Lecture-5:

Hyperlipidemia
Lipids
 Lipids are water insoluble organic molecules that play important roles in
the body.
 There are many types of lipids, most important of them are:
 Cholesterol
 Triglycerides
 Phospholipid
Lipoproteins
 Lipids require carriers for their transport in the blood, as they are insoluble in
water. These carriers are known as lipoproteins.
 Thus, lipoproteins consist of:
1. Lipids such as Cholesterol, Cholesterol esters, Triglycerides, Phospholipid
2. Proteins known as apo-protein, such as apo-A, apo-B etc.

Types of Lipoproteins
 Triglyceride (TG) carrying lipoproteins
1. Chylomicrons (CM)
2. Very Low Density Lipoproteins (VLDL)

 Cholesterol (C) carrying lipoproteins

1. Low Density Lipoprotein (LDL)
2. High Density Lipoprotein (HDL)
 Metabolism of Lipoproteins
Acetyl-CoA

HMG-CoA
Bile acids
+ Cholesterol
Dietary lipid

Cholesterol
Bile acids

Via lymph
Bad cholesterol:
LDL-cholesterol is called bad cholesterol since it can build up within the walls
of the arteries, forming plaque. This plaque restricts blood flow to the heart and
brain, increasing the chances of having a heart attack or brain stroke.

Good cholesterol:
HDL-cholesterol is called good cholesterol since it helps the body to remove
free-cholesterol from extra-hepatic tissues.
Hyperlipidemia
 Hyperlipidemia means high serum lipids (e.g. cholesterol, TG) that may
increase the risk of different types of coronary heart diseases.

 Caused by:
1. Genetic abnormalities:
Apoprotein synthesis may be stopped. In the absence of Apo C-II,
lipoprotein lipase (LPL) enzyme has no activity.
LDL receptors absent or defective.

2. Environmental factors:
Diet enriched in saturated fat and cholesterol, but low in fiber.
Metabolic disorders such as Diabetes, Obesity, Hypothyroidism.
 Classification of Hyperlipidemia

Depending on the causes, hyperlipidemias are of two types:

1. Primary: Resulting from a single inherited gene defect, or more commonly,

are caused by a combination of genetic and environmental factors.

2. Secondary: Resulting from a more generalized metabolic disorder; such as

diabetes mellitus, obesity, hypothyroidism, or primary biliary cirrhosis.
 Fredrickson classification of primary hyperlipidemia
Hyperlipidemia Common Name Lipoprotein Lipid Elevated
Type Elevated Major Minor

Type I Hyper chylomicronemia CM TG ↑↔ C

Type IIa Hypercholesterolemia LDL C -

Type IIb Mixed Dyslipidemia LDL, VLDL C TG

Type III Dysbetalipoproteinemia IDL C, TG -

Type IV Hypertriglyceridemia VLDL TG ↑↔ C

Type V Mixed Hypertriglyceridemia CM, VLDL TG ↑↔ C

CM = Chylomicron; LDL = Low Density Lipoprotein; VLDL = Very Low

Density Lipoprotein; IDL = Intermediate Density Lipoprotein; C = Cholesterol;
TG = Triglyceride; ↑↔ = Elevated or normal
 Lipid profile

Lipid/Lipoproteins Reference value

Total-cholesterol 120-200 mg/dL

Triglycerides (TG) < 150 mg/dL

LDL-C < 130 mg/dL

HDL-C > 40 mg/dL

Ref: AACC, 2015; National Cholesterol Education Program (NCEP), 2001.
Management of Hyperlipidemia
1. Diet and Exercise
 Diet rich in cholesterol, high carbohydrate, red meat should be
restricted.
 Dairy food and excessive alcohol should be restricted.
 Vegetables, fibers, fruits and marine fish should be eaten more.
 Walking regularly

2. Drugs
 Antihyperlipidemic drugs
 Antihyperlipidemic drugs
Drug Class Examples Principal Mode of Action
Statins Simvastatin Decrease Cholesterol synthesis by
Atorvastatin inhibiting HMG CoA reductase, resulting
Fluvastatin in increased LDL receptor synthesis
Rosuvastatin

Fibrates Gemfibrozil Decrease hepatic production of VLDL .

Fenofibrate Increase lipolysis of serum TG by
increasing lipoprotein lipase activity
Cholesterol Ezetimible Reduces cholesterol absorption at the
absorption inhibitors brush border membranes in the intestinal
lumen, resulting in less plasma LDL.

Bile acid Cholestyramine Inhibit reabsorption of bile acids while

sequestrants Colesevelam increase their excretion through feces,
Cholestipol resulting in decrease of plasma LDL

Nicotinic acid (Niacin or Vitamin B3) Decrease hepatic production of VLDL

 Sites of actions of antihyperlipidemic drugs

Acetyl-CoA
HMG-CoA
reductase
HMG-CoA
❶ (-) ❶
Bile acids (+)
+ Cholesterol
Dietary lipid (+) Cholesterol
Bile acids
❹

(-) ❷
❺
(-) ❸
Via lymph

(+)
❷

❶ Statins
❷ Fibrates
❸ Cholesterol absorption inhibitor
❹ Bile acid sequestrants (+) Promote
(+) ❷
❺ Nicotinic acid (-) Inhibit
Cholesterol Biosynthesis in Liver cells

HMG-CoA reductase
 Cellular Cholesterol homeostasis

VLDL
③ Blood cholesterol

remnants
(IDL)

LDL

LIVER CELL
 Statins: Mechanism of Action
Decrease cholesterol biosynthesis by inhibiting HMG-CoA reductase enzyme.
Depletion of intracellular cholesterol causes hepatic cells to up-regulate LDL -
receptors. This results in increased LDL-receptor mediated hepatic uptake of
LDL, thus reduces the level of circulating cholesterol.

Features:
1. Statins mainly indicated
in Hyperlipidemia Type
IIa and IIb.
2. Drugs of choice for LDL
reduction.
3. Reduce cardiovascular
mortality.
4. Less beneficial for
homozygous familial
hypercholesterolemic
patients lacking
functional LDL-receptors.
5. Contraindicated in
pregnancy.
 Fibrates: Mechanisms of Action
Liver Circulation
↑ Apo A-I
HDL
↑ Apo A-II

CMR/IDL
LPL
LDL ↓ TG VLDL
↓ FFA ↑ LPL
↑ Acetyl CoA
synthase
Acetyl CoA LDL

Fig. 1 Fig. 2

1. Inhibit triglyceride (TG) synthesis; reduce production of VLDL and thus their
release into the circulation.
2. Increase lipoprotein lipase activity, which catabolizes chylomicrons and VLDL.
Thus,increase their clearance and decrease plasma TG level.
3. Increase HDL production through improved Apo A-I and Apo A-II synthesis.
Features of fibrates
1. Mainly decrease plasma TG, and also tend to reduce LDL-C and raise
HDL-C.
2. Adjunctive therapy to diet.
3. Hypertriglyceridemia (Type IV and V), Combined hyperlipidemia (Type IIb)
with low HDL-C.
4. Adverse effects: GI upset, cholelithiasis, myositis
5. Contraindications: Hepatic or renal dysfunction, pre-existing gallbladder
disease.
How is cholesterol absorbed?
Mechanism of action: Cholesterol absorption inhibitor (Ezetimible)

1. Enterohepatic circulation
of Cholesterol.
2. Enlarged view of
intestinal lumen and
brush border.

Reduces cholesterol
absorption by binding to
cholesterol transporter at the
brush border membranes in
the intestinal lumen.

Reduction of cholesterol
absorption results in less LDL
in the circulation.
 Bile acids: Enterohepatic Recirculation

(Bile acid reabsorption)

(Bile acid excretion)

 Mechanism of action: Bile Acid Sequestrants
Bile Acid ↑ Synthesis of BA
↓ BA Pool
Sequestrants from Cholesterol

↓ Intrahepatic
Cholesterol Pool

↑ LDL-Receptor
Expression

↑ VLDL/LDL
Clearance

↓ Plasma LDL-C

The liver uses cholesterol to produce bile acids (BA). Bile acid sequestrants bind to
bile acids, inhibit reabsorption of bile acids while increase their excretion through
feces. When bile acid levels are reduced, the liver starts to take cholesterol from the
bloodstream to make more bile acids, resulting in decrease of plasma LDL-C level.
 Mechanism of action: Niacin
Niacin
↓ FA mobilization from ↓ FA synthesis/
Adipose tissue Esterification

↓ TG synthesis

Niacin (-) ↓ Assembly of Apo B –containing lipoproteins

↑Apo B degradation

↓ VLDL production/release

↓ Lipolysis of VLDL to LDL

↓ Plasma LDL
1. Decreases hepatic production of VLDL. Consequently, VLDL release into the
circulation decreases and the reduced plasma VLDL results in reduced lipolysis to
LDL. Net result is the decrease in plasma LDL level.
2. Also reduces HDL clearance, but not reduces HDL synthesis, thus resulting in
increased plasma HDL levels.