•DISORDERS OF LIPID

METABOLISM
 Objectives
• Understanding of normal metabolism of lipids
essential to an understanding of abnormal metabolism.
These lectures will present:

• - an overview of normal lipid metabolism

• - the role of hyperlipidaemia in atherosclerosis

• - an approach to investigating lipid abnormalities

•
• - a review of disorders of lipid metabolism
 BACKGROUND

– Defects of lipid metabolism cause significant

morbidity and mortality

– Hypercholesterolaemia and hypertriglyceridaemia

associated with increased risk of atherosclerosis
leading to coronary artery disease

– Hypertriglyceridaemia predisposes to pancreatitis

 Background
• Lipids are substances of diverse chemical
structure which are insoluble in aqueous
media
• Yield fatty acids & complex alcohols after
hydrolysis (eg glycerol)
• May contain charged or polar groups that
make them amphipathic & ideal for placement
in cell membranes
 Background
• Lipids are broadly subdivided into:
– Cholesterol
– Fatty acids
– Acylglycerols
– Sphingolipids
– Prostaglandins
– Terpenes
 Cholesterol
• Key component of cell membranes

• Synthesized de novo from acetyl CoA with HMG

CoA reductase as the rate limiting step

• Synthesis regulated by intracellular cholesterol

levels

• 90% of chol synthesis takes place in liver and GIT.

 Cholesterol
• Free chol cytotoxicity minimised by
esterification (mediated by ACAT within cells
and by LCAT on HDL)

• Liver central in chol metabolism:

– Bile acids synthesis
– Free chol in bile
– Re-secreted in lipoproteins
 Fatty Acids
• C12-C26 fatty acids with even number of C-
atoms important for human nutrition

• Catabolised through beta oxidation

• Ketogenesis arises when formation of acetyl

CoA exceeds oxaloacetate supply.
 Acylglycerols
• Glycerol backbone onto which FA’s can be esterified to
each or any of the 3 carbons (mono/di/tri –glycerides.

• Trigs from plant sources unsaturated and liquid at

room temp.

• Animal trigs usually saturated and solid at room

temperature

• Storage & transport form of energy

 Acylglycerols

• Derived from dietary fatty acids , de novo

synthesis and from FA’s from adipose tissue
 Sphingolipids
• Sphingosine to which a fatty acid may be
attached to form a ceramide (an intermediate
compound in the formation of):

– Sphingomyelin

– Galactocylceramide

– glucosylceramide
 Prostaglandins
• Derivatives of fatty acids (Arachidonic acid)

• Hormone like action but are synthesized at the

site of action in almost all tissues.
 Terpenes
• Five carbon units which include vitamins A, E
and K.
 Lipoproteins
• Lipids
– hydrophobic and insoluble in water.

– transported in plasma therefore, as lipoproteins

– Core (triglyceride and cholesterol esters) surface

(phospholipids, free chol and proteins)
Lipoproteins
 Lipoproteins
• Vary in size, density and electrophoretic mobility.
• Chylomicrons, VLDL IDL LDL HDL
– Origin preβ broad β β α

• Physicochemical properties determined by

relative content of Tg, chol, ppl and apoprotein.

• Lipid content metabolised during circulation and

apoprotein is exchanged
 lipoproteins
lipoprotein Density Ep mobility apoproteins Content Function(s)
g/ml
chylomicron <0.96 Origin (-0 A, B48,C,E 90% TG, 4% Carries
CHOL, 2% dietary TG
PROTEIN
vldl 0.96-1.006 Pre Beta B100, C, E 60% TG, Carries
20% CHOL, Endogenous
10% PROT TG
idl 1.006–1.019 Broad beta B100, E 30% CHOL,
30% TG ,15
% PROT
ldl 1.019-1.063 beta B100 50% CHOL, Carries chol
25% PROT,
5% TG
hdl 1.063-1.21 Alpha (+) A, C , D, E 20% CHOL Reverse chol
50% PROT transport
5% TG
Lipoproteins
 Apoproteins
• Proteins occurring in complexes with lipids

– Structural role

– Necessary for release and synthesis of lipoproteins

– Co-factors for lipid metabolising enzymes

– Receptor binding

• Most apolipoproteins transfer between lipoproteins

 apoporoteins
apolipoprotein Site of synthesis Found in lipoproteins functions

(a) liver LP (a) unclear

A-I git, liver hdl, chylo structural in hdl

activates lcat

A-II git, liver hdl structural in hdl

B-48 git chylo structural in chylo

B-100 liver vldl idl ldl receptor binding

structural in vldl idl ldl

C-I liver chylo, vldl ,hdl activates lcat

modulates vldl clearance

C-II liver chylo, vldl ,hdl activates lpl

C-III liver chylo, vldl ,hdl inhibits lpl

inhibits binding of chylo & vldl to
receptors

D liver, cns hdl Carrier of hydrophobic particles e.g.

bilirubin

E liver, macrophages chylo, hdl vldl, idl Receptor binding

 LIPID TRANSPORT AND METABOLISM
IN PLASMA
• Metabolic processes include:

– transfer of apolipoproteins between lipoproteins

–
– transfer of lipids between lipoproteins

– metabolism of lipid content by enzymatic action

– clearance of lipoproteins from the plasma via

receptors,
EXOGENOUS PATHWAY
 EXOGENOUS PATHWAY
• Post-absorptive stage pathway which delivers
dietary lipids to tissues.

• CM secreted into lymphatics: cysterna chyli :

thoracic duct: jugular: systemic circulation.

• CM cleared from plasma 6 - 8 hours after a meal.

•
 EXOGENOUS PATHWAY
• Chylo donate Apo A-I to HDL and receives Apo C-II and Apo E

• Apo C-II stimulates LPL on capillary endothelial surfaces, hydrolysing

TG to glycerol and FFA.

• FFA are released into the circulation to be extracted by muscle,

adipose and mammary tissue.

• TG metabolism depletes core of the CM particle

• Structural integrity maintained by moving excess surface

components to nascent HDL, and by replacing the core TG with
cholesterol ester.
 EXOGENOUS PATHWAY
• Cholesterol derived from surface free cholesterol and tissue free -
cholesterol, taken up by HDL and esterified by LCAT; requires (apo A-I
activated).

• Esterified chol transferred to chylo by CETP

• Apo C-II and apo E are returned to HDL.

• Transfer of apo C-II to HDL converts particle to chylomicron remnants.

• Only apo B-48 and apo E remain & particle contains much less TG and
more CE than the original chylomicron.

• Cleared by the hepatic remnant receptor thru apo E

ENDOGENOUS PATHWAY
 ENDOGENOUS PATHWAY
• Resembles the exogenous pathway, in the
earlier stage, but is much slower.

• Liver produces VLDL continuously to transport

TG and cholesterol to the peripheral tissues

• Production rises with obesity, excess alcohol

or caloric intake, insulin resistance and certain
genetic conditions.
 ENDOGENOUS PATHWAY
• VLDL interaction with HDL contributes more apo C-II and
apo E.

• TG are metabolised by LPL and free fatty acids are delivered

to peripheral tissues.

• Free cholesterol is taken up by HDL, esterified by LCAT, and

returned as cholesterol ester along with the cholesterol
ester derived from tissue cholesterol taken up by HDL.

• Transfer of apo C-II & apo E to HDL, converts particles to

IDL.
 ENDOGENOUS PATHWAY
• 50% of IDL taken up by the LDL receptor,
which recognises apo B-100 and apo E.

• The rest is converted to LDL by the action of

hepatic TG lipase (HTGL) in the liver

• Transfer of apo E to HDL, converts the

particles to LDL.
 ENDOGENOUS PATHWAY
• Apo B-100 is the only protein in LDL.

• Half-life of 3 days and delivers cholesterol to

peripheral tissues, thru LDL receptor (at low
LDL levels) or by the macrophage scavenger
receptor (at high LDL levels).
 LDL RECEPTOR
• LDL receptor located on cell surfaces of all cells that require cholesterol.

– 75% of circulating LDL is taken up by the liver.

– Recognises and binds apo B-100 or apo E.

– Binds and internalises LDL, IDL and some HDL.

– Receptor is recycled repeatedly.

– Synthesis and expression are up or down regulated by decreased or increased

levels of intracellular cholesterol

– Mutations in the gene coding for the LDL receptor cause familial
hypercholesterolaemia
 OTHER LIPOPROTEIN RECEPTORS

• The LRP receptor (LDL receptor-related protein or

remnant receptor) occurs in the liver and binds
apo E.
– Binds chylo remnants, IDL and some HDL and is not
subject to up or down regulation.
•
• The scavenger receptors class A 1 and 2 are found
on macrophages and bind oxidised or acetylated
LDL.
REVERSE CHOLESTEROL TRANSPORT
 REVERSE CHOLESTEROL TRANSPORT
• Excess tissue cholesterol returned to liver by
the reverse cholesterol transport pathway.

• Endogenous cholesterol synthesis can then be

down-regulated by feedback inhibition.

• Only HDL have been shown to take up cellular

cholesterol.
 REVERSE CHOLESTEROL TRANSPORT
• Nascent HDL accepts free chol from chylo, VLDL
and peripheral tissues forming small spherical
particles (HDL3).

• Free chol esterified by LCAT and packed into a

lipid core, forming larger spherical particles
(HDL2).

• Some HDL2 cleared by liver via scavenger

receptor class BI (SR-BI) thus delivering CE
directly to the liver.
 REVERSE CHOLESTEROL TRANSPORT
• Most HDL2 cycled back to HDL3, by transfer
of CE back to the TG-rich chylomicron
remnants and VLDL in exchange for TG via
CETP.

• These lipoproteins are eventually cleared by

hepatic LDL receptor, thereby delivering CE to
the liver.
 FUNCTIONS OF HDL

• Promotes uptake of cholesterol from peripheral tissues

• Esterifies free chol before subsequent delivery to the

tissues

• Provides apo CII and supplies Apo E

• Inhibits LDL oxidation & removes lipid peroxides through

PON (paraoxonase) activity

•
 ROLE OF HYPERLIPIDAEMIA IN
ATHEROSCLEROSIS
• Hyperlipidaemias accelerate atherosclerosis, of
the coronary arteries, aorta etc

• Atherosclerosis: underlying disorder involving

the intima of medium size and large arteries

• Leads to accumulation of mainly cholesterol and

foam cells, and the development of an atheroma
which narrows the arterial lumen.
 ROLE OF HYPERLIPIDAEMIA IN
ATHEROSCLEROSIS
• Compromises circulation to the heart (CAD),
brain (cerebrovascular disease), kidneys (renal
artery stenosis and hypertension) and extremities
(peripheral vascular disease), especially when
complicated by rupture and thrombosis.

• CAD (ischaemic heart disease) is the commonest

cause of death and early invalidism in Western
society.
 ATHEROSCLEROSIS
Atherosclerosis accelerated by:

– High circulating lipid levels

– Cigarette smoking which produces superoxide
radicals
– Ageing
– Endothelial damage caused by hypertension,
toxins, viruses, immune attack, smoking
 CAD risk factors

• Increasing age
• Male gender
• Family history of premature CAD
• Hypercholesterolaemia
• Cigarette smoking
• Hypertension
• Diabetes mellitus
• Obesity
• Sedentary lifestyle
• Others (hyperuricaemia, oral contraceptives, abnormal
fibrinogen levels).
 You went on Atkins and lost 90 pounds, lowered your
cholesterol, cured your high blood pressure and now you are
walking five miles a day! But I’m warning you, a low-carb diet
is bad for your health!
 CAD risk factors
• Risk factors increase the likelihood of
developing CAD.

• Smoking and hypertension 2X risk

• Hypercholesterolaemia 3X risk.
– Hypercholesterolaemia of familial type 100X risk.
 CAD risk factors
• High LDL/HDL ratio predisposes to the
development of CAD.
• Apo (a) has marked homology with
plasminogen.
• Competitively inhibits conversion of
plasminogen to plasmin favouring thrombus
formation.
• Levels genetically determined
• Elevated Lp(a) levels 3X risk.
 CAD risk factors
• Small dense LDL 3-5 X risk compared to same
level of conventional LDL.

• Occur in ~15% of the population in association

with hypertrig, low HDL-cholesterol and
insulin resistance
What fits your busy schedule better, exercising one
hour a day or being dead 24hrs a day?
INVESTIGATION OF HYPERLIPIDAEMIA
• Patients should be investigated for lipid disorders if
they have:

– Positive family history of premature CAD (< 55 years)

– CAD/ peripheral vascular disease / cerebrovascular disease
– Any other risk factors for CAD
– Clinical signs of hyperlipidaemia
– Diseases known to be associated with secondary
hyperlipidaemia
– Pancreatitis or a lipaemic fasting plasma
– Increased cholesterol or triglyceride detected incidentally
 LABORATORY INVESTIGATIONS
• EDTA plasma after overnight fast (essential for TG)

• Recent AMI or other events evoking an acute phase

response (within the preceding 6 weeks) causes falsely
low cholesterol levels.

• Biological variability of cholesterol is 5-10% and of

triglyceride is about 25% (more if non-fasting).

• Diagnosis and management should preferably be based

on repeat measurements 2 weeks apart.
 Lab investigations
• Lipid profile (TChol, TG, HDL-C, LDL-C):
– Total chol and TG measured enzymatically.
– HDL chol measured enzymatically after all non-HDL
lipoproteins are immunologically rendered non-reactive.
– LDL-C directly measured or calculated using Friedewald's
formula:
• LDL cholesterol = total cholesterol – HDL cholesterol - TG / 2.2
• Not valid if TG > 4.5 mmol/l
– Apo A-I, apo B-100 and Lp(a) are measured by protein
measuring technique (RIA, nephelometry, or turbidimetry)
 Lab investigations
• Lipid profile (TChol, TG, HDL-C, LDL-C):
– Total chol and TG measured enzymatically.
– HDL chol measured enzymatically after all non-HDL
lipoproteins are immunologically rendered non-reactive.
– LDL-C directly measured or calculated using Friedewald's
formula:
• LDL cholesterol = total cholesterol – HDL cholesterol - TG / 2.2
• Not valid if TG > 4.5 mmol/l
– Apo A-I, apo B-100 and Lp(a) are measured by protein
measuring technique (RIA, nephelometry, or turbidimetry)
 Lab investigations
• Appearance of plasma after overnight refrigeration:

– creamy layer present - increased chylomicrons (Type I)

–
– creamy layer and turbid infranatant (Type V pattern)

– turbid infranatant - increased VLDL or IDL (Type IIb or IV pattern)

– clear infranatant - normal VLDL and IDL (Type IIa pattern)

• Appearance of serum after refrigeration does not assess

levels of cholesterol-rich LDL or HDL.
Frederickson classification
 Frederickson & Levy classification
• Phenotypic classification based on pattern of elevation of lipoproteins, as
seen on lipid electrophoresis.

• Adopted by W.H.O.

• Useful in identifying some of the inherited (primary) hyperlipidaemias

• Only a few patterns are specific to a single disease entity

• Relatives with the same disease (e.g. FH) can have different patterns

• Patterns can change over time or with treatment and diet, and no account
is taken of HDL levels
 Lipid electrophoresis

• Gel stained with a lipophilic dye (Sudan Black, Oil

Red O)

• Positions to which lipoproteins migrate are

named according to protein electrophoresis:

βglobulins albumin
(-) origin beta pre-beta alpha (+)
chylo LDL VLDL HDL
Lipid electrophoresis
 Desirable values
• Cholesterol
Ideal level < 5.2 mmol/l
Mild to moderate hypercholesterolaemia 5.2 – 7.5 mmol/l
Severe hypercholesterolaemia 7.5 – 15.0 mmol/l
Very severe hypercholesterolaemia > 15 mmol/l * usually homozygous FH

Triglyceride
Ideal level < 2.5 mmol/l
Mild hypertriglyceridaemia 2.5 – 5.0 mmol/l
Moderate hypertriglyceridaemia 5.0 – 11 mmol/l
Severe hypertriglyceridaemia 11 – 150 mmol/l

LDL cholesterol
Ideal level < 3.5 mmol/l

HDL cholesterol
Ideal level > 1.2 mmol/l * low HDL is non-ideal
 Desirable values
apolipoprotein B
Ideal level < 100 mg/dl

apolipoprotein A
Ideal level > 120 mg/dl * low apo A is non-ideal

lipoprotein (a)
Ideal level < 30 mg/dl
 Classification of hyperlipidaemias

• pure hypercholesterolaemia

• pure or predominant hypertriglyceridaemia

• mixed hyperlipidaemia

• Secondary
 Pure Hypercholesterolaemia: FAMILIAL
HYPERCHOLESTEROLAEMIA (FH)

• Autosomal dominant, inherited defect of the

LDL receptor.

• > 15 mM total cholesterol (TC) in homozygotes

and usually die of CAD before 20 years.

• 8 mM - 11 mM TC in heterozygotes with CAD

manifesting in 40’s.
Pure Hypercholesterolaemia: FAMILIAL
HYPERCHOLESTEROLAEMIA (FH)
• Clinically patients often have :

– tendon xanthomata, especially on the Achilles tendon

(cholesterol ester deposition in macrophages).

– Arcus cornealis (deposition of cholesterol in the

cornea)
–
– xanthelasmata (deposition of cholesterol in the
eyelids) often occur.
Pure Hypercholesterolaemia: FAMILIAL
HYPERCHOLESTEROLAEMIA (FH)
• Some LDL receptor gene mutations causing FH
include:

• receptor-negative (non-functional gene product)

• receptor-defective (binding of LDL reduced to 1-10% of

normal)

• and internalisation-defective (binds normally but unable

to transport LDL into the cell).
Pure Hypercholesterolaemia: FAMILIAL
HYPERCHOLESTEROLAEMIA (FH)
• Failure of internalisation results in failure to
down regulate HMG-Co A reductase at normal
plasma cholesterol levels.
• Increased macrophage uptake of oxidised LDL.
• Patients present as type II(a) or (b)
Pure Hypercholesterolaemia: FAMILIAL
HYPERCHOLESTEROLAEMIA (FH)
• IDL poorly cleared by the LDL receptor in
homozygotes thus more is converted to LDL.

• Treatment: homozygotes - low fat diet and

drugs, but also require plasma
exchange/apheresis
 Pure Hypercholesterolaemia: FAMILIAL
BINDING DEFECTIVE APOLIPOPROTEIN B-100
• co-dominantly inherited and is not as
common as FH.

• Mutation in apo B-100 gene decreases binding

to the LDL receptor.
•
• Decreased rate of clearance of LDL from
plasma and thus causing hyperchol.
 Pure Hypercholesterolaemia: AUTOSOMAL
RECESSIVE HYPERCHOLESTEROLAEMIA (ARH)
• Very rare and phenotypically mimics
Homozygous FH.

• Arises from an absence of an adaptor protein

that is required for LDL receptor function.

• Functional abnormality of the LDL receptor,

with a resultant increase in plasma LDL levels.
 Pure Hypercholesterolaemia:
POLYGENIC HYPERCHOLESTEROLAEMIA
• Accounts for 85% of patients with high LDL cholesterol.

• Arises from involvement of several genes.

• Cholesterol levels usually not more than 10 mM

• Type IIa or IIb pattern.

• Increased risk of CAD, but xanthomata are not a

feature.
 HOMOZYGOUS CETP DEFICIENCY
• Causes formation of very large "HDL" particles
that may become atherogenic

• Cholesterol accumulates in HDL because it

cannot be exchanged for reverse transport.

• Affected patients display no symptoms or

signs but have HDLs > 3.9mmol/L.
 FAMILIAL
HYPERALPHALIPOPROTEINAEMIA
• Elevated HDL level is HDL > 2.1 mmol/L.

• Autosomal dominant or polygenic.

• Total cholesterol may be elevated due to an

increase in HDL cholesterol (and apo A1).

• Associated with a decreased incidence of CAD.

 Mixed Hyperlipidaemia: FAMILIAL
COMBINED HYPERLIPIDAEMIA (FCHL)
• 1-2% of people in the Western World.

• Accounts for 10% of cases of hyperchol, but also causes

hyperTG or mixed hyperlipidaemia.

• Autosomal dominant inheritance involving several

different genes

• Overproduction of apo B hence increased VLDL

secretion and increased LDL.
• Increased risk of CAD
If vegetarian diet is good for losing weight,
how come they use grain to fatten pigs and
cows?
 Mixed Hyperlipidaemia: FAMILIAL
DYSBETALIPOPROTEINAEMIA (Broad beta
disease)
• Usual apo E phenotype is E3/E3 (others E2, E4 & Eu )

• Apo E2 homozygotes have low affinity for remnant receptor

and LDL receptor

• Usually E2/E2 needs coupling with another inherited

hyperlipidaemia or alcoholism, obesity, diabetes or
hypothyroidism to cause hyperlipidaemia .
•
 Mixed Hyperlipidaemia: FAMILIAL
DYSBETALIPOPROTEINAEMIA (Broad beta
disease)
• Presents in adulthood with:
– yellow fat deposits in palmar creases
– orange/yellow tubero-eruptive xanthomata over bony
prominences.

• Increased risk of CVD

• “Broad beta" band due to excess IDL and chylomicron

remnants.

• Diagnosis is confirmed by apo E phenotyping.

Pure Hypertriglyceridaemia: FAMILIAL
HYPERTRIGLYCERIDAEMIA
• Autosomal dominant causing increased Tg.
– Decreased VLDL catabolism
– Excess TG synthesis by the liver
– Increased VLDL secretion.

• Chylomicrons may also persist as VLDL competes

for lipoprotein lipase.

• Patients often asymptomatic.

Pure Hypertriglyceridaemia: FAMILIAL
HYPERTRIGLYCERIDAEMIA
• Slightly increased cholesterol and low HDL.

• Obese, hyperglycaemic and hyperinsulinaemic

with hyperuricaemia and hypertension.
• .
• Fish oils (omega-3 fatty acids) have a dramatic
effect on lowering the TG probably by
decreasing hepatic VLDL synthesis.
Pure Hypertriglyceridaemia: FAMILIAL
LIPOPROTEIN LIPASE DEFICIENCY
• Autosomal recessive defect

• Retention of Chylomicrons.

• VLDL cleared by alternative ill-understood pathway possibly

macrophage related.

• Presents in childhood with eruptive xanthomata or

recurrent abdominal pain.

• Low fat diets and fat soluble vitamins supplementation.

Pure Hypertriglyceridaemia: FAMILIAL
APO C-II DEFICIENCY
• Autosomal recessive defect in apo C-II

• Chylomicrons accumulate in plasma (and

sometimes VLDL too

• Transfusion of normal plasma will cause a

rapid drop of plasma TG
 SECONDARY HYPERLIPIDAEMIA
• Account for ±40% of hyperlipidaemias and affect ±5%
of adults.

• Should always be excluded if hyperlipidaemia is

present.

• Treatment of the underlying disorder corrects the

hyperlipidaemia.

• Precipitates or worsens a coexistent inherited

hyperlipidaemia.
 SECONDARY HYPERLIPIDAEMIA
HYPOTHYROIDISM
• Decreased catabolism of VLDL, IDL and LDL.
• Hyperchol with normal or slightly raised Tg

• RENAL DISEASE
• Nephrotic syndrome - apolipoprotein synthesis
stimulated as a consequence of proteinuria.
• Lipoproteins are not lost in the urine at the same
rate as other proteins,
• hypercholesterolaemia, with normal or raised Tg.
 SECONDARY HYPERLIPIDAEMIA
• cholestasis
• diversion of biliary cholesterol and phospholipids
into the blood-stream leads to hyperchol and
variable hyperTG.

• Lipoprotein X occurs in plasma.

• hepatic TG lipase impaired, causing an

accumulation of TG-rich lipoproteins
 SECONDARY HYPERLIPIDAEMIA
• DIABETES -MELLITUS
• Over-production of VLDL

• Prolonged insulin deficiency also decreases LPL

activity,
• Poorly controlled diabetics have severe
hypertriglyceridaemia and chylomicronaemia
which may lead to acute pancreatitis.

• HDL cholesterol levels are low.

 SECONDARY HYPERLIPIDAEMIA
• ALCOHOL
• hypertrig due to increased VLDL synthesis due to
increased fatty acid synthesis (acetyl co a) and
decreased fatty acid oxidation.

• These patients may have eruptive xanthomata

and pancreatitis.

• Moderate alcohol intake increases HDL

cholesterol, which is beneficial!
The ultrasound says it’s a keg of bud
light!
 SECONDARY HYPERLIPIDAEMIA
• OBESITY
• Increased VLDL synthesis from increased fatty
acid delivery to the liver (dietary excess or insulin
resistance)

• Associated with low HDL levels.

• All abnormalities are reversible by weight

reduction.
 HYPOLIPIDAEMIA (all rare)
• ABETALIPOPROTEINAEMIA

• Defect in synthesis of apo B.

• Homozygous mutated microsomal TG transfer protein which adds
neutral lipid to apo B during the synthesis of chylo and VLDL
• Truncation of apo B which cannot act as a template for the
formation of chylomicrons and VLDL.
• Chylomicrons, VLDL and LDL are absent, with very low plasma
cholesterol and TG.
• Fat malabsorption
• membrane abnormalities manifesting as acanthocytosis (red cells),
retinitis pigmentosa and ataxic neuropathy.
 HYPOLIPIDAEMIA (all rare)
• FAMILIAL HYPOBETALIPOROTEINAEMIA
• Low total cholesterol or LDL cholesterol, or total
apo B.
• Signs and symptoms are similar to
Abetalipoproteinaemia but less severe.
• Arises from truncation mutants of apoB which
are poor carriers of intracellular triglycerides;
• VLDL synthesis markedly impaired but not
entirely absent
 HYPOLIPIDAEMIA (all rare)
• ANALPHALIPOPROTEINAEMIA (Tangier Disease)
• Absent HDL.

• Defect in ABC1 transporter protein which brings

cholesterol from within cells to the surface for transfer to
apo A1 and the generation of HDL.

• Cholesterol poor Apo A1 rapidly cleared from circulation by

the kidney.

• Presents with large orange tonsils, corneal opacities and

neuropathy.
 HYPOLIPIDAEMIA (all rare)
• LCAT DEFICIENCY
• Excess unesterified cholesterol in plasma and
tissues.

• All lipoproteins have abnormal structure, VLDL is

elevated.

• Haemolytic anaemia, premature atherosclerosis

and renal insufficiency