1. Basics of Lipid and Lipoprotein Metabolism
John R. Guyton, M.D.
Associate Professor of Medicine
Duke University
Durham, NC

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

3. (More Than Cholesterol Synthesis) Farnesyl Pyrophosphate
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.

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

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

6. NORMAL CHOLESTEROL METABOLISM
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

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

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

9. STRUCTURE OF PLANT STEROL ESTERS
Cholesterol
Sitosterol HO HO O
C - O
Sitosterol Ester

10. NORMAL CHOLESTEROL ABSORPTION
1,300 mg/day
400 mg/day
17,400 mg/day
Oil phase
850 mg/day
Ezetimibe competes
For cholesterol here

11. NORMAL CHOLESTEROL ABSORPTION
1,300 mg/day
400 mg/day
17,400 mg/day
Oil phase
850 mg/day
Defect in ABCG5/G8
transporter causes
phytosterolemia

12. NORMAL CHOLESTEROL METABOLISM
Role of Bile Salts, cholesterol, phospholipids in gall stone formation.
Importance of Bile Salts for cholesterol absorption
Key concepts: bile salt absorption inhibitors
Bile acid binding compounds:
Welchol
Cholestyramine
Colestipol
Fiber
Surgery: Partial ileal bypass.

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

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

15. NORMAL CHOLESTEROL METABOLISM
Tissue
pools
70G
0.85 G
ABS CHOL
0.8 G
SYN CHOL
0.35 G BA*
1.3 G
CHOL
17.35 G
BA*
17 G
BA*
.20 G CHOL
0.65 G CHOL
50%
95%
.20 G
0.4 G CHOL
.65 G
.35 G
1.20 G
CHOL + BA
* BA = BILE ACIDS

16. NORMAL TRIGLYCERIDE METABOLISM
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.

17. Structures of Fatty Acids
18:0 HO O C
cis-18:1 -6 HO O
trans-18:1 -6 C HO O C
18:2 -6 HO O C
18:3 -3 HO

18. Structures of Fatty Acids
16:0 (palmitic) HO O C
cis-18:1 -6 (oleic) HO O
trans-18:1 -6 (elaidic) C HO O C
18:2 -6 (linoleic) HO
(alpha
linolenic) O
18:3 -3 C HO O C
20:5 -3 (EPA) HO

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

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

22. Effect of Carbohydrate Restriction on Carbohydrate-induced Hypertriglyceridemia
Treatment: Fast for average 5 days, then consume low CHO diet.
Composition of diet:
7-15% CHO 25-30% Prot 60-65% Fat
Reisell et al., Am J Clin Nutr 1966;19:84

23. Lipoprotein Metabolism

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

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.

38. Apolipoproteins B/E receptor ligand *E2:IDL; *E4: Diet Responsivity
apoE
LpL inhibitor; antagonizes apoE
apoC-III
LpL activator
apoC-II
Inhibit Lp binding to LDL R; LCAT activator
apoC-I
apoB-48
Structural protein of all LP except HDL
Binding to LDL receptor
apoB-100
Tg metabolism; LCAT activator; diet response
apoA-IV
HL activation
apoA-II
HDL structural protein; LCAT activator;RCT
apoA-I

39. Metabolic Relationships Among Lipoproteins1.
VLDL
LDL 2. 3. TG
HDL
Lipoprotein Lipase`

40.  TRIGLYCERIDES
SMALL
DENSE LDL
 HDL

41. Role of CETP in Triglyceride/ Cholesteryl Ester Exchange
VLDL
LDL TG TG
CETP
HDL
HDL
CETP CE CE

42. Role of Triglycerides in Producing Small Dense LDL or HDL
CETP
Lipase CE CE CE TG TG TG
1. CE exchanged for TG
2. TG removed

43. UNINHIBITED LYPOLYSIS
Dyslipidemia of Metabolic Syndrome
UNINHIBITED LYPOLYSIS
FREE
FATTY
ACIDS
CETP TG CE
CETP TG CE
LIPASE
VLDL
sdLDL
HDL
LDL
FATTY ACIDS GLYCEROL
HDL CATABOLISM

44. Distribution of LDL Size Phenotypes According to Triglyceride Levels
Cumulative percent of cases
Phenotype A
(light fluffy LDL)
Phenotype B
(small dense LDL)
Austin et al, Circulation 1990; 82:495
Triglyceride (mg/dl)

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:

46. Role of PPAR*  and  in VLDL, LDL and HDL metabolism
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 (?)
* Peroxisome Proliferator Activated Receptor

47. HDL and Reverse Cholesterol Transport

48. HDL and Reverse Cholesterol Transport
Tangier Disease

49. HDL and Reverse Cholesterol Transport

50. HDL and Reverse Cholesterol Transport

51. HDL and Reverse Cholesterol Transport

52. HDL and Reverse Cholesterol Transport
LDL-R

53. HDL and Reverse Cholesterol Transport
LDL-R
50% of HDL C may
Return to the liver
On LDL via CETP

54. Lipoprotein(a), or Lp(a)
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.
Apo(a)
“LDL”
-S-S-

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