CHOLESTEROL, BILE SALTS,

LIPIDS AND LIPOPROTEINS METABOLISM

Max Efui Annani-Akollor (PhD)
Dept of Molecular Medicine
SMD, KNUST
 KNUST COVID-19 AWARENESS

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Virus is changing itself with even more serious ramifications.
It is important we all adhere to the safety protocols
 Objectives

• An overview of bile salt metabolism

• The role of bile salts in lipid metabolism
• An overview of cholesterol metabolism
• The role of cholesterol in lipid and general metabolism
• Types and properties of Lipids and lipoproteins
• Abnormalities in lipid metabolism leading to disease
BILE SYNTHESIS & METABOLISM
 BILE - DIGESTION AND ABSORPTION OF FATS
•Biological detergents synthesized by the liver, stored in the gall bladder &
secreted into the intestine
•Form spherical structures/micelles assisting in absorption by diffusion-complete
for FA MGs, less for others
•Emulsification enhanced by bile salts & intestinal fluid, surface reducing effect.
•Hydrophobic portion (tails of FA) are oriented inside of the micelle, with heads
(hydrophilic portion) outside
•Move lipids from the intestinal lumen to the cell surface
•FA, glycerol, phosphoric acid, choline, ethanolamine, sphingosine, cholesterol &
Vits. ADEK absorbed in the intestinal mucosa.
 BILE - DIGESTION AND ABSORPTION OF FATS
•Absorbed fat re-synthesized into chylomicrons.
•Carnitine palmitoyl transferase regulates the transport of palmitate across
muscle cell membrane.
•This enzyme is in turn regulated by Malonyl CoA
•Therefore palmitate ox. affects carbohydrate metabolism
•Lipases, pancreatic and intestinal juice catalyses the hydrolysis of TG, chol. & PL
•Cobra & bee venoms contain Phospholipase A2. When injected into the blood,
produce lysophospholipids that disrupt cellular membranes and lyse blood cells.
EXCRETION
1) Very little faecal fat is excreted< 5-19% of ingested fat.
2) Sterols from plants, unlike chol are not absorbed and are excreted in fat.

ADIPOSE TISSUE
 Fat stored in mesenchymal cells (fat cells)
 Hydrolysis fats (ACTH, epinephrine, norepinephrine ↑)
 Actively undergo all phases of CHO metabolism, converts glucose to FA.

 Glucose → Pyruvate → Acetyl CoA →FA. (Insulin↑)

EMULSIFICATION BY BILE SALTS

Bile salts as emulsifying agents

interact with the dietary lipid particles
& the aqueous duodenal contents,
thereby stabilizing the lipid particles
as they become smaller, and
preventing them from coalescing.
 BILE ACIDS

• The most abundant bile acids in human bile are chenodeoxycholic

acid (45%) & cholic acid (31%).
• These are referred to as the primary bile acids.
• Intestines - the primary bile acids are acted upon by bacteria and
converted to the secondary bile acids - lithocholate (from
chenodeoxycholate) and deoxycholate (from cholate).
• These conversions include deconjugation and 7-alpha
dehydroxylation, which produce the secondary bile acids
 SYNTHESIS OF BILE SALTS

In humans, the ratio of the glycine to the taurine conjugates is normally 3:1.
 BILE SALTS
• Derivatives of bile acids/cholesterol
• Consist of a sterol ring structure with a side chain
• to which a molecule of glycine or Taurine is covalently attached by an amide
linkage
• The 1o bile acids enter the bile as glycine or taurine conjugates.
• Both 1o & 2O bile acids are reabsorbed by the intestines and
delivered back to the liver via the portal circulation
 Primary
bile acids

Secondary
bile acids

Bile salts-
glycine or taurine
conjugated to
bile acids in liver Recent R & D efforts focusing on bile acid receptors
5% lost in feces as drug targets for treating liver disease, liver cancer,
metabolic disease.
 ENTEROHEPATIC CIRCULATION OF BILE SALTS

 Recycling bile - is achieved by the enterohepatic circulation.

 Specific transporters in the terminal ileum move bile salts from the
lumen of the digestive tract to the intestinal capillaries.
 They are then transported directly to the liver via the hepatic
portal vein.
 Hepatocytes take up bile salts from the blood, and increase the
secretion of bile salts into the bile canaliculi.
ENTEROHEPATIC CIRCULATION OF BILE SALTS
95% of the bile released to the small
intestine is recycled via the enterohepatic
circulation, while 5% of the bile salts are lost
in the feces.
In the alkaline bile, the bile acids and their
conjugates are assumed to be in a salt form
—hence the term "bile salts.“
The reaction catalyzed by the 7-hydroxylase
is the rate limiting step in bile acid synthesis.
SYNTHESIS OF
PRIMARY
BILE ACIDS

Conversion of 7-hydroxycholesterol to the bile acids requires several steps. Only the relevant
co-factors needed for the synthesis steps are shown
• In the liver, the carboxyl group of primary and secondary bile acids is
conjugated via an amide bond to glycine or taurine before their
being re-secreted into the bile canaliculi.
• These conjugation reactions yield glycoconjugates and
tauroconjugates, respectively.
• The bile acids are carried from the liver to the gallbladder, where
they are stored for future use.
• The process of secretion from the liver to the gallbladder, to the
intestines & final reabsorption is termed the enterohepatic
circulation
 CLINICAL SIGNIFICANCE OF BILE ACID SYNTHESIS

1) Synthesis and excretion of bile acids in the feces represent the only
significant mechanism for the elimination of excess cholesterol.
2) Bile acids & phospholipids solubilize cholesterol in the bile, thereby
preventing the precipitation of cholesterol in the gallbladder.
3) Bile acids facilitate the digestion of dietary TAGs by acting as
emulsifying agents that render fats accessible to pancreatic lipases.
4) They facilitate the intestinal absorption of fat-soluble vitamins.
 7-a-hydroxylase
Primary
- cholic acid
bile acids
+ cholesterol

Secondary
bile acids

• Hypercholesterolemia is often treated with “sequestrants” that bind bile acids in the
intestine. These compounds:
prevent reabsorption of bile acids
increase conversion of cholesterol to bile acids
increase bile salt elimination in feces
• Dietary fiber also sequesters bile acids
Increased elimination of cholesterol from the body
 CHOLESTEROL METABOLISM

Cholesterol (C27)

The four-ring nucleus of cholesterol is cyclopentanoperhydrophenanthren

(Note not benzene ring; animals cannot synthesize benzene ring)
CHOLESTEROL SYNTHESIS, TRANSPORT, AND EXCRETION
 CHOLESTEROL METABOLISM
•Bad reputation in more recent years due to its association with
deposition & blood vessel blockage.
•Excess deposition in the major blood vessels leads to
atherosclerosis - the leading contributory factor in CADs.
•Important as a
•Component of plasma membrane structure;
•Precursor for lipid digestion (bile salts), lipid soluble vitamins; and steroid
hormones.

•All cholesterol is transported through the circulation in LP particles.

•The greatest proportion is used in bile acid synthesis.
 CHOLESTEROL METABOLISM

•Four-ring nucleus of cholesterol - cyclopentanoperhydrophenanthren

(Note not benzene ring; animals cannot synth benzene ring)
• Found in all cells - and synthesized from ACoA in animal tissue –
mainly liver and intestinal mucosa.
•Chol - present in membrane/tissues and in plasma LPs as free
cholesterol or, combined with a long-chain FFA, as CE.  
• Eliminated in the bile as cholesterol or bile salts. 
•Occurs in foods of animal origin e.g egg yolk, meat, liver, and brain. 
 Phytosterols
• Sterols of vegetable origin are called "phytosterols".
• They have the same basic structure as cholesterol, but differ in the
side chains attached to C17.
• Phytosterols, such as stigmasterol from soybean oil, are of interest
because they lower blood cholesterol levels
• They decrease intestinal absorption of both exogenous and
endogenous cholesterol
 CHOLESTEROL METABOLISM
• Cholesterol too waxy – affects transport
• Esterified for transport by lipoproteins and storage in cells as
Cholesteryl Esters
• Synthesis and utilization of cholesterol
• tightly regulated to prevent accumulation & abnormal deposition within the
body.
• abnormal deposition of cholesterol & cholesterol-rich lipoproteins occurs in
large arteries especially the coronary arteries.
• Important precursor for steroid hormones
 CHOLESTEROL METABOLISM
• Normal healthy adults synthesize cholesterol at a rate of approx.
1g/day and consume ≈ 0.3g/day.
• Serum levels of cholesterol in the body is about 150 - 200 mg/dL

• Levels maintained primarily by controlling de novo synthesis and in

part by the dietary intake of cholesterol
• About 50% cholesterol in the body is derived from biosynthesis and
de novo in the liver= 10% & intestines= 15% .
 BIOSYNTHESIS OF
CHOLESTEROL

• Cholesterol synthesis occurs in the cytosol and microsomes from

ACoA by the Mevalonate pathway
• Synthesis begins with the transport of ACoA from the mitochondria
to the cytosol
• ACoA can also be derived from cytoplasmic oxidation of ethanol
by ACoA synthetase
• Reducing equivalents in cholesterol biosynthesis is NADPH similar
to FA synthesis
 CHOLESTEROL BIOSYNTHESIS
• ACoA’s are converted to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA
(C6)- a common step to steroid and ketone bodies synthesis
• 2 Acetyl-CoA Acetoacetyl-CoA + CoASH
• Acetyl-CoA + Acetoacetyl-CoA HMG-CoA
• HMG-CoA is also an intermediate on the pathway for synthesis of
ketone bodies from acetyl-CoA.
• This reaction is catalyzed by HMG-CoA synthase which is cytosolic
• N/B HMG-CoA synthase in ketosis is mitochondrial
BIOSYNTHESIS OF CHOLESTEROL - THE MEVALONATE PATHWAY
 CHOLESTEROL BIOSYNTHESIS
• 2 FPP undergoes head-to-tail condensation catalysed by NADPH-
requiring enzyme, squalene synthase - associated with ER, to form
squalene
• Squalene undergoes a two step cyclization to yield lanosterol
• Through a series of 19 additional reactions, lanosterol is converted to
cholesterol.
• Intermediates in cholesterol biosynthesis can be diverted to the
synthesis of other molecules i.e. dolichol : N-linked glycoprotein and
coenzyme Q or the side chain of heme a.
 Decreased Levels of Dolichol result in:
• Decrease in energy
• Compromised immune system
• Hormone imbalance or deficiency
• Low sperm count
• Cell damage or cell death
• Poor brain function
• Nervous disorders & Depression
Decreased Levels of Ubiquinone (CoQ10) result in:

•The heart, liver & kidney have highest CoQ10 conc.

•CoQ10 is protective!
•Required in the ETC
 REGULATION OF CHOLESTEROL METABOLISM
The cellular supply of cholesterol is maintained at a steady level by
four distinct mechanisms:

1. Regulation of HMGCoA-reductase activity and levels. The enzyme

is controlled by four distinct mechanisms:
a) Feed-back inhibition - cholesterol – (allostery)
b) Rate of enzyme degradation - cholesterol (allostery)
c) Covalent modification though phosphorylation-dephosphorylation –by
AMP-activated protein kinase and associated enzymes
d) Control of gene expression - cholesterol
 REGULATION OF CHOLESTEROL METABOLISM
2) Regulation of excess intracellular free cholesterol through the activity of
Acyl-CoA: cholesterol acyltransferase, ACAT
3) Regulation of plasma cholesterol levels via LDL receptor-mediated
uptake and HDL-mediated reverse transport.
4) Hormonal regulation of HMGR expression & activity is achieved by
the covalent modification of HMG-CoA reductase. The enzyme exists in
phosphorylated (inactive) and dephosphorylated(active) forms.
Glucagon & epinephrine promote phosphorylation (inactivation) and inhibits
HMGR expression respectively to negatively affect cholesterol biosynthesis.
Insulin conversely promotes dephosphorylation activating then HMGR enzyme
activity and promoting cholesterol synthesis.
 FATE OF CHOLESTEROL:
BILE ACID AND STEROID BIOSYNTHESIS
• Cholesterol is transported in the plasma predominantly as CE
associated with lipoproteins
• Dietary cholesterol is transported from the small intestine to the
liver within chylomicrons.
• Cholesterol synthesized by the liver and any dietary cholesterol in
the liver that exceeds hepatic needs, is transported in the serum
within LDLs.
• The liver synthesizes VLDLs and these are converted to LDLs
through the action of endothelial cell-associated LPL.
 THE UTILIZATION OF CHOLESTEROL

• Cholesterol - in plasma membranes can be extracted by HDLs and

esterified by lecithin cholesterol acyl transferase (LCAT) for storage
• The cholesterol acquired from peripheral tissues by HDLs can then be
transferred to VLDLs & LDLs via the action of cholesteryl ester transfer
protein (which is associated with (Apo-D).
• This reverse cholesterol transport allows peripheral cholesterol to be
returned to the liver in LDLs.
UTILIZATION
OF
CHOLESTEROL
 FATE OF CHOLESTEROL
BILE ACID AND STEROID BIOSYNTHESIS
• Ultimately, cholesterol is excreted in the bile as free cholesterol or
as bile salts ff conversion to bile acids in the liver
• Cholesterol is usually oxidized by mixed function oxidases
(hydroxylases) to give:
• Bile acids
• Steroid hormones such as Progesterone, Cortisol, Aldosterone ,
Estrone , Testosterone
• And Vit D
 CLINICAL ASPECTS:
Serum cholesterol is correlated with the incidence of
atherosclerosis and CHD.
 Changes in diet play an important role in reducing serum
cholesterol: Substitution in the diet of PUFA and MUFA for some of
the saturated FAs is most beneficial.
Lifestyle affects the serum cholesterol level
When diet changes fail, hypolipidemic drugs will reduce serum
cholesterol and triacylglycerol:
• Cholestyramine resins: Block reabsorption of bile acids. 
• Sitosterols: Acts by blocking the absorption of cholesterol from the
gastrointestinal tract. 
• Mevocore or lovastatin: inhibitors of HMGR 
• Clofibrate or gemfibrozil: exert their effect by diverting esterification to
oxidation of free fatty acids. 
• Probucol: Increase LDL catabolism via receptor independent pathway, prevents
oxidation of LDL 
• Nicotinic acid: reduces the flux of FFA by inhibiting adipose tissue lipolysis,
thereby inhibiting VLDL production by the liver.
LIPOPROTEINS
 LIPOPROTEINS

 Macromolecular complexes of Protein-Lipid combination

Synthesised (Majority) by the liver and the intestines.
Physiological function is to transport dietary and endogenously
synthesised lipids in the blood.
Lipoproteins contain one or more specific proteins - apolipoproteins

Spherical particles:
Core: relatively non-polar
Surface: relatively polar
 STRUCTURE OF LIPOPROTEINS

 Differ in protein to lipid ratio and in electrophoretic mobility

 Apoprotein play imp’t roles in interaction of lipoproteins with cell
surface receptors.
 Functions of Apo lipoproteins
Activate enzymes that metabolize lipoproteins
Increase & maintain the structural stability/integrity of lipoproteins
Recognition sites for cell-surface receptors
Facilitate uptake of lipoprotein into cells
Facilitates the transport cholesterol in plasma
 CLASSIFICATION OF LIPOPROTEINS
5 classes based on density or behaviour upon ultracentrifugation
/floatation rates), which depends on their hydrated densities.

Chylomicron (Largest; lowest in density due to high lipid/protein ratio;

highest % wt TGs)
VLDL (Very Low Density Lipoprotein; 2nd highest in TG as % of wt)
IDL (Intermediate density lipoprotein)
LDL (Low Density Lipoprotein, highest in cholesteryl esters as % of wt)
HDL (High Density Lipoprotein; highest density due to high protein/lipid ratio)
Lipoproteins
 CHARACTERIZATION IN HUMAN PLASMA

Chylomicrons VLDL LDL  HDL

Electrophoretic mobility Origin Pre-Beta Beta Alpha

Density less than 0.96 0.96-1.006 1.006-1.063 1.063-1.21

Diameter (nm) 100-1000 30-90 20-25 10-20
Apolipoproteins B48, Al, All B100 CI, CII B100 AI, AII, CI
Composition (% of total content)
Protein 2 10 20 40
Lipid 98 90 80 60
Lipid component (% of total lipid content)
Triacylglycerols 88 55 12 12
Cholesteryl esters 4 24 59 40
Phospholipids 8 20 28 47
Free fatty acids - 1 1 1
 For young healthy research subjects, ~70 kg (154 lb), these data
represent averages across individuals studied, percentages
represent % dry weight:

% cholesterol & % %
Density (g/mL) Class Diameter (nm) % protein
cholesterol ester phospholipid triacylglycerol
>1.063 HDL 5–15 33 30 29 4-8
1.019–1.063 LDL 18–28 25 46-50 21-22 8-10
1.006–1.019 IDL 25–50 18 29 22 31
0.95–1.006 VLDL 30–80 10 22 18 50
<0.95 Chylomicrons 75-1200 1-2 8 7 83-84
 LIPOROTEINS RELEVANT TO CORONARY ATHEROSCLEROSIS
• Very-low-density lipoproteins (VLDLs)
• Triglycerides
• Low-density lipoproteins (LDLs)
• Cholesterol - primary core lipid
• Greatest contributor to coronary heart disease (CHD)
• High-density lipoproteins (HDLs)
• Low in Cholesterol
• Apolipoprotein abnormalities may lead to abnormal lipid metabolism
and metabolic disorders such as:
– Atherosclerosis – Cardiovascular disease
– Stroke – Alzheimer’s disease
 CHYLOMICRONS (SUMMARY)
• Largest, lightest of particles
• Synthesized in intestinal mucosa
• Carry Triglyceride of dietary origin
• Appear after a fatty meal
• Milky plasma
• Cleared in 8 to 12 hours
• Via lipoprotein lipase
• Converts TG to FFA and Glycerol
• Heparin and Apo C-II cofactors
 VERY LOW DENSITY LIPOPROTEIN (VLDL)
(SUMMARY)
• Synthesized & secreted by liver from CHO, FA and others
• Principal carrier of endogenous TG also contains Chol
• Excess VLDL ↔ Elevated TG
• Contains Apo B100
• Metabolized by LPL to FFA (cell permeable)
• t1/2 of 2-4 hours, turnover of VLDL < chylomicrons
• IDL & LDL are derived from VLDL metabolism
• Elevated LDL results from increased VLDL secretion or from
decrease in LDL catabolism
 LOW DENSITY LIPOPROTEIN (LDL) (SUMMARY)

• The cholesterol-rich LDL particles are much smaller, more dense and
have a longer half-life than their precursors - VLDL.
• Principal lipid is cholesterol (up to 75%)
• Derived mainly from VLDL catabolism via IDL
• Contains Apo B100 - Allows binding to LDL receptor
• Differ from the precursor, VLDL, in a much lower TG content.
• Binds to LDL-R & delivers cholesterol for synthesis
 LIPOPROTEIN (a) [Lp(a)]

Variant of LDL, Lp(a) is now known to be present in essentially all

plasma, in concentrations varying from <1 mg/dL to >200 mg/dL.
↑ levels of Lp(a) are associated with atherosclerosis.
Lp(a) resembles LDL in lipid composition with a higher protein
content. In addition to Apo B100, it has the unique apolipoprotein (a).
Despite its Apo B100 content, it remains unresolved whether Lp(a) is
catabolised via the LDL receptor.
If present in ↑ Lp(a) would give rise to a band in the region between
LDL and VLDL in a lipoprotein electrophoretic run.
 THE INTERMEDIATE DENSITY LIPOPROTEINS (IDL)
VLDL remnants - transient intermediates formed during the
conversion of VLDL to LDL.
Due to transient existence, IDL are not detected in normal plasma.
However, in certain forms of hyperlipidaemia, IDL excess in the
plasma may produce a characteristic ‘broad beta’ band in LP
électrophorèses & thus can become a major determinant of both
serum total cholesterol and TG concentrations
 HIGH DENSITY LIPOPROTEINS (HDL)
• Smallest, most dense and most soluble
• Secreted as a small protein-rich particle by liver (and intestine in
nascent form (HDL3)
• Lipid to protein ratio is 1 : 1; Chol≈25% ; PL≈20% ;TGs≈ (5%).
• Apo A1 of HDL activates LCAT which catalyzes synthesis of CE using
fatty acids cleaved from lecithin.
• HDL mediates reverse transport of cholesterol
• Subgroups – HDL- 1, HDL-2, HDL-3, and HDL-4 differ in protein &
lipid content, shape, structure, and density
 HIGH DENSITY LIPOPROTEIN (HDL)

• Progressive loss of PL, chol, and CE when HDLs are transformed from
HDL- 1 to HDL-4.
• Discoidal HDL3 acquires protein from catabolism of TG-rich LPs to
become mature, spheroidal HDL2 particles.
• Protective effect via HDL2
• Inverse relationship between HDL and CAD
• Good Cholesterol - ↑ plasma levels of HDL- C
• Bad cholesterol - ↑plasma levels of LDL-C
• Bacterial & viral infections, some inflammatory disease
 PLASMA APOLIPOPROTEINS
Major protein components of LP referred to as apoproteins
 Essential structural components of lipoprotein particles, necessary
for their synthesis and catabolism.
 Act as cofactors or activators of certain enzymes associated with
lipid and lipoprotein metabolism.
Classified alphabetically (A thru E) - order in which they emerge
from a chromatographic column: eg Apo C-II Apo C III,
Involved as transfer proteins, receptor recognition LP, thus
controlling the rate of tissue uptake of chol or TGs.
 MAJOR ENZYMES IN LIPOPROTEIN METABOLISM

• Lipoprotein Lipase
• Located in muscle and adipose tissue
• Hydrolyzes chylomicron and VLDL Triglyceride
• Lecithin-Cholesterol Acetyltransferase
• Found in plasma
• Esterifies free cholesterol on HDL surface
• Triglyceride Lipase
• Located in liver
• Hydrolyzes TG within IDL and HDL particles
 LIPOPROTEIN METABOLISM PATHWAY IS
SIMPLIFIED INTO 3 MAIN PATHWAYS

1) Exogenous pathway - Lipids from food

2) Endogenous pathway - Lipids synthesized by the liver

3) Reverse cholesterol transport - Cholesterol from tissues to liver

 LIPOPROTEIN METABOLISM
Lipoprotein metabolism involves the following:

Lipoprotein assembly and secretion - synthesis & post-synthetic

modification of apolipoproteins
Enzymatic modification of lipid components e.g. hydrolysis of TGs
LPL enzyme-catalysed transfer of their apolipoproteins
Receptor - mediated internalization and intracellular catabolism of
the modified remnants
 Reverse Cholesterol Transport
 EXOGENOUS PATHWAY

The chylomicrons, containing primarily dietary lipids, secreted by

the intestines & metabolised via the exogenous lipid pathway.
Both endo & exo pathways involve HDL, lipolytic enzymes and
transfer proteins.
Chylomicrons -mainly metabolised in adipose and muscle tissue
which contains high conc’s of the enzyme lipoprotein lipase (LPL).
LPL located on the luminal surface of the vascular endothelium is
activated by Apo C-II.
 EXOGENOUS PATHWAY
Chylomicrons reach the circulation via lymph, and are subject to the
action of LPLs in the blood capillaries of muscle and adipose tissue,
where TGs are hydrolyzed to FA & glycerol.
Bulk of FAs are taken up by adipocytes and stored as fat; glycerol is
utilised in the liver for synthesis of PL & TGs.
Chylomicron remnant contains Apo E, taken up at the Apo B:E
receptor (and other pathways) for “recycling”. May be used in the
synthesis of VLDL and HDL by liver cells.
Chylomicron remnants also interact with HDL in the 'reverse transfer'
of cholesterol
 EXOGENOUS PATHWAY
•Some patients may have a LPL deficiency resulting in elevated
chylomicron concentration (type I hyperlipidemia).
•No evidence that chylomicrons are pro-atherogenic; being
probably too large to penetrate the vascular endothelium.
• Apolipoproteins (Apo B-48, Apo A-I and Apo A-IV) are assembled
into chylo which are secreted into mesenteric lymph, ultimately
entering the systemic circulation.
• Secretion depends on the presence of Apo B.
Summary of lipoprotein metabolism.
 ENDOGENOUS CYCLE

The liver - primary site of endogenous VLDL synthesis (some

originates from the intestine).
 TGs of hepatic VLDL are synthesised post-prandially from glucose
or from FA and glycerol mobilised from chylomicron metabolism.
Cholesterol is either synthesised de novo or derived from
intracellular degradation of chylomicron remnants.
These lipids are assembled with PL & ALPs, mainly Apo B-100 &
Apo E, before secretion into the circulation via the lymphatics
 ENDOGENOUS CYCLE
Nascent VLDL particles acquire more Apo C from circulating HDL or
other LPP.
In peripheral tissues they are converted to IDL as TAGs are
removed by the hydrolytic action of LPL activated by Apo C-II.
LDL particles acquire more Apo C from circulating HDL or other
lipoproteins- with most formed in the liver from lipids derived from
endogenous synthesis
Conversion of VLDL to IDL and LDL & their subsequent receptor-
mediated catabolism constitute the endogenous lipid pathway.
 ENDOGENOUS CYCLE
A small portion of IDL is taken up by hepatocytes through interaction
with receptors that recognise their Apo E components, converting
them to LDL
LDL are the main carriers of cholesterol in plasma, dependant on the
presence of the LDL –R which recognises Apo B-100.
Most of the LDL in plasma is removed via this receptor mediated path
and defects in the LDL-R results in ↓ clearance of circulating LDL.
Some may enter cells by an unregulated receptor independent
mechanism, especially when plasma LDL levels are high.
 Lipoprotein metabolism
With removal of TGs and some proteins, the % weight that is CE increases. VLDL
are converted to IDL, and eventually to LDL.

VLDL  IDL  LDL

The lipid core of LDL is predominantly cholesteryl esters.
 METABOLISM OF SYNTHESIS OF LDL

LDL Particles are recognized by the LDL-Receptor - a single-pass

transmembrane glycoprotein
 LDL uptake is by receptor-mediated endocytosis, involving
formation of a clathrin-coated pit & pinching off of a vesicle holding
the receptor & LDL cargo.
LDL is released from the receptor within the acidic environment of
the endosome, and the receptor is returned to the plasma
membrane. Cholesterol is released & may be reused, e.g., for
membranes synthesis.
 THE LDL RECEPTOR (Binding domain)

The LDL-binding domain on the exterior side of the plasma membrane recognizes & binds Apo B-
100. Once the receptor with bound LDL is taken into a cell by endocytosis, the LDL-binding
domain faces the lumen of the vesicle & later the lumen of the endosome.
 REGULATION OF LDL SYNTHESIS
•Synthesis of LDL-R is suppressed by high intracellular cholesterol.
• Involves ↓release of Sterol Regulatory Element-Binding
Proteins (SREBPs)- transcription factors that bind to the sterol
regulatory element DNA sequence TCACNCCAC.
• SREBP family of transcription factors activate transcription of genes
for the LDL-R, as well as for enzymes essential to cholesterol synthesis
such as HMG-R
•↓synthesis of LDLR prevents cholesterol uptake by cells with the
deleterious consequence of excess dietary cholesterol remaining in
the blood as LDL-C.
 REGULATION OF LDL SYNTHESIS
 A secreted protease PCSK9 degrades the LDL receptor in liver.
Mutations that increase PCSK9 activity lead to increased plasma
LDL because LDL is not taken up by liver cells.
 Mutations that lead to decreased PCSK9 activity are associated
with low plasma LDL. Drug companies are evaluating feasibility and
consequences of inhibiting PCSK9.
Mutations affecting the LDLR are associated with the most common
form of the disease Familial Hypercholesterolaemia.
Defective apoproteins - e.g., familial defective Apo B-100 leads to
impaired binding of LDL
 HDL AND 'REVERSE CHOLESTEROL TRANSPORT‘
Cholesterol is excreted in the bile.
Chol from extra-hepatic tissues is transported to the liver, to
prevent its accumulation in these cells.
HDL mediates this transfer. Nascent HDL, synthesised by the liver,
contain very little TGs and cholesterol esters.
The downloading of cholesterol to these disc-like HDL particles is
mediated by the enzyme……………
LCAT transfers an unsaturated FA from lecithin to the 3 p-
hydroxyl group of cholesterol, producing lysolecithin and a
cholesterol ester.
 HDL AND 'REVERSE CHOLESTEROL TRANSPORT‘

LCAT - activated by Apo A-I, Apo A-II, Apo A-IV, & Apo C-I.
 LCAT is packed inside the HDL particle; part of the CETP complex,
which also contains Apo A-I, - major cofactor for LCAT, and Apo D.
Chol for esterification by LCAT in the above reaction comes from
the other LP as well as from extrahepatic cells.
Most of the esterified cholesterol is transferred back to LDL, IDL and
chylomicron remnants by the CETP and reaches the liver.
This pathway is termed the ‘Reverse Cholesterol Transport' and delivers cholesterol to the liver
via receptor-mediated uptake of the IDL, LDL, and chylomicron remnants.
 ATHEROSCLEROSIS
• Atherosclerosis is a disease where artery walls become less elastic and thicker
with fatty materials accumulating beneath the inner lining of an arterial wall.
• Hypertensives, diabetics & those with high levels of cholesterol are at ↑ risk
• Prevention of is aided by eliminating the controllable risk factors.

Normal schematics : Arteriosclerosis:

Cell layers adjacent to the lumen of arterial blood vessel. Cell layers adjacent to the lumen of arterial blood vessel.
 DEVELOPMENT OF AN ATHEROSCLEROTIC PLAQUE

Modified/Oxidized LPs) enter

endothelium and
subendothelium & bind to
proteoglycans
Taken up by macrophages
foam cells aggregate, 
Inflammation, Thrombosis 
Damage/Necrotic death

Various conditions can initiate formation of a lesion in

the endothelium lining the arterial lumen.
 ATHEROSCLEROTIC LESION Lipid
core

Fibrous
• Inflammatory response cap
Media

•Including cytokine production Lumen

– T lymphocyte

•Activated by oxidized lipids in LDL. – Macrophage foam

cell (tissue factor+)

•Cytokines - inflammatory cells – “Activated” intimal

MC (HLA-DR+)

•More lipids=more inflammation. – Normal medial SMC

•Media thickens
•Adventitia accommodates
•The lumen compromised.
•An eccentric plaque is formed.
 ATHEROSCLEROTIC LESION

• Metalloproteinases weaken plaque

• Shoulders subject to stress/shear
• Plaque rupture  tissue factors released
• Platelet thrombus completes the occlusion leading to the acute
coronary event
• Over time, exposure to oxygen radicals results in oxidation of
polyunsaturated fatty acids within LDL & modification of the
apolipoprotein.
 DYSLIPIDEMIA

Lipid disorders are classified as—

Primary : also called Familial, due to genetic effects
Secondary: other underlying disorder that leads to alterations in
plasma lipid & lipoprotein metabolism
Based on Frederickson's classification of lipid disorders
Hyperlipidaemia  - most common form of dyslipidemia
also classified according to type of lipid elevation:
hypercholesterolemia, hypertriglyceridemia or both in combined
hyperlipidemia. ↑ level of  lipoprotein may also be classified as a
form of hyperlipidemia
 PRIMARY HYPERLIPIDAEMIAS
• Familial Hypercholesterolaemia , autosomal dominant, inherited
defect of LDL-R
• Patients with FHC usually have an ↑ in cholesterol with ↑ LDL-C
• Homozygote – very high cholesterol levels (die of CAD before 20yrs)
• Heterozygote cholesterolaemia - Intermediate levels of cholesterol
(CAD in their forties)
• Treatment:
• Homozygotes - low fat diet & drugs, but also require plasma apheresis (removal of LDL
by filtering plasma through affinity columns) or liver transplant.
• Heterozygotes - rigorous diet (low cholesterol, low saturated fat) plus lipid lowering
drugs. Most effective are HMG-CoA reductase inhibitors - Statins which lower
cholesterol 30-50%
 Frederickson Classification of Lipid Disorders 
Type Average of
Elevated Serum
overnight Associated clinical disorders Serum TC Refrig. LPE LPs
particles TG
serum
Lipoprotein lipase deficiency, ↑­TG
I Creamy top layer Chylomicrons
Apolipoprotein C-II deficiency
N ++ Pos, clear Normal
(chylos)
Familial hypercholesterolemia, polygenic
hypercholesterolemia, nephrosis,
IIa Clear LDL
hypothyroidism, familial combined
++ N Neg, clear ­β band ↑­LDL
hyperlipidemia

IIb Clear LDL, VLDL Familial combined hyperlipidemia ++ + Neg, cloudy ­, pre- β ­↑LDL, VLDL
­↑Chol, TG,
III Turbid IDL Dysbetalipoproteinemia + + Occ., cloudy ­pre- β
VLDL

Familial hypertriglyceridemia, familial

IV Turbid VLDL combined hyperlipidemia, sporadic N+ ++ Neg, cloudy ­α-2 ↑­VLDL
hypertriglyceridemia, diabetes

Creamy top, ↑­VLDL

V turbid bottom
Chylomicrons, VLDL Diabetes + ++ Pos, cloudy ­α-2
Chylos

Note that the WHO classification is simply a biochemical phenotypic classification based on
which lipoprotein is raised. Also the classification was devised before the importance of HDL as
a prognostic indicator was recognized. + = increased; ++ = Greatly Increased; N= normal; N+ =
normal or increased
 Frederickson Classification of Lipid Disorders 
Hyperlipo- Increased
Synonyms Defect Main symptoms Treatment
proteinemia lipoprotein
Acute pancreatitis, lipemia
Buerger-Gruetz syndrome or
Decreased lipoprotein retinalis,
Type I a familial Chylomicrons Diet control
lipase(LPL) hepatosplenomegaly
hyperchylomicronemia
eruptive skin, xanthomas,
Familial apoprotein CII
b Altered ApoC2
  deficiency      
c   LPL inhibitor in blood
       
Familial Xanthelasma, arcus senilis, Bile acid sequestrants,
Type II a LDL receptor deficiency LDL
hypercholesterolemia tendon xanthomas statins, niacin
Decreased LDL
Familial combined Statins, niacin,
b receptor and LDL and VLDL  
hyperlipidemia fibrate
  increased ApoB
Familial Defect in Apo E 2 Tuboeruptive xanthomas and
Type III IDL Fibrate, statins
  Dysbetalipoproteinemia synthesis palmar xanthomas
Increased VLDL and
Type IV Familial hypertriglyceridemia VLDL pancreatitis at high TG levels Fibrate, niacin, statins
decreased elimination
Increased VLDL
VLDL and
Type V   production and   Niacin, fibrate
chylomicrons
decreased LPL
 SECONDARY HYPERLIPIDAEMIA
A/Cs for ±40% of hyperlipidaemias & affect ±5% of adults.
Should always be excluded if hyperlipidaemia is present.
Treatment of the underlying disorder corrects the hyperlipidaemia.
A secondary cause of hyperlipidaemia will precipitate or worsen a
coexistent inherited hyperlipidaemia.
Hypothyroidism
Renal disease
Liver disease
Diabetes
Alcohol
Obesity
 LABORATORY INVESTIGATION
The 1st and most important concern is to confirm the presence of
hyperlipidaemia in a sample taken after an overnight fast of at least 10hrs.
Initial testing include measurements of TC, TG and HDL-C, which enables
calculation of LDL-C.
 Assess the nature and severity of the patient's hyperlipidaemia, and search
for underlying causes of 2’dary hyperlipidaemia before attributing it as a
primary hyperlipidaemia.
The appropriate biochemical tests depends on the history and presentation.
 BASE LINE
When faced with hypercholesterolaemia or hypertriglyceridaemia, always
exclude the secondary causes of hyperlipidaemia by appropriate tests:
 2 hour post-prandial blood glucose
 KFTs (urea, creatinine, urine protein)
 LFTs including GGT (correlates with alcohol intake)
 TSH
 HYPOLIPIDAEMIAS
They are rare.

Abetaliproteinaemia
Familial hypobetalipoproteinaemia
Analphalioproteinaemia
LCAT Deficiency

N /B Read Up
 CALCULATED/INDIRECT LDL CHOLESTEROL
•Indirect measurement of LDL is performed by using the Friedewald
equation - a formula developed by William Friedewald to calculate
the concentration of LDL, in the bloodstream.
•Calculates the concentration of LDL based upon the presence of
TC, HDL and TG levels
• Fairly accurate and widely employed , some factors could cause
LDLc levels to be incorrect using this calculation.
•Users of the calculated LDLc values must be cognizant of the
assumptions on which the formula is based:
FE assumes that
1)All cholesterol is VLDL, LDL, & HDL
2)Chylomicrons, IDL, and Lp(a) are not significant contributors to TC -
being usually low in cholesterol
3)Fasting plasma does not contain chylomicrons
4) Non-fasting specimens can have chylomicrons
5) FE-derived LDL misclassifies patients at low end of LDL spectrum
• [LDL-C] = [TC] – [HDL-C] – [TG]/5 (1) mg/dl
• [LDL-C] = [TC] – [HDL-C] - (TG/2.2) (2) mmol/L

TG > 400 mg/dL indicates the presence of chylomicrons/remnants

Type III hyperlipidemia is characterized by high -VLDL, which has a
3:1 TG:C ratio
If non-fasting specimen is used, the VLDL-TG value may be inaccurate
(contribution by chylomicron-TG and LDL-C is underestimated).
If these caveats are borne in mind, the formula provides a
reasonable estimate of the LDLc concentration.
 DIRECT LDL CHOLESTEROL

• Direct measurements of LDL are determined without a calculation

but not commonly performed especially where TGs are very high.
• In some cases, test kits can measure LDL subtypes etc
•Older direct methods involve precipitation with heparin or polyvinyl
sulfate
• New methods involve precipitation of VLDL, IDL, & HDL with
polyvalent antibodies to Apo A & Apo E.
• LDL is almost exclusively Apo B-100
 TREATMENT
Diet-
Avoid Alcohol,
Excess Salt,
Lose Excess Weight,
Increase dietary fibre
Reduce dietary cholesterol
Drugs –statins e.g. HMG-CoA reductase inhibitors, (e.g. simvastatin,
atorvastatin), which inhibit rate-limiting step in hepatic synthesis of
cholesterol, lower total and LDL-C
Bile acid sequestrants - cholestyramine , bind bile acids in GIT and reduce
enterohepatic circulation of cholesterol, lower total and LDL cholesterol
 CLINICAL SIGNIFICANCE OF
PLASMA CHOLESTEROL CONCENTRATION

• Atheroscleosis: prolonged hypercholesterolaemia

• Familial hypercholesterolaemia; Mgt: cholestyramine: combines with bile acids
and prevent reabsorption, therefore excrete cholesterol, sitosterol ppt into chol.
And prevent absorption. Large doses of niacin
• Hypothyroidism:
• ↑LDL: atherogenic
• ↓HDL: reverse cholesterol transport
• Hypercholesterolaemia & hypertriglyceridaemia
• Hypocholesterolemia: Hepatitis, anaemia, cachexia, severe hyperthyroidism
• Acanthocytosis: low LDL , results in retinitis, pigmentosa, CNS
• Tangier’s disease: low HDL results in yellow gray tonsils
 LIPIDOSES AND XANTHOMATOSES
•Xanthomatosis:  a deposition of yellowish lipid/cholesterol-rich material that can
appear anywhere in the body in various disease states. Cutaneous manifestations
of lipidosis in which lipids accumulate in large foam cells within the skin. Associated
with hyperlipidaemias - both1o & 2o. Infiltration of tissues with cell of RE packed
with lipids/cholesterol.
•Lipidoses: infiltration of tissues with cell of RE packed with lipids. Also known as
sphingolipidoses. Genetically acquired. Deficiency or absence of a catabolic enzyme
•Gaucher’s disease :
•Niemann-Pick disease: Read Up!!!
•Tay-Sachs syndrome:
•Fabry's Disease: