoA Reductase is inhibited by
phosphorylation, catalyzed by AMP-
Dependent Protein Kinase (which also
regulates fatty acid synthesis and
catabolism).
This kinase is active when cellular AMP is
high, corresponding to when ATP is low.
Thus, when cellular ATP is low, energy is not
expended in synthesizing cholesterol.
HMG CoA reductase - Phosphorylation
Long-term regulation is by varied formation and
degradation of HMG-CoA Reductase and other
enzymes of the pathway for synthesis of cholesterol.
 Regulated proteolysis of HMG-CoA Reductase:
• Degradation of HMG-CoA Reductase is
stimulated by cholesterol, oxidized derivatives of
cholesterol, mevalonate, & farnesol
(dephosphorylated farnesyl pyrophosphate).
 Regulated transcription:
• A transcription factor SREBP-2 (sterol
regulatory element binding protein #2)
responds to cellular levels of sterols. (The
related SREBP-1 has a role in regulating fatty
acid synthesis.)
• SREBP-2 is a transcription factor that
activates transcription of genes for HMG-CoA
Reductase and other enzymes of the pathway
for cholesterol synthesis.
 Sterol Derivatives :Bile Acids
• Are formed in major
breakdown pathway
for cholesterol
• Are mostly cholic &
chenodeoxycholic
acids
Fig 18.25
– Form bile salts by
combining with
glycine or taurine
• 95% of bile acids are
absorbed by ileum 18-62
• Bile acids (e.g., taurocholic acid, see
below) are polar derivatives of cholesterol
made in the liver, that act as detergents
in the intestine, emulsifying dietary fats
to make them more accessible to digestive
enzymes.
Enterohepatic Circulation
Hyperlipidemia can lead to disease
• When there is too much
cholesterol /LDL in your body
(because of diet and the rate at
which the cholesterol is
processed) it is deposited in
arteries, including those of the
heart, which can lead to
narrowing of the arteries and
heart disease.

• Studies of people with heart

disease have shown that
lowering cholesterol/LDL
reduces the risk for dying from
heart disease, having a heart
attack, or needing heart bypass
surgery or angioplasty. 11
 Lipids and Lipoproteins
Cardiovascular Risk Assessment
• Direct correlation of plasma concentration
of lipids and lipoproteins and coronary
heart disease.
– Risk related to:
• Total cholesterol in plasma.
• LDL-cholesterol.
– Inverse relationship with HDL concentration.
– Triglycerides = direct relationship.

12
 Lipoprotein Profile
• Cholesterol levels are measured in milligrams (mg) of cholesterol per deciliter
(dL) of blood.
• Desirable or optimal levels for adults with or without existing heart disease
are:
– Total cholesterol: Less than 200 mg/dL.
Moderate risk >200-239 mg/dL.
High risk >240 mg/dL.
– Low Density Lipoprotein (LDL) cholesterol: Less than 100 mg/dL.
near/Above optimal : 100-129 mg/dL
borderline high: 130-159 mg/dL
High risk :160 – 189 mg/dL
– High Density Lipoprotein (HDL): 30 -60 mg/dL or higher.
– Triglycerides: Less than 150 mg/dL.
borderline high: 151- 199 mg/dL
High :200 – 499 mg/dL
Very High : > 500 mg/dL
13
 Ratio of Lipoprotein
• T.Chol / HDL.Chol ratio : < 4 Optimal
4 – 5 Borderline
> 6 High Risk
• LDL.Chol / HDL.Chol ratio : < 3 Optimal
3 – 4 Borderline
> 6 High Risk

• The National Cholesterol Education Program recommends

that healthy adults over 20 years of age have their
cholesterol levels checked once every 5 years.
 Health Effects of Fats
• Excess fat intake contributes to many diseases
including:
1. Obesity
2. Diabetes
3. Heart disease

 How?
1. High fat diets = high kcal diets
2. High saturated fat intake raises blood
cholesterol
Health Effects of Lipids

• Benefits from monounsaturated

fats and polyunsaturated fats
• Benefits from omega-6 and
omega-3 fats
1. May reduce blood cholesterol

Copyright 2005 Wadsworth Group, a division of Thomson Learning

 Lipids and Lipoproteins
Cardiovascular Risk Assessment
• Other risk factors.
– Male sex.
– Age.
– Smoking.
– High plasma cholesterol (>LDL-cholesterol).
– Low plasma HDL.
– Hypertension.
– Obesity.
– Sedentary lifestyle.
– Diabetes.
– caffeine

18
three things to help lower blood
cholesterol
– Reduce the amount of saturated fat and
cholesterol in his diet.
– Lose some weight. Losing weight can help
lower your LDL and total cholesterol levels, as
well as raise your HDL and lower your
triglyceride levels.
– Be physically active for at least 30 minutes
most, if not all, days.
 Statin Drugs (optional slide)

• Statin drugs inhibit the enzyme

HMG-CoA reductase
• Statins also increase cholesterol
uptake from the bloodstream by
resulting in more LDL receptor
expression
• Vytorin is actually a combination
drug made of simvastatin and
ezetimibe, (Zetia) which prevents
cholesterol absorption from the
digestive tract.
20