Faculty of Allied Medical Sciences

Department of Medical Laboratory

Sciences (MLS)
Zarqa University, Jordan

Advanced Clinical Biochemistry

0701701

Presented by: Khalil Abu Yahya

Thaer Salman
Younis Abu Najm
Alaa Alian
Content:
-Introduction
- Hyperlipidemia &Hypercholesterolemia
-Clinical significant LDL
-Current treatment
-Disadvantage of current treatment
-Biochemistry..introduction
-Function
- Clinical significant
-Future Directions Emerging research
Introduction
 PCSK9 ( Proprotein Convertase Subtilisin/Kexin type 9 ):
an enzyme (serine protease) encoded by the
PCSK9 gene, is predominantly produced in the
liver.

 PCSK9 binds to the LDL receptor (LDL-R) on the

surface of hepatocytes, leading to the
degradation of the LDL-R and subsequently to
higher plasma LDL-C levels
Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) Is a Key
Regulator of LDL-R Recycling

1. PCSK9 mediates degradation of the LDL-R by interacting with the

extracellular domain and targeting the receptor for degradation1
2. PCSK9 is highly expressed in the liver,small intestine,and kidney
 PCSK9 inhibitors: are a new class of drugs that
lower low-density lipoprotein (LDL), or “bad,”
cholesterol.

 PCSK9 inhibitors: are set to revolutionize the

management of atherosclerotic risk. There are
two FDA-approved medications: alirocumab
(Praluent) and evolocumab (Repatha)
 PCSK9 Inhibitors

 Are monoclonal antibodies.

 Target and inactive PCSK9 in the liver.
 Dramatically decrease LDL-C.
 The importance of cholesterol and other lipoproteins

 Cholesterol is vital to health and well-being, but

excess cholesterol in the bloodstream is a key
contributor to artery-clogging plaque, which can
accumulate and set the stage for a heart attack.

 Most cholesterol in the body is made in the (liver

and the intestines (80 %).

 Only about( 20%) comes from food

 Our bodies' package cholesterol and other lipids
into protein-covered particles (lipoproteins) that
mix easily with blood and move cholesterol and
other fats throughout the body.

 Cholesterol and other lipids circulate in the

bloodstream in several different forms (VLDL,
LDL, HDL).

 The liver clears cholesterol and LDL build-up

from the body.
 Hypercholesterolemia and Hyperlipidemia
Hypercholesterolemia: is the presence of high
.levels of cholesterol in the blood

high levels of :)Hyperlipoproteinemia( Hyperlipidemia

.lipoproteins i n the blood

any abnormalities of lipid and :Dyslipidemia

.lipoprotein levels in the blood
 Hypercholesterolemia and Hyperlipidemia

Elevated levels of non-HDL cholesterol and

LDL in the blood may be a consequence of
diet, obesity, inherited (genetic) diseases
(such as LDL receptor mutations in
familial hypercholesterolemia), or the
presence of other diseases such as
.an underactive thyroid type 2 diabetes and
 In the UK, components of cholesterol are measured in units called millimoles per
litre of blood (mmol/L). As a guide, these are the values healthy adults should aim
for [Heart UK. Getting a cholesterol test]

Total cholesterol Below 5

Non-HDL or ‘bad’ cholesterol Below 4

LDL cholesterol Below 3

HDL or ‘good’ cholesterol Above 1 for men and 1.2 for women

The lower the better – above 6 is considered a high

TC:HDL ratio
risk

Below 2.3 (non-fasting)

Triglycerides
Below 1.7 (fasting)
There is five major groups of lipoprotein.
.Clinically tow important: LDL and HDL
Clinical effects of hyperlipidemia
1. Atherosclerosis.
Clinical Significance of Hyperlipidemia
2. Cardiovascular disease including:
 Coronary artery disease.
 Peripheral artery disease.
 Cerebrovascular disease.

These conditions can lead to serious complications

such as
Heart attack and Stroke.
Clinical Significance of
Hyperlipidemia
Clinical Significance of Hyperlipidemia

3. Impact on overall health, Elevated lipid

levels leading to complications such as:

 Pancreatitis.
 Fatty liver disease.
 Metabolic syndrome.
 Treatment
1. Lifestyle modifications
 Follow a healthy diet:
- Low in saturated fats, trans fats, and cholesterol
- High in fruits, vegetables, whole grains, and lean
proteins.
 Increase physical activity:
- aiming for at least 150 minutes of moderate-
intensity exercise per week.
Treatment
2. Medications
Treatment
 Statins: These are the most commonly prescribed
medications for lowering cholesterol levels. They
work by blocking an enzyme in the liver that is
responsible for producing cholesterol.

 Ezetimibe: This medication works by blocking the

absorption of cholesterol in the intestines.
 Treatment
 Fibrates and niacin: These medications can help
lower triglyceride levels and raise HDL
cholesterol levels.
 PCSK9 inhibitors: These medications help lower
LDL cholesterol levels by increasing the
liver's ability to remove cholesterol from the
blood.
Side effects of Statins and Ezetimibe
Some potential side effects of Statins and Ezetimibe
may include:

1. Muscle pain or weakness.

2. Liver damage.
3. Digestive issues.
4. Increased risk of developing diabetes.
Function of PCSK9
PCSK9 binds to the LDL receptor (LDLR) on the-
surface of liver cells
This binding leads to the degradation of LDLR,-
reducing the liver's ability to remove LDL
cholesterol from the bloodstream
:Implications for Cholesterol Metabolism

Higher levels of PCSK9 result in decreased LDLR activity,

.leading to higher levels of LDL cholesterol in the blood
Lower levels of PCSK9 result in increased LDLR activity,
leading to lower levels of LDL cholesterol in the blood
 Aspect PCSK9 Inhibitors Statin Drugs

Mechanism of
,Inhibit PCSK9 enzyme Inhibit HMG-CoA reductase
Action

Usually administered via

Typically taken orally as a pill,
Administration subcutaneous injection every
.usually once daily
.2 to 4 weeks

Significantly lowers LDL

LDL Cholesterol Lower LDL cholesterol levels,
cholesterol levels, often by
Reduction .typically by 20% to 60%
.more than 50%

Common adverse effects

Common adverse effects
include muscle pain
include injection site
Adverse Effects (myalgia), liver enzyme
reactions, flu-like symptoms,
abnormalities, and digestive
.and muscle pain
.issues

Typically more affordable

Generally more expensive
Cost compared to PCSK9
.than statin drugs
.inhibitors
Future Direction Emerging research:
1-Future research could unravel the impact of PCSK9
inhibition on inflammation, endothelial function, and
. thrombosis
2-Exploring Novel Therapeutic:
future research may explore alternative therapeutic
modalities for inhibiting PCSK9, such as small
molecules, RNA-based approaches, gene edition
technologies
Long-acting Formulations Developing -3 •
longer-acting to reduce the frequency
.of administration

trategies to lower the cost of PCSK9-4 •

inhibitors or increase access to these
. therapies may also be explored
 REFERENCES
• 1.↵ Goldstein JL,
• Hobbs HH,
• Brown MS
• . Familial hypercholesterolemia. The Metabolic and Molecular Bases
of Inherited Disease. 2001:2863–2913.
• Google Scholar
• 2.↵ Slack J
• . Risks of ischaemic heart-disease in familial hyperlipoproteinaemic
states. Lancet. 1969;2:1380–1382.
• 3.↵ Leigh SE,
• Foster AH,
• Whittall RA,
• Hubbart CS,
• Humphries SE
THANKS