Lipid metabolism 2

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.

1. LIPID METABOLISM -
Lipoprotein Metabolism

2. Lipid Structure
HO
Cholesterol
COOH
COOH
COOH
HO
HO
HO
+
Fatty Acids
Glycerol
COO
COO
COO
Triglycerides
COO
COO
OPOON
Phospholipid: Lecithin
+

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 Areductase, 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
cholesterol and other isoprenoids.
Dolichols
translational modification of
proteins known as N
glycosylation in the form of
dolichol
phosphate.
as a membrane anchor for the
formation of the
oligosaccharide Glc3
GlcNAc2 (where Glc is
glucose, Man is mannose, and
GlcNAc is N
acetylglucosamine).

4. NORMAL CHOLESTEROL METABOLISM
Tissue
pools
70G
0.8 G
SYN CHOL*
*SYN CHOL = CHOLESTEROL SYNTHESIS
0.4 G CHOL

5. NORMAL CHOLESTEROL METABOLISM
Tissue
pools
70G
.65 G
.20 G
.20 G CHOL 0.65 G CHOL
0.85 G
ABS CHOL
50%
0.4 G CHOL
0.8 G
SYN CHOL*
*SYN CHOL = CHOLESTEROL SYNTHESIS
1.3 G
CHOL

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

7. 400 mg/day
1,300 mg/day
NORMAL CHOLESTEROL ABSORPTION
Oil phase

8. 400 mg/day
1,300 mg/day
17,400 mg/day
NORMAL CHOLESTEROL ABSORPTION
Plant sterols compete
For cholesterol here
Oil phase

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
Ezetimibeis used along with a low cholesterol/low fat diet and exercise to
help lower cholesterol in the blood.Ezetimibemay be used alone or with
other drugs (such as "statins" or fibrates).Ezetimibeworks 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 steroltransportersABCA1,ABCG5, and ABCG8 may play a role in the pathogenesis of human
cholesterol related gallbladder diseases. ... Bile acids may promote an active conformation of
purifiedABCG5/G8either by global stabilization of thetransporteror by binding to a specific site
onABCG5/G8.
This protein is a member of the White subfamily. The protein encoded by this gene functions as a half-
transporterto 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.

13. Bile Acid Synthesis
HO
Cholesterol
OH
OH
OH
COOH
OH
OH
COOH
OH
COOH
OH
OH
COOH
Chenodeoxycholic
Acid
Lithocholic
Acid
Cholic
Acid
Deoxycholic
Acid

14. NORMAL CHOLESTEROL METABOLISM
Tissue
pools
70G
0.8 G
SYN CHOL
.65 G
.20 G
0.85 G
ABS CHOL
50%
0.4 G CHOL
1.3 G
CHOL
.20 G CHOL 0.65 G CHOL

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)

20. FATTY
ACIDS
(ALBUMIN)
TG (VLDL)
TG (CHYLO-
MICRONS)
LIPO-
PROTEIN
LIPASE
Fatty Acid and Triglyceride Flux

21. Plasma
Triglyceride
(VLDL)
Dietary Carbohydrate Increases
VLDL Production
Dietary
Carbohydrate

22. Effect of Carbohydrate Restriction on
Carbohydrate-induced Hypertriglyceridemia0
500
1000
1500
2000
2500
3000
Initial LevelEnd of FastInpatient 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

23. Lipoprotein Metabolism

24. Cholesterol Ester Synthesis
HO
Cholesterol
COOH
COO
COO
OPOON+
Cholesterol
Ester
COO
COO
COO
OPOON+
Lysolecithin
Lecithin-Cholesterol Acyl Transferase (LCAT)
Acyl-Cholesterol Acyl Transferase (ACAT)

29. Lipoproteins:
Separation by –
Electrophoresis
Density
Size by
Electron Microscopy

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. IDLis one of the five major groups of lipoproteins (Chylomicrons, VLDL,IDL, LDL,
HDL) that enablefatsand 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.

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
Apolipoproteinsare 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 calledphosphatidylcholine–sterol O-acyltransferase) is anenzymethat converts
freecholesterolintocholesteryl ester(a more hydrophobic form of cholesterol), which is then sequestered into the core of
alipoproteinparticle, eventually making the newly synthesizedHDLspherical and forcing the reaction to become unidirectional since the
particles are removed from the surface. The enzyme is bound tohigh-density lipoproteins(HDLs) andlow-density lipoproteinsin theblood
plasma.
[5]
LCAT deficiencycan cause impaired vision due to cholesterol corneal opacities, anemia, and kidney damage.

39. Metabolic Relationships
Among Lipoproteins
LDL
1.
3.2.
Lipoprotein
Lipase`
TG
HDL
VLDL

40. TRIGLYCERIDES
HDL
SMALL
DENSE LDL

41. Role of CETP in Triglyceride/
Cholesteryl Ester Exchange
VLDL CETPHDL
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
thelipoproteins.

42. Role of Triglycerides in Producing
Small Dense LDL or HDL
TG
TG
TG
CE CE CE
CETP Lipase
1. CE exchanged for TG2. 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-
densitylipoprotein(LDL
) plays a key role in the
development and
progression of
atherosclerosis &
cardiovascular disease. ...
ModifiedsdLDLis a
potent inductor of
inflammatory processes
associated with
cardiovascular disease.

44. Distribution of LDL Size Phenotypes
According to Triglyceride Levels0
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)
Cumulative percent of cases
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. Nature2000; 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 (?)

47. HDL and Reverse Cholesterol Transport

48. HDL and Reverse Cholesterol Transport
Tangier Disease
Tangier diseaseis an inheriteddisordercharacterized 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.

49. HDL and Reverse Cholesterol Transport

50. HDL and Reverse Cholesterol Transport

51. HDL and Reverse Cholesterol Transport

52. LDL-R
HDL and Reverse Cholesterol Transport

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)

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