Biochemistry 545/645

November 17 , 2022th

Lipid Metabolism
Why is HMGCoA synthase not It is also used for
considered a primary regulatory enzyme ketone body Cholesterol Synthesis
in cholesterol synthesis? formation
COO - COO - isopentenyl pyrophosphate
2NADPH 2NADP+ [3ATP] CO2 + Pi
acetyl-CoA CH2 CH2 CH2
+ CH3 - C - OH CH3 - C - OH CH3 - C isoprene unit
acetoacetyl-CoA HMGCoA CH2 CH2 CH2
synthase HSCoA
C O HMGCoA CH2OH CH2- O – P – O - P
reductase
SCoA
What is the major regulatory enzyme in 2 isoprenes condense
HMG-CoA cholesterol synthesis?
geranyl pyrophosphate (C10)
HMGCoA reductase is the target
of what class of cholesterol 1 isoprene
acetoacetate, 3- lowering drugs?
hydroxybutarate statins – lovostatin, atorvastatin farnesyl pyrophosphate (C 15)
(lipitor) etc

2 farnesyl-PP combine
cholesterol

squalene (C30)
ring formation (cyclase)

HO HO
lanosterol
liver endocrine glands
What compounds are derived from cholesterol?
bile salts steroid hormones
 Production of Bile Acids from
21 22 24 27 Cholesterol
18 20 23 25
12
16 26
11 13 17
1 19 9
2 14 15
10 8 7α hydroxylase
3 double bond reduction,
HO 7 hydroxylation 3α 7α
5 (deoxycholates) and 3α 7α 12α
4 6 HO OH
(cholates)
side chain oxidation

O
COOH C NHCH2COO - glycocholic acid, pK=4
OH OH
glycine, taurine -NHCH2CH2SO3- taurocholic acid, pK=2

made-liver
conjugation Where are bile acids made and
stored -
stored?
gall
bladder
HO OH HO OH Intestine (solubilize fats)

Why is the recycling of bile acids

bacteria in gut remove
cholic acid, pK = 6 back to the liver clinically relevant?
glycine and taurine 95% recycled to
(deconjugate) and liver for
Since the steroid nucleus cannot be broken down within the
dehydroxylate position reconjugation but
human body, elimination as bile acids is a major pathway for
7. not hydroxylation
getting rid of cholesterol. Bile acid sequestering drugs can block feces (secondary bile
recycling back to the liver with greater amounts of bile acids
acids)
eliminated in the feces. Cholestyramine functions in this manner.
 Hypercholesterolemia is a risk factor for
cardiovascular disease. Total cholesterol is not as
important in considering risk as is distribution of
cholesterol between LDL (“BAD”) and HDL
(“GOOD”) particles. Devlin 6th edition
 So What does HDL (aka “The Good
Cholesterol”) Do? HDL HDL-CII

ApoB-48
chylomicron remnants
Nascent
lipoprotein ApoCII Chylomicron
recycling
HDL ApoA
ApoB-48
HDL ApoCII
ApoE Chylomicron
cholesterol
ApoE
bile acids A positive correlation exists
between which plasma lipoprotein
and coronary heart disease? LDL ApoB-100

An inverse correlation? Nascent

reverse cholesterol transport HDL VLDL

ApoB-100
lecithin:cholesterol acyl-transferase ApoCII
VLDL
ApoE
C
CE C C
C
HDL C peripheral cell
HDL
LDL

HDL-CIIE
 Serum Lipid/Lipoprotein Levels and
Cardiovascular Disease Risk
Total Cholesterol Level Risk Assessment

Less than 200 mg/dL (180 optimal) Desirable, lower risk for coronary heart disease

200-239 mg/dL Borderline, increased risk

>240 mg/dL High blood cholesterol, doubles risk for

cardiovascular disease

HDL Cholesterol Level Risk Assessment

Less than 40 (men)/50 Major risk factor for cardiovascular disease

(women) mg/dL

>60 mg/dL Considered protective against heart disease

LDL Cholesterol Level Risk Assessment

Less than 100 mg/dL Optimal

130-160 mg/dL Borderline increased risk

>160 mg/dL High

 Serum Lipid/Lipoprotein Levels and
Cardiovascular Disease Risk
Triglyceride Level Risk Assessment

Less than 150 mg/dL Normal

150-200 mg/dL Borderline

>200 mg/dL High, when combined with low HDL or

high LDL appears to speed up
atherosclerosis

healthy plasma hyperlipidemic plasma

 Lowering Cardiovascular Risk Therapeutically

Drugs targeting serum cholesterol / LDL

can be used • Statins – inhibit endogenous cholesterol synthesis

together • Sequestrants – interfere with bile acid reabsorption from the gut

• Niacin – inhibits triglyceride synthesis, decreases VLDL production;

also increases HDL levels
• Fibrates – affects the transcription of genes encoding protein
components of lipoproteins reducing VLDL and increasing HDL
• PCSK9 inhibitors – block down regulation of LDL receptors
 Statins are Competitive Inhibitors of HMG-CoA
Reductase
Binding of
E+S [ES/EP] E + P mevalonic acid and
HO Lipitor to HMG-
COOH CoA reductase is
NADPH NADP H3C
OH
mutually exclusive
HMG-CoA mevalonic acid
HMG-CoA
atorvastatin
reductase lipitor
cholesterol

1/ v0 [Competitive Inhibitor]

VMAX unchanged E+ S ES
1/ VMAX +
I

1/ [S] EI
 Mechanism of Action of Bile Acid Sequestrants
VLDL

HMG-CoA HMG-CoA statin

LDL cholesterol
LDL cholesterol

bile acids bile acids

bile acids ezetimibe cholestryramine bile acids - sequestered feces

Ezetimibe
(Zetia) blocks
absorption of
cholesterol
Low Density Lipoprotein Recycling

Familial Hypercholesterolemia
bad cholesterol • LDL Receptor (95%)

• ApoB (4%)

gain of function mutations • PCSK9

loss of function mutations lower serum cholesterol

PCSK9 Binds LDLR and Promotes Its Lysosomal
Degradation
 The Fully Human Monoclonal Antibody Alirocumab
Increases LDL Receptor Levels and Lowers Serum LDL

combination therapy - increased synthesis of

LDLR and decreased degradation
Y treatment decreases cholesterol to very low
levels
some concern that such low levels may have
long term adverse effects
Atherosclerosis (Athero – Gruel or Paste,
Sclerosis – Hardness)
Ischemia – reduction in
blood flow (oxygen
delivery) to a part of the
body
Infarction – Death of cells
(necrosis) as a
consequence of ischemia
Factors Involved in the Formation of Atherosclerotic
Plaques, Rupture, and Thrombosis
 Hemostasis Overview
Vessel injury
Collagen/VWF
exposure
platelet adhesion/release reaction tissue factor
serotonin
vasoconstrictio
thromboxane A2
n
ADP blood coagulation
cascade
platelet aggregation
platelets –
thrombocytopenia –
bleeding disorder
thrombin
reduced blood primary hemostatic plug
flow

platelet fusion/contraction fibrin

stable hemostatic plug

Primary Hemostasis – Platelet Adhesion

circulating blood
Von Willebrand factor
endothelium

collagen

platelets contain receptors for VWF (GP1B) and collagen

vessel damage (GPVI and Integrin α2β1) that promote platelet adhesion to
sites of vessel damage

platelet

receptor (adhesion)

Von Willebrand factor unfolds receptor (aggregation)

due to shear stress
 Primary Hemostasis – Platelet
Activation/Aggregation
platelet

receptor (aggregation)

receptor (adhesion)

ADP,
ADP, platelet activation
TxA2
TxA2
release reaction clopidogril
aggregation
ADP (ligand) - P2Y12 (receptor)

c
Exposure of negatively charged
phospholipids and
polyphosphates on the platelet
stati thromboxane A2 (ligand) – TPα (receptor)

surface

e m o aspirin

r y h
i ma l u g fibrinogen/fibrin, von

p r p Willebrand factor, fibronectin

GPIIb/IIIa
 Myocardial Infarction (MI): Diagnosis

Lactate dehydrogenase: tetramer of 4

polypeptide chains. Chain type is tissue
dependent.
LDH1 HHHH Myocardium/RBC
Enzyme
LDH2 HHHM Myocardium/RBC activity

LDH3 HHMM Brain and Kidney LDH1/2

LDH4 HMMM
CPK2
LDH5 MMMM Liver and Skeletal Muscle

1 2 3 4
Creatine phosphokinase: dimer of 2
days after infarct
polypeptide chains. Chain type is tissue
dependent.
Isozymes of the muscle protein
CPK1 BB Brain troponin are thought to increase early
during MI and before permanent
CPK3 MM Muscle damage ensues

CPK2 BM Restricted to myocardium