The bile salts such as cholic acid contain a hydrophobic side and a hydrophilic side, thus allowing bile salts to dissolve at an oil-water interface, with the hydrophobic surface in contact with the non-polar phase and the hydrophilic surface in the aqueous medium. This detergent action emulsifies fats and yields mixed micelles, which allow attack by water-soluble digestive enzymes and facilitate the absorption of lipids through the intestinal mucosa. Mixed Micelles also serve as transport vehicles for those lipids that are less water-soluble than fatty acids, such as cholesterol or the fat-soluble vitamins A, D, E, and K. Thus, efficient absorption of lipids depends on the presence of sufficient bile acids to solubilize the ingested lipids.
3. HMG CoA Reductase
(More Than Cholesterol Synthesis)
Acetyl CoA
HMG CoA
Mevalonate
Farnesyl Pyrophosphate
Cholesterol
HMG CoA Reductase
Isopentenyl
adenine
(transfer RNA)
Prenylation of
signalling peptides
(ras, rho, etc.)
Ubiquinones
(CoQ-10, etc.)
Dolichols
Inhibition of other key products of mevalonate may relate to
nonlipid effects & rare side effects of statins.
HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, officially
abbreviated HMGCR) is the rate-controlling enzyme (NADH-dependent, EC 1.1.1.88; NADPH-
dependent, EC 1.1.1.34) of the mevalonate pathway, the metabolic pathway that produces
Dolicho
translatio
proteins
glycosyl
dolichol
phospha
as a mem
formatio
oligosac
GlcNAc
glucose,
GlcNAc
acetylglu
6. Key concepts: synthesis
– Primary synthetic sites are extrahepatic, but liver
is key regulator of homeostasis
Key concepts: absorption
– Largest source is biliary secretion, not diet.
– Normal absorption: 50%
– For cholesterol to be absorbed it must:
• undergo hydrolysis (de-esterification by esterases)
• be incorporated into micelles
• be taken up by cholesterol transporter
• be re-esterified and incorporated into chylomicrons
NORMAL CHOLESTEROL METABOLISM
9. STRUCTURE OF PLANT STEROL ESTERS
HO
Cholesterol
Sitosterol
HO
O
C - O
Sitosterol Ester
10. 400 mg/day
1,300 mg/day
17,400 mg/day
850 mg/day
NORMAL CHOLESTEROL ABSORPTION
Ezetimibe competes
For cholesterol here
Oil phase
Ezetimibe is used along with a low cholesterol/low fat diet and exercise to
help lower cholesterol in the blood. Ezetimibe may be used alone or with
other drugs (such as "statins" or fibrates). Ezetimibe works by reducing
the amount of cholesterol your body absorbs from your diet.
11. 400 mg/day
1,300 mg/day
17,400 mg/day
850 mg/day
NORMAL CHOLESTEROL ABSORPTION
Defect in ABCG5/G8
transporter causes
phytosterolemia
Oil phase
The sterol transporters ABCA1, ABCG5, and ABCG8 may play a role in the pathogenesis of human
cholesterol related gallbladder diseases. ... Bile acids may promote an active conformation of
purified ABCG5/G8 either by global stabilization of the transporter or by binding to a specific site
on ABCG5/G8.
This protein is a member of the White subfamily. The protein encoded by this gene functions as a half-
transporter to limit intestinal absorption and promote biliary excretion of sterols. It is expressed in a tissue-
specific manner in the liver, colon, and intestine.
12. Role of Bile Salts, cholesterol, phospholipids in
gall stone formation.
Importance of Bile Salts for cholesterol absorption
NORMAL CHOLESTEROL METABOLISM
Key concepts: bile salt absorption inhibitors
– Bile acid binding compounds:
• Welchol*
• Cholestyramine
• Colestipol
• Fiber
– Surgery: Partial ileal bypass.
*Lowering cholesterol decreases the risk of heart disease and helps prevent
strokes and heart attacks. Colesevelam is also used along with a proper diet and
exercise to lower high blood sugar in people with type 2 diabetes.
15. 17 G
BA*
NORMAL CHOLESTEROL METABOLISM
Tissue
pools
70G
0.8 G
SYN CHOL
17.35 G
BA*
0.85 G
ABS CHOL
0.35 G BA*
.35 G
.65 G
.20 G
1.20 G
CHOL + BA
50% 95%
0.4 G CHOL
1.3 G
CHOL
* BA = BILE ACIDS
.20 G CHOL 0.65 G CHOL
16. Key concepts: absorption
– Triglyceride (i.e. energy) assimilation is key to
the survival of the organism.
– Dietary triglyceride must be hydrolyzed to fatty
acids, mono-glycerides and glycerol prior to
absorption.
– Fatty acids must partition to micellar phase for
absorption.
– For transport, triglyceride must be reconstituted
from glycerol and fatty acid and incorporated into
chylomicrons.
NORMAL TRIGLYCERIDE METABOLISM
17. Structures of Fatty Acids
C
HO
O
C
HO
O
C
HO
O
C
HO
O
C
HO
O
18:0
cis-18:1 -6
trans-18:1 -6
18:2 -6
18:3 -3
18. Structures of Fatty Acids
C
HO
O
C
HO
O
C
HO
O
C
HO
O
C
HO
O
16:0 (palmitic)
cis-18:1 -6 (oleic)
trans-18:1 -6 (elaidic
18:2 -6 (linoleic)
18:3 -3
(alpha
linolenic)
C
HO
O 20:5 -3 (EPA)
22. Effect of Carbohydrate Restriction on
Carbohydrate-induced Hypertriglyceridemia
0
500
1000
1500
2000
2500
3000
Initial Level End of Fast Inpatient Low
CHO Diet
Outpatient
Low CHO Diet
Reisell et al., Am J Clin Nutr 1966;19:84
Treatment: Fast for average 5 days, then consume low CHO diet.
Composition
of diet:
7-15% CHO
25-30% Prot
60-65% Fat
32. Pancreatic Lipase Movement
Most pancreatic
lipase is secreted
into the pancreatic
duct, but some moves
back into capillaries.
33. Chylomicron Role in Pancreatitis
Pancreatic lipase acts
on chylomicrons
adherent to capillary
endothelium, producing
fatty acid anions, or
soaps. By detergent
action, cell membranes
are disrupted, releasing
more lipase, and
additional fatty acid
anions are produced in
a vicious cycle.
34. IDL is one of the five major groups of lipoproteins (Chylomicrons, VLDL, IDL, LDL,
HDL) that enable fats and cholesterol to move within the water-based solution of the
bloodstream. ... VLDL is a large, triglyceride-rich lipoprotein secreted by the liver that
transports triglyceride to adipose tissue and muscle.
35.
36.
37.
38. Apolipoproteins
B/E receptor ligand *E2:IDL; *E4: Diet ResponsivityapoE
LpL inhibitor; antagonizes apoEapoC-III
LpL activatorapoC-II
Inhibit Lp binding to LDL R; LCAT activatorapoC-I
apoB-48
Structural protein of all LP except HDL
Binding to LDL receptor
apoB-100
Tg metabolism; LCAT activator; diet responseapoA-IV
HL activationapoA-II
HDL structural protein; LCAT activator;RCTapoA-I
Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fat and cholesterol) to form lipoproteins. They transport the
lipids through the lymphatic and circulatory systems. The lipid components of lipoproteins are insoluble in water.
Lecithin–cholesterol acyltransferase (LCAT, also called phosphatidylcholine–sterol O-acyltransferase) is an enzyme that converts
free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol), which is then sequestered into the core of
a lipoprotein particle, eventually making the newly synthesized HDL spherical and forcing the reaction to become unidirectional since the
particles are removed from the surface. The enzyme is bound to high-density lipoproteins (HDLs) and low-density lipoproteins in the blood
plasma.[5] LCAT deficiencycan cause impaired vision due to cholesterol corneal opacities, anemia, and kidney damage.
41. Role of CETP in Triglyceride/
Cholesteryl Ester Exchange
VLDL CETP HDL
TG
CE
LDLCETPHDL
TG
CE
Cholesteryl ester transfer protein (CETP), also called plasma
lipid transfer protein, is a plasma protein that facilitates the
transport of cholesteryl esters and triglycerides between
the lipoproteins.
42. Role of Triglycerides in Producing
Small Dense LDL or HDL
TG
TG
TG
CE CE CE
CETP Lipase
1. CE exchanged for TG 2. TG removed
43. FREE
FATTY
ACIDS
Dyslipidemia of Metabolic Syndrome
VLDL CETP
TG
CE
HDL LDL
CETP
TG
CE
LIPASE
sdLDL
FATTY ACIDS
GLYCEROL
HDL
CATABOLISM
UNINHIBITED
LYPOLYSIS
Low-
density lipoprotein (LDL
) plays a key role in the
development and
progression of
atherosclerosis &
cardiovascular disease. ...
Modified sdLDL is a
potent inductor of
inflammatory processes
associated with
cardiovascular disease.
44. Distribution of LDL Size Phenotypes
According to Triglyceride Levels
0
10
20
30
40
50
60
70
80
90
100
0 50 100 150 200 250 300
Phenotype A
(light fluffy LDL)
Phenotype B
(small dense LDL)
Cumulativepercentofcases
Triglyceride (mg/dl)
Austin et al, Circulation 1990; 82:495
45. Peroxisome Proliferator-Activated Receptor:
A Nuclear Receptor for Metabolic Genes
a, Basic mechanism of action of
nuclear hormone receptors: bind
to a specific sequence in the
promoter of target genes (called
hormone response elements), and
activate transcription upon
binding of ligand. Several nuclear
hormone receptors, including
the retinoic acid receptor, the
vitamin D receptor and PPAR, can
bind to DNA only as a heterodimer
with the retinoid X receptor, RXR,
as shown. b, some PPAR and
PPAR ligands.
Kersten et al. Roles of PPARs in health
and disease. Nature 2000; 405: 421-424
46. Role of PPAR* and in VLDL,
LDL
and HDL metabolism
* Peroxisome Proliferator Activated Receptor
PPAR
Tissues: Liver, kidney, heart,
muscle.
Ligands: fatty acids, fibrates
Actions: Stimulate production
of apo A I, lipoprotein lipase,
increase expression of ABC
A-1, increase FFA uptake and
catabolism, decrease FFA
and VLDL synthesis.
PPAR
Tissues: Adipose tissue and
intestine.
Ligands: arachidonic acid,
Glitazones
Actions: increase expression
Of ABC A-1, increase FFA synthesis and
uptake by adipocytes, increase
insulin sensitivity (?)
48. HDL and Reverse Cholesterol Transport
Tangier Disease
Tangier disease is an inherited disorder characterized by significantly reduced levels
of high-density lipoprotein (HDL) in the blood. HDL transports cholesterol and certain
fats called phospholipids from the body's tissues to the liver, where they are removed
from the blood.
53. LDL-R
50% of HDL C may
Return to the liver
On LDL via CETP
HDL and Reverse Cholesterol Transport
54. • An atherogenic lipoprotein
containing apo(a) and apoB.
• 20-30% of people have levels
suggesting C-V risk.
• Black subjects have Lp(a)
normal range twice as high
as white and Asiatic subjects.
• Apo(a) sequence similar to plasminogen, and Lp(a)
interferes with spontaneous thrombolysis.
• Lp(a) levels highly genetic, resistant to diet and drug
therapy, although niacin may help.
“LDL”
Apo(a)
-S-S-
Lipoprotein(a), or Lp(a)
55.
56.
57. Summary – Lipid and
Lipoprotein Metabolism
• Cholesterol absorption, synthesis, and
disposition
• Triglyceride/fatty acid transformations and
energy metabolism
• Lipoprotein core and surface components
• Lipoprotein origins and destinations governed
by apo’s
• Derangement in the metabolic syndrome
• Reverse cholesterol transport – the dominant
direction
• Lipoprotein(a)
• Lipoproteins in the arterial wall