LIPID METABOLISM

INTRODUCTION
Lipids are a group of organic compounds which are insoluble in water but soluble in fat solvents
such as ether, alcohol, chloroform and benzene and are utilized during metabolism

IMPORTANCE OF LIPID
1. Reservoirs of high energy value
2. Constituents of cell membrane and cell structures
3. Constituents of nervous tissue
4. Precursors of bile acid
5. Precursors of steroid hormones
6. Form insulating and protective coating

TYPES OF LIPIDS
1. Triglycerides: Stored in adipose tissue, they are a major source of energy.
2. Cholesterol: Important for cell membrane integrity, hormone synthesis, and bile acid
production.
3. Phospholipids: Crucial for the structure of cell membranes.
4. Lipoproteins: Complexes that transport lipids in the blood, including:
○ Chylomicrons: Carry triglycerides from the intestine to tissues.
○ Very Low-Density Lipoproteins (VLDL): Carry triglycerides from the liver to tissues.
○ Low-Density Lipoproteins (LDL): Transport cholesterol to cells (“bad cholesterol”).
○ High-Density Lipoproteins (HDL): Remove cholesterol from tissues to the liver for
excretion (“good cholesterol”).

GENERAL LIPID METABOLISM

Digestion—Absorption—Resynthesis—Metabolism
1. Digestion:
– Lingual lipase and Pancreatic Lipase hydrolyze TG to form FFA and monoglycerol;
Esterase hydrolyze CE to chol. and FFA
2. Absorption:
– FFA and glycerol diffuse into mixed micelles making them soluble and absorbed into
intestinal epithelium
– Chylomicron eventually enters the systemic circulation via the thoracic duct and
gets transported to the liver for metabolism
3. Metabolism:
– LPL hydrolyzes TG to FFA and glycerol.
– Many tissues degrade FFA by beta-oxidation to produce ATP
– Glycerol released is either converted to glycogen or oxidized

CHOLESTEROL
● Introduction
– Only found in animals and humans
– A member of biological compounds known as sterols
– Composed of a four ring structure known as cyclopentanophenathrene ring
– Meat, egg yolk sea food and diary products are sources of cholesterol
– 30-60% dietary cholesterol absorbed daily
– ↑ TG enhances cholesterol absorption
– 90% of synthesis occur in liver and gut
– Newly absorbed cholesterol inhibits synthesis

● Reverse Cholesterol Transport Pathway

– Peripheral cells accumulate cholesterol via uptake of lipoproteins and de novo
cholesterol synthesis
– Most cells do not have a mechanism for catabolizing cholesterol
– Cells that synthesize steroid hormones can convert cholesterol to glucocorticoids
– Intestinal cells can secrete cholesterol into the lumen or on the skin surface
– Most cells therefore require the RCTP to reduce their cholesterol content

LIPOPROTEINS
● Introduction
– A class of macromolecules associated with lipid transport
– Lipoproteins are complex particles that have a central hydrophobic core of non-
polar lipids, primarily cholesterol ester and TG sorrounded by outer hydrophilic
membrane consisting of protein (apolipoprotein), phospholipid and free cholesterol

● Types
○ Chylomicron:
– Produced from the intestine; eletrophoretic mobility-origin, density-<0.95, chol-4%,
protein-1%, TG-88%, contains-apos A, B-48, C and E
○ VLDL:
– Produced in the liver and intestine; mobility-pre-beta, density-<1.006, chol-23%,
 –
protein- 7%, TG-56%, contains apos-B,C and E
○ LDL:
– Produced mainly from VLDL; mobility-beta, density-1.019-1.063, has only apoB-100.
contains TG-20%, 20% protein, 55% cholesterol
○ HDL:
– Produced mainly from the liver and intestine; mobility-alpha, density-1.063-1.210,
has apos A,C,E. Contains 50% protein,chol-20%, TG-5%

● Metabolism
– Lipoproteins transport lipids in 3 separate pathways through the body.
– They are;
1. Exogenous pathway
2. Endogenous pathway
3. Reverse cholesterol transport pathway
– The exogenous pathway transports dietary lipids via chylomicrons to the liver
– The endogenous pathway is responsible for transportation of hepatic lipids via VLDL
and LDL to the peripheral tissues
– Reverse cholesterol pathway employs the use of HDL to transport cholesterol from
peripheral tissue to the liver for excretion or reuse
– LDL can also be degraded by a non-specific pathway
– This pathway is not subject to normal feed back regulation
– With ↑LDL levels, macrophages take up larger amounts of oxidized LDL for
degradation
– Can cause atherosclerotic plaque
– 35-64% of LDL degraded by the regulated pathway
– LDL carries most cholesterol in circulation. Has different sizes
– An abundance of small dense LDL particles are associated with obesity, T2DM,
hyperTG, low HDL, infection and inflammatory disease because;
– They have decreased affinity for LDL receptors
– Are more susceptible to oxidation leading to enhanced uptake by macrophages
– They easily enter the arterial wall and bind more avidly to intraarterial proteoglycan
● Reverse Cholesterol Transport Pathway
– Peripheral cells accumulate cholesterol via uptake of lipoproteins and de novo
cholesterol synthesis
– Most cells do not have a mechanism for catabolizing cholesterol
– Cells that synthesize steroid hormones can convert cholesterol to glucocorticoids
– Intestinal cells can secrete cholesterol into the lumen or on the skin surface
 – Most cells therefore require the RCTP to reduce their cholesterol content

LIPID METABOLISM DISORDERS

Investigation of Lipid Disorders
– Investigating lipid disorder involves the following approach
– To ascertain if the cause of the abnormal lipid is primary or secondary
– Secondary could be screened for by determining TSH, glucose, liver enzymes, kidney
function etc
– If positive, they should be treated for these before therapy for the lipid disorder
● Primary Causes:
– In primary causes, the plasma lipids are usually much higher and the history from
the patient on his family relatives is helpful
– 7.5mmol/L (TC) and > 4.9mmol/L (LDL) are often reported for familial
hypercholesterolaemia
– ↑TC, LDL-C and low HDL-C are risk indicators of CHD
– Serum TC value of <5.2 and LDL-C level of <3.4 mmol/L are desirable
– <0.9mmol/L for HDL-C is considered low
– <1.8 for TG is normal
Better risk assessment index has been put to use. TC/HDL-C ratio is a better predictor of
CHD
– Low risk-3.3-4.4
– Moderate risk-7.1-11
– High risk->11
– Also LDL-C/HDL-C ratio can be used
– Low risk-0.5-3.0
– Moderate risk-3.0-6.0
– High risk->6.0
– Serum Lp (a) has been demonstrated to be an independent risk factor for CHD.
However, there is still need for better standardization

1. Hyperlipidemia
● Introduction
Hyperlipidemia is a general term for elevated levels of lipids (cholesterol and triglycerides)
in the blood.
● Types
It is classified into two types:
○ Primary Hyperlipidemia: Genetic disorders affecting lipid metabolism.
 ○ Primary Hyperlipidemia: Genetic disorders affecting lipid metabolism.
○ Secondary Hyperlipidemia: Caused by lifestyle factors or underlying conditions
(e.g., diabetes, hypothyroidism, obesity).
Common types of hyperlipidemia:
○ Hypercholesterolemia: High levels of cholesterol, particularly LDL, in the blood.
○ Hypertriglyceridemia: Elevated levels of triglycerides in the blood.

● Implications of Hyperlipidemia
– Hyperlipidaemia may or may not be associated with symptoms
– Response to Injury Hypothesis (Atherosclerosis):
– ↑ in plasma lipoproteins especially oxidized LDL and cholesterol would cause toxic
injury to the endothelium
– Results to further attraction and adhesion of monocytes convert to scavenger cells
– They (scavengers) localize sub-endothelially and continue to take up oxidized lipids
– Leads to development of fatty streaks and foam cells

● Management of hyperlipidemia
– For patients with total cholesterol towards the upper limit of normal, dietary therapy may
be advised
– Very high levels of cholesterol especially in association with LDL-C will require both dietary
and drug intervention
– For TG also, vigorous dietary and drug therapy essential for conc. exceeding 10-12mmol/L
● Drugs for Treatment
○ Statins- HMG-CoA inhibitors
– Often preferred bc of its very little side effects; well tolerated
– Inhibits HMG CoA reductase which is involved in chol. Synthesis
– Effective in lowering LDL-C from 20-40%

○ Bile Acid Sequestrants

– Work by binding bile acids making them unavailable for cholesterol absorption
– May have uncomfortable side effects like constipation
– eg- cholestyramine

○ Fibric Acid Derivative

– Bind dietary lipids causing a ↓ in conc.
– ↓TG, ↓VLDL-C & ↑HDL-C
– eg-clofibrate, betafibrate
 ○ Probucol
– Poorly absorbed in the gut and is concentrated in many lipid-rich tissues
– Stops lipid oxidation and macrophage uptake
– Has little influence on TG, lower mainly cholesterol

○ Niacin
– reduce LDL-C & increase HDL-C
– side effects-can be hepatotoxic, hyperuricaemia and glucose intolerance

2. Familial Hypercholesterolemia (FH)

● Cause: Genetic mutations affecting LDL receptor function, leading to reduced clearance of
LDL cholesterol from the blood.
● Consequence: Extremely high LDL levels, resulting in early-onset atherosclerosis and
cardiovascular disease.
● Symptoms: Xanthomas (cholesterol deposits in the skin and tendons), early heart attacks,
and strokes.
● Treatment: Statins, bile acid sequestrants, PCSK9 inhibitors, and lifestyle modifications.

3. Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)

● Cause: Genetic mutation in the apolipoprotein E gene (ApoE), impairing the clearance of
chylomicron and VLDL remnants.
● Consequence: Elevated cholesterol and triglycerides, leading to atherosclerosis and
peripheral vascular disease.
● Symptoms: Xanthomas, premature atherosclerosis.
● Treatment: Lifestyle changes, fibrates, and statins.

4. Familial Chylomicronemia Syndrome (FCS)

● Cause: Deficiency of lipoprotein lipase or apoC-II (necessary for chylomicron breakdown).
● Consequence: High levels of chylomicrons and triglycerides in the blood, leading to
recurrent episodes of acute pancreatitis.
● Symptoms: Severe hypertriglyceridemia, abdominal pain, hepatosplenomegaly, eruptive
xanthomas.
● Treatment: Extremely low-fat diet, omega-3 fatty acids, fibrates.

5. Tangier Disease (Familial Alpha-lipoprotein Deficiency)

● Cause: Mutation in the ATP-binding cassette transporter A1 (ABCA1) gene, leading to
reduced HDL levels.
● Consequence: Decreased ability to transport cholesterol to the liver for excretion, leading
to cholesterol accumulation in tissues.
● Symptoms: Enlarged tonsils with orange discoloration, hepatosplenomegaly, peripheral
neuropathy, and early-onset atherosclerosis.
● Treatment: No specific treatment; management involves reducing cardiovascular risk
factors.

6. Abetalipoproteinemia
● Cause: Mutations in the MTTP gene, leading to defective formation of apolipoprotein B-
containing lipoproteins (e.g., VLDL, LDL).
● Consequence: Inability to absorb dietary fats and fat-soluble vitamins.
● Symptoms: Steatorrhea (fatty stools), failure to thrive, ataxia, retinitis pigmentosa (eye
disease), and peripheral neuropathy.
● Treatment: High-dose vitamin E supplementation, low-fat diet, and fat-soluble vitamin
supplementation (A, D, E, K).

7. Hypolipoproteinemia
● Cause: Genetic disorders leading to low levels of lipoproteins.
● Types:
○ Familial Hypobetalipoproteinemia: Low LDL cholesterol due to mutations in the
APOB gene.
○ Familial Hypoalphalipoproteinemia: Low HDL cholesterol, increasing the risk of
cardiovascular disease.
● Consequence: Increased risk of fatty liver disease and cardiovascular disease.
● Treatment: Treatment focuses on managing cardiovascular risk factors and improving lipid
profiles.

8. Dyslipidemia
● Introduction
– Abnormal circulating levels of lipids and lipoproteins caused by either genetic or
environmental factors affecting the synthesis, clearance or catabolism of
lipoproteins in circulation

● Types and their Example

– Primary or Secondary
 ○ Primary Dyslip:
Is caused by inherited defects in lipoprotein formation, transportation or
degradation
Types:
– Hyperchylomicron: caused by LPL and apo C11 deficiency
– HyperLDL: caused by familial deficiency of apo B-100
– HyperLDL&VLDL: caused by deficiency of apo E
– HyperVLDLnemia: caused by deficiency of apoB-100 and LPL
– Mixed lipaemia: caused by deficiency of LPL, apoC-11, CETP

○ Secondary Dyslip:
Due to underlying disorder leading to alteration in lipids and lipoprotein levels
Examples:
1. Liver diseases
2. Diabetes mellitus
3. Alcoholism
4. Hypothyroidism and Hyperthyroidism
5. Other hormonal changes
6. Nephrotic syndrome

CORONARY HEART DISEASE

● Introduction
– Coronary Heart Disease (CHD), also known as coronary artery disease (CAD), is a
condition in which the coronary arteries that supply blood to the heart muscle
become narrowed or blocked due to the buildup of fatty deposits (atherosclerosis).
This impairs blood flow to the heart, leading to chest pain (angina), heart attacks
(myocardial infarction), and other complications.

● Risk Factors
1. Age
2. Gender
3. Smoking
4. Hypertension
5. Physical Inactivity
6. Stress
7. Family History-Heredity
● Modifiable Risk Factors
1. Hyperlipidaemia
2. Smoking
3. Hypertension
4. Stress
5. DM
6. Obesity
7. Physical Inactivity
8. Diet high in saturated fat & cholesterol

● Non-Modifiable Risk Factors

1. Heredity-certain family groups susceptible to premature atherosclerosis
2. Age-↑risk with↑ age
3. Gender-males more susceptible to atherosclerosis than females

● Symptoms of Coronary Heart Disease

The symptoms of CHD may vary depending on the severity of the condition and the
degree of artery blockage.
1. Angina (Chest Pain)
2. Shortness of Breath
3. Heart Attack (Myocardial Infarction)
4. Fatigue
5. Heart Failure