Lipid metabolism in Health and

Disease: Plasma lipids, Lipid Profile

in diseases.

DR DADA A.O.

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 CONTENTS
• Lecture Objectives
• Introduction
• What are plasma lipids?
• What are plasma lipoproteins?
• What are the types of lipoproteins
• Lipoprotein metabolism
• Lipid and Lipoprotein Disorders
• Clinical features and treatment of lipid
disorders
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 OBJECTIVES
• Students should be able to differentiate plasma
lipids from plasma lipoprotein
• Students should be able to identify the various
lipoproteins
• Students should understand lipoprotein
metabolism and the various pathways
• Students should know the various lipid disorders
• Students should understand the clinical features,
usefulness of lipid profile test and treatment

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INTRODUCTION
•Lipidology is the study
of abnormal lipid
metabolism
•Lipids are everywhere
in the body
•Perform critical role in
almost all aspects of
biological life
•Present in food
(exogenous), or
synthesized in the body
(endogenous)
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 WHAT ARE PLASMA LIPIDS?
• Organic compounds poorly soluble in water
but soluble in organic solvents
• Four main types of lipids in the body
– Cholesterol
– Fatty acid
– Triglyceride
– Phospholipid

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 WHAT ARE PLASMA LIPIDS?
• Fatty acids
– Occur as straight chains
– Can be saturated (no double bonds, mono-unsaturated or
polyunsaturated (containing one or more double bonds)
– Can esterify with glycerol == Triglyceride
– May occur as non esterified or free (NEFA)
– Fatty acids are not found in a free state in nature;
commonly they exist in combination with glycerol (an
alcohol) in the form of triglyceride.
– By the action of lipase on adipose tissues, NEFA is
released, bound to albumin and transported to liver and
muscle
– Lipolysis takes place in the cytoplasm and it is a process
whereby triglyceride is broken down to fatty acids and
glycerol.

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 WHAT ARE PLASMA LIPIDS?
• Fatty acids
• The resulting fatty acids are oxidized by β-oxidation into
acetyl CoA, which is used by the Krebs cycle; while the
glycerol that is released from triglycerides after lipolysis
directly enters the glycolysis pathway as DHAP.
• Fatty acids can be short chain (4-8 carbon); medium chain
(10-14 carbon) and long chain (14-18 carbon)

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 WHAT ARE PLASMA LIPIDS?
• Cholesterol
– A sterol derivative, and the main sterol in animals
– High molecular weight solid alcohol
– Has tetracyclic perhydrocyclopentanophenanthrene skeleton
– A molecule contains 27 carbon atoms
– The starting point in many metabolic pathways (steroid hormone,
vitamin D, bile acid) making it a precursor of bile acids and steroid
hormones
– About 50% of normal dietary intake is absorbed while the rest is
excreted in the faeces
– About 250-750mg per day is ingested in the average western diet;
about twice this amount is synthesized by body cells per day
– Exist in two forms in the plasma: Free and esterified (which makes it
further less soluble in water.

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 WHAT ARE PLASMA LIPIDS?
• Cholesterol
– 3-hydroxy-3-methylglutaryl coenzyme A reductase
(HMG-CoA reductase) is the rate limiting enzyme
in cholesterol synthetic pathway
– The enzyme is controlled by negative feedback
through the intracellular cholesterol concentration
• Phospholipid
– Complex lipid
– Similar to triglycerides in structure but contains
phosphate and nitrogenous base in place of one
of the fatty acids

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 WHAT ARE PLASMA LIPIDS?
• Triglyceride
– A product of the
esterification of glycerol
and fatty acids
– Dietary fat is in the form
of triglyceride
– Neutral fat that does not
mix with water
– The form in which fatty
acids are stored in the
body (adipose tissue)
and transported in the
plasma (Chylomicron)

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 WHAT ARE PLASMA LIPOPROTEINS?
• Lipoproteins (LP) are spherical soluble protein-lipid
complexes
• This is the form in which lipids are transported in the
body
• The water soluble groups of proteins, phospholipids
and free cholesterol face outwards and surround an
inner insoluble core of triglyceride and cholestrol
esters.
• The classification of LP is based on their density which
is inversely related to their size/volume (Density= M/V)
• The greater the lipid:protein ratio, the larger the size
and the lower the density

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 WHAT ARE PLASMA LIPOPROTEINS?
• Chylomicrons
– largest & least dense.
– Transports exogenous lipids from intestine to cells of the body
– form creamy layer on plasma at 4 degree centigrade.
• VLDL
• transport endogenous lipid from liver to cells.
• IDL
• transient , not normally present in plasma, formed during the conversion of
VLDL to LDL
• LDL
– mainly cholesterol; carries cholesterol to cells. LDL2 & LDL3 – Smaller
molecules, more atherogenic and more easily oxidized than larger LDL1.
• HDL
– most dense, involved in the transport of cholesterol back to liver from cells.
Other types are HDL2 & HDL3.
N.B: Fasting plasma contains only VLDL, LDL & HDL particles.

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 WHAT ARE PLASMA LIPOPROTEINS?
• Proteins in Lipoproteins are called Apoproteins.
• Functions of Apoproteins
– AI: Chylomicrons & HDL: LCAT activator
– A2 : Chylomicrons & HDL: LCAT activator
– B48: Chylomicrons : Identification of
chylomicron remnant by the LDL receptors in the liver
– B100: IDL, VLDL, LDL: LDL receptor binding
– C2: Chylomicrons & VLDL: Lipoprotein lipase activator
– C3: Chylomicrons, HDL, VLDL, IDL: Lipoprotein lipase
inhibitor -
– E: Chylomicrons, HDL, VLDL, IDL: IDL & remnant particle
receptor binding

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 WHAT ARE PLASMA LIPOPROTEINS?
• Apo A, Apo B, Apo C, Apo D, Apo E all
synthesized in the liver

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 WHAT ARE PLASMA LIPOPROTEINS?

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 WHAT ARE PLASMA LIPOPROTEINS?
• CHYLOMICRON
– Density is 0.93g/ml
– MW: 0.4-30x109 g
– Diameter: >70mm
– Electrophoretic mobility: origin
– Composition by % weight:
• Cholesterol unesterified:2
• Cholesterol esterified: 5
• Phospholipid: 7
• TG: 84
• Protein: 2
– Apoproteins: A, B48, C
– Half Life: 8hours
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• VLDL
– Density is 0.97g/ml
– MW: 5 – 10 x109 g
– Diameter: 25-75mm
– Electrophoretic mobility: Pre beta
– Composition by % weight:
• Cholesterol unesterified: 5-8
• Cholesterol esterified: 11-14
• Phospoholipid: 20-23
• TG: 44-60
• Protein: 2
– Apoproteins: B100, C
– Transports hepatic
synthesised TG & Cho
– Half life: 1-3hours
16
 WHAT ARE PLASMA LIPOPROTEINS?
• LDL
– Density is 1.003g/ml
– MW: 2.75x109 g
– Diameter: 19-22mm
– Electrophoretic mobility: beta
– Composition by % weight:
• Cholesterol unesterified: 13
• Cholesterol esterified: 39
• Phospholipid- 17
• TG – 11
• Protein – 20
– Apoproteins: B100, E
– Half life: 24-48hours
– Catabolized in the liver &
peripheral tissues
– Intracellular freecholesterol
regulates cholesterol
homeostasis
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• IDL
– Density is 1.003g/ml
– MW: 3.9 - 4.8 x 109 g
– Diameter: 22-24mm
– Electrophoretic mobility: broad beta
– Composition by % weight:
• Cholesterol unesterified-8
• Cholesterol esterified – 22
• Phospholipid- 25
• TG – 30
• Protein – 15
– Apoproteins: B100, E
– Short lived
– Cholesterol amount is equal to
TG
– Apo E determines the
continued catabolic process of
IDL to LDL
17
 WHAT ARE PLASMA LIPOPROTEINS?
• HDL • HDL and LDL can be
– Density is 1.12g/ml precipitated and
– MW: 1.75-3.6 x 105 g
– Diameter: 4-10mm
measured.
– Electrophoretic mobility: Alpha • Friedewald Equation:
– Composition by % weight: – LDL- cholesterol = Total
• Cholesterol unesterified: 6
cholesterol - HDL-chol -
• Cholesterol esterified: 13
• Phospholipid- 28 TG/2.2
• TG – 3 – Equation applies if TG is
• Protein – 50 equal or less than 5.O
– Apoproteins: A, C, E mmol/L .
– Half life: 5days
– Has 3 subtypes: HDL-C,
HDL-2, HDL-3

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 LIPOPROTEIN METABOLISM
• HDL – reverse cholesterol transport
– carries cholesterol from non hepatic cells to the liver – reverse
cholesterol transport.
– HDL is synthesized in both intestine and hepatic cells. It is secreted
as small, nascent HDL particles rich in free cholesterol,
phospholipids, apo A & E
– HDL can be formed from surface coat of VLDL and chylomicrons.
– Factors that affect HDL synthesis include oestrogen- higher in
menstruating women than menopausal women or men.
– HDL is cardio protective.
– HDL<1.0mmol/L increases cardiovascular risk; HDL value can be
increased by lifestyle changes like smoking cessation, regular
exercise and weight loss.
– Low HDL is seen DM2, Obesity and metabolic syndrome which are
also at increased risk factors for cardiovascular disease

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 LIPOPROTEIN METABOLISM
• HDL – reverse cholesterol transport.
• HDL is cardioprotective due to the following reasons:
1. Reverse Cholesterol system
2. Increased atherosclerotic plaque stability
3. Protection of LDL from oxidation
4. Maintenance of the integrity of vascular endothelium
• LCAT is present on HDL and catalyses the esterification of free
cholesterol
– It is activated by apo AI, the predominant apoprotein in HDL.
– Most of the esterified cholesterol is transferred to LDL, VLDL and
chylomicron remnants which ultimately ends up in the liver.
– Some may be stored within the core of HDL particles and taken to the
liver.
• Cholesterol ester transfer protein (CETP) is involved in this
process. The HDL derived cholesterol can be off loaded in the
liver and secreted in bile or taken up and utilized for steroid
synthesis. Inverse relationship exists between HDL & TG.

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 LIPOPROTEIN METABOLISM
• Exogenous Pathway
– Chol. and FA released from dietary fats by digestion
together with bile are absorbed into intestinal mucosa
cells where they are esterified to form cholesterol
esters & TG.
– These together with phospholipids, apo A & apo B48
are then secreted into lymphatic system as
chylomicrons.
– Secretion is dependent on apo B48.
– Chylomicron enters systemic circulation via thoracic
duct where apo C & E, derived from HDL, are added to
chylomicrons in the lymph & plasma.
– Lipase in capillary walls is activated by apo C2.
– It hydrolyses TG to FA and glycerol.
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 LIPOPROTEIN METABOLISM
• Exogenous Pathway
– TG is taken up by adipose and muscle cells or bound to
albumin in plasma while Glycerol enters hepatic glycolytic
pathway.
– Chylomicron particles get smaller and release some apo A
and C with phospholipids which then become incorporated
to HDL particles.
– Chylomicron remnants enriched in apo B & E and
cholesterol bind rapidly to hepatic LDL receptor related
protein, which recognizes apo B/E (endocytosis)
– Within the hepatic cells, cholesterol is used/repackaged
with apo B100 (VLDL)
– TG delivered to the liver undergoes β-oxidation to provide
energy for the biosynthetic activity of the liver.

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 LIPOPROTEIN METABOLISM
• Endogenous Pathway
– Liver is the main source of endogenous lipid.
– TG is synthesized from Fatty acid and glycerol, which may be derived
from fat stores and glucose, respectively.
– Hepatic cholesterol can either be derived from chylomicrons remnants
via exogenous pathway or synthesized.
– Lipids are transported from liver as VLDL – a large TG rich particle
consisting also apo B100, apo C & apo E.
– Following hepatic release/secretion of VLDL, it incorporates additional
apo C from HDL particles within the circulation.
– VLDL is hydrolysed by Lipase in peripheral tissues → VLDL remnants or
IDL which contains cholesterol & TG as well as apo B100 and apo E.
– VLDL remnants are rapidly taken up by the liver or converted by the
action of hepatic lipase to LDL by losing apo E & TG.

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 LIPOPROTEIN METABOLISM
Endogenous Pathway
• LDL is cholesterol rich-and contains only apo B100.
• It represents 70% of total plasma Cholesterol concentration.
• It can be taken up by most cells, but mainly by the liver.
• LDL or B/E receptor of the liver recognizes and binds apo B of LDL →
particles broken down by lysosomes releasing cholesterol.
• Cholesterol can be incorporated to cell membrane or used in steroid
synthesis – adrenal cortex or ovary.
• Feedback control system in the liver to avoid accumulation of cholesterol
is by reducing rate of synthesis of LDL receptor if plasma cholesterol is
excessive.
• LDL causes damage to tissues as seen in atheroma formation.
• Alternative route for removal of LDL – via the reticuolendothelial system
(Scavenger cell pathway) which only recognizes modified LDL e.g. oxidized
form.

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 Lipid and Lipoprotein Disorders:
Hypercholesterolemia
• Primary Causes • Secondary Causes
– Obstructive Jaundice
• Familial
– Nephrotic Syndrome
Hypercholesterolemia
– Hypothyroidism
• Familial combined – Dysglobulinemia
hyperlipoproteinemia
– Cushings Syndrome
• Polygenic – Acute Intermittent
Hypercholesterolemia Porphyria

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 Lipid and Lipoprotein Disorders:
Hypertriglyceridemia
• Primary Causes • Secondary Causes
• Familial – Alcoholism
Hyperchylomicronemia – DM
• Primary – Obesity
Hyperprebetalipoproteinemia – OCP
– Pregnancy
• Hyperchylomicronemia &
– Nephrotic Syndrome
Hyperprebetalipoproteinemia
– Renal Failure
• Familial combined – Glucocorticoid
hyperlipoproteinemia therapy
– Glycogen Storage
Disorders

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Lipid and Lipoprotein Disorders:
Hypertriglyceridemia
• Mechanism of hypertriglyceridaemia include:
– Nephrotic Syndrome: ↓decreased clearance and
↑biosynthesis
– Excessive alcohol intake and high carbohydrate intake:
↑ hepatic secretion of VLDL, impaired lipolysis, and
↑FFA fluxes from adipose tissue to the liver
– Renal Failure: ↓decreased clearance
– glycogen storage diseases such as von Gierke’s
disease, which is caused by mutations in glucose-6-
phosphatase: The inability to mobilize hepatic glucose
during fasting → hypoinsulinemia and increased
release of free fatty acids from adipose

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 Lipid and Lipoprotein Disorders:
Hypertriglyceridemia
 Glucocorticoid excess: ↑ VLDL synthesis and
hypertriglyceridaemia. Patients with Cushing syndrome
can also have mild elevations in plasma LDL-C
 Hypothyroidism: associated with elevated plasma LDL-C
due primarily to a reduction in hepatic LDL receptor
function and delayed clearance ofLDL. Conversely, plasma
LDL-C is often reduced in the hyperthyroid patient.

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 Lipid and Lipoprotein Disorders:
Hyperlipoproteinemia
• Secondary hyperlipidaemia (caused by other
diseases) :
• Causes- DM, Obesity, Alcohol, Oestrogen, Beta
blockers, Thiazide, Von Gierke’s Disease, SLE,
Thyroid dysfunction, eg. Primary hypothyroidism,
Cholestasis, Renal failure,eg. Nephrotic
syndrome, Anorexia nervosa, Drugs or Toxins eg.
Ciclosporin, Chlorinated hydrocarbons.
•

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 Lipid and Lipoprotein Disorders
• Disorders of Lipid Metabolism-
• Fredrickson's classification of hyperlipidaemias was based
on electrophoretic mobility as –alpha(HDL), pre–B(VLDL), B
(LDL) and Chylomicrons. This was not a diagnostic
classification.

• Type I: ↑Chylomicron Chylomicrons, HDL

• Type IIa: ↑B LDL
• Type IIb: ↑B & pre – B VLDL & LDL
• Type III: ↑Broad B IDL
• Type IV: ↑pre– B VLDL
• Type V: Chylomicrons Chylomicrons, VLDL,
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 Lipid and Lipoprotein Disorders
• Primary Hyperlipoproteinaemias-
• The causes are complex , including combination of genetic factors and dietary factors as well
as environmental factors.
• Chylomicron syndrome –
– due to familial lipoprotein lipase deficiency,
– an autosomal recessive disorder.
– Presentation as a child with abdominal pain is typical.
– Gross elevation of triglycerides due to accumulation of uncleared chylomicron.
– Lipid stigmata include eruptive xanthomata, hepatomegaly and lipaemia retinalis.
– Treatment includes a low fat diet.
• Familial hypercholesterolaemia-
– Inherited as autosomal dominant trait.
– Inheritance of one mutant gene that codes for LDL receptor results in impaired LDL
catabolism and hypercholesterolaemia.
• Familial defective apo B3500 –
– Due to mutation in the apoB gene,
– This leads to replacement of arginine at 3500 amino acid position for glutamine
– ApoB is the ligand on LDL particle for the LDL receptor.
– It is associated with hypercholesterolaemia and premature coronary artery disease.

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 Lipid and Lipoprotein Disorders
• Familial combined hyperlipidaemia –
– Autosomal dominant trait and increased of coronary artery disease in
family members.
– Lipid may not be significantly elevated; cholesterol 6-9mmol/L and
triglyceride 2-6mmol/L.
• Familial hypertriglyceridaemia –
– Low HDL concentration. Develops after puberty and rare in childhood. Overproduction of
VLDL.
• Type III Hyperlipoproteinaemia –
– Reduced clearance of chylomicron and VLDL remnants.
• Polygenic hypercholesterolaemia -
– One of the most common causes of hypercholesterolaemia. It is a result of complex
interaction between multiple environmental and genetic factors. LDL is raised and no tendon
xanthomata.
• Hyperalphalipoproteinaemia-
– Results in elevated plasma HDL and can be inherited as autosomal dominant condition. Total
cholesterol can be elevated with normal LDL cholesterol.

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 Lipid and Lipoprotein Disorders
• Others:
• -Inherited disorder of low plasma HDL (Hypoalphalipoproteinaemia)
e.g. Apo A1 deficiency, associated with premature cardiovascular
disease.
• -Tangier’s disease – very low HDL, Defect in the ABC1 gene involved
in HDL transport.
• -Abetalipoproteinaemia-LDL deficiency with impaired chylomicron
and VLDL synthesis.
• -LCAT deficiency- accumulation of free unesterified cholesterol in
tissues results in corneal opacities, renal damage , premature
atherosclerosis and haemolytic anaemia.
• -Fish eye disease- LCAT defect, low HDL and eye abnormalities.

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 CLINICAL FEATURES
• Acute coronary heart
disease
• Diabetes mellitus
• Hypertension
• GIT symptoms
(pancreatitis)
• Obesity
• Xanthomas and other skin
lesions
• Corneal arcus,
Xanthelasma other eye
symptoms

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 INVESTIGATIONS
• Plasma lipids should not be assessed in
patients who are acutely ill, for example acute
myocardial infarction, as plasma cholesterol
concentration may be decreased due to the
acute-phase response.
• Wait for about 3 months after the event,
although if a sample is taken within 12 h of an
event, a ‘true’ result may be obtained.

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 INVESTIGATIONS
• Investigations include: • Other Investigations:
– Lipid profile – History of alcohol,
– FPG, Glucose studies medications and analysis
– Liver function test of same
– Thyroid function test
– Plasma and Urinary
proteins
– Dynamic function tests
for test
– Electrolytes, urea,
creatinine
– Genetic studies
– CRP
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 TREATMENT
• Life-style change, diet and exercise
• Treatment of secondary hyperlipidaemias
• Treat primary disease as well as lowering lipid.

• Statins: Their mode of action is primarily via inhibition of HMG-CoA

(hydroxymethylglutaryl-coenzyme A) reductase, the rate-limiting enzyme in the
cholesterol biosynthesis pathway.
• Fibrates: Promote receptor-mediated clearance of LDL after stimulating its
secretion, causing this catabolism to occur at a 20% greater rate compared to an
untreated patient. This action results in an overall decrease in VLDL, increase VLDL
catabolism, fatty acid oxidation, and elimination of triglyceride rich particles by
enhancing synthesis of lipoprotein lipase, which in turn results in 30-60% decrease
in total plasma triglycerides; HDL may increase modestly in some
hypertriglyceridemic patients
• Bile Salt Sequestrants: bind to the negatively charged bile acids in the intestine,
inhibiting their lipid solubilizing activity and thus blocking cholesterol absorption.

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 TREATMENT
• Ezetimibe: Potent and selective inhibitor of cholesterol absorption that has been
shown to reduce the overall delivery of cholesterol to the liver, thereby promoting
the synthesis of LDL receptors, with a subsequent reduction of serum LDL-C.
• Nicotinic acid: Decreases the fractional catabolic rate of HDL-apo AI without
affecting the synthetic rates. Additionally, niacin selectively increases the plasma
levels of Lp-AI (HDL subfraction without apo AII), a cardioprotective subfraction of
HDL in patients with low HDL.
• Omega-3 fats: By increasing the amount of lipoprotein lipase and decreasing LDL,
VLDL, and chylomicron size, triglycerides can be lower in hypertriglyceridemia
patients.

Drugs Chol. TG HDL LDL

• Statins RRR R H RRR
• Fibrates R/- RRR HH R/-
• Bile salt-sequestrants R H/- H R
• Ezetimibe R R H R
• Nicotinic acid RR RRR HHH RR
• Omega-3 fats R/- RR H R/-

R- Reduced, H- Increased, - Normal.

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 – THANK YOU
– QUESTIONS

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 REFERENCES
• Slide 1:
https://www.broadlearnings.com/lessons/lipids/
• Slide 15 and 27:
https://www.google.com/url?sa=i&url=https%3A
%2F%2Fwww.shutterstock.com%2Fsearch%2Flip
oprotein-structure&psig=AOvVaw2-
XFCRw2tWpvDAksfX0-
LE&ust=1690477508847000&source=images&cd
=vfe&opi=89978449&ved=0CBEQjRxqFwoTCODu
orqBrYADFQAAAAAdAAAAABAE

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