1. LIVER Glucose can can NOT be made from fatty acids Glucose
Ketone bodies
Glucose
Fatty acids
Glycerol
VLDL
Glucose can
can NOT be made
from fatty acids
TCA cycle
FED FASTING

2. Roles of Various Tissues in TG metabolism: MUSCLE
Glucose
Fatty acids
Ketone bodies
Glucose
Acetyl-CoA
Lactate
(anaerobic)
TCA cycle
(aerobic)
Not possible
FED FASTING

3. Hormone sensitive lipase Insulin  mobilization
Control by
Hormone sensitive lipase
Insulin  mobilization
VLDL Chylomicrons
(liver) (intestine)
L.P.Lipase
Albumin
Fatty acids
Fatty acids
Triacylglycerol
Glucose
Glycerol
Control by
GLUT-4 & L.P.Lipase
Insulin  uptake
FED FASTING

4. PPAR 
Increased PPAR activity increases the amount of many adipocyte proteins as well as proteins in other tissues.
Thiazolidinediones (TZDs) increase the sensitivity of tissues to the effects of insulin;Type II diabetics have decreased insulin sensitivity.
TZDs work by increasing the activity of PPAR
The exact reason for the increased insulin sensitivity is not clear.

5. INTESTINE Food & Bile salts Bile salts Fatty acids 2-Monoacylglycerol
Pancreatic Lipase
Fatty acids
2-Monoacylglycerol
Other lipids
Acly-CoA
Triacylglycerol
Apolipoprotein B-48
Chylomicrons
Lymph

6. Chylomicron formation
The process is analagous to VLDL formation in the liver BUT Apolipoprotien B-48 is used rather than Apolipoprotien B-100
Lipids are packaged as apolipoprotein B-48 is being synthesized:
chylomicron
From Shelness & Sellers (2001) Curr Opin Lipidology 12:

7. Chylomicron formation
The same gene gives rise to both Apolipoprotien B-48 and Apolipoprotien B-100.
The mRNA for apoliprotein B-48 is derived from the apolipoprotein B-100 mRNA by tissue specific mRNA editing.
In intestinal cells an enzyme deaminates a specific cytidine nucleotide to Uridine. This highly specific C to U change introduces a stop codon, resulting in a shorter protein: apolipoprotein B-48
CAA
B100 (made in liver)
mRNA editing
Stop codon
UAA
B48 (made in intestine)

8. BRAIN Fatty acids Glucose Glucose Ketone bodies Not metabolized
Acetyl-CoA
TCA cycle
FED FASTING

9. Lipid Transport Three Major Lipoprotein Pathways Albumin
Chylomicron pathway
Delivery of dietary lipid to tissues
VLDL
Delivery of lipid synthesized by liver to tissues
HDL
Cholesterol scavenger
Albumin
Transport of free fatty acids
Specialized Carriers
Some steroids
Some vitamins

10. Lipoprotien Structure Typical of Chylomicron or VLDL

11. Lipid Transport
The term lipoprotein refers to a particle that contains lipid plus apolipoprotein.
The term apolipoprotein refers to a protein without the associated lipid.
Example: VLDL is a lipoprotein, and apolipoprotein B-100 is a protein component of VLDL

12. Lipid Transport Important core apolipoproteins Apolipoprotein B-100
Liver - formation of VLDL
Apolipoprotien B-48
Intestine - formation of chylomicrons
A shortened version of apolipoprotein B-100 shortened through RNA editing
Apolipoproteins A-I and A-II
Central protein component of HDL
Made in Liver and intestine

13. Lipid Transport Apolipoproteins added extra-cellularly
Apolipoproteins C-I, C-II, C-III
C-II is required for the activation of lipoprotein lipase
C-III ia an antagonist of lipoprotein lipase
C-I is a modulator of cholesterol exchange
Apolipoprotein E
Involved in recognition and uptake of lipoproteins by the liver
Three common alleles (E2, E3, E4)
E2/E2 is a risk factor for hyperlipoproteinemia
E4 is a risk factor for Alzheimer Disease

14. VLDL Pathway

15. VLDL Liver Blood B-100 - Apolipoprotein B-100 TG - Triagylglycerol
PL - Phospholipid
Ch - Cholesterol
ChE - Cholesterol ester TG
PL, Ch, ChE
VLDL
Cholesterol
Cholesterol ester

16. VLDL Liver Blood HDL VLDL B-100 B-100 TG PL, Ch, ChE TG PL, Ch, ChE C

17. VLDL Liver Blood Lipoprotein Lipase M HDL u s c l VLDL e Adipose
o C
t e
h l
e l l i a M u s c l e TG
PL, Ch, ChE C
HDL E
VLDL
B-100 TG
PL, Ch, ChE E C
Adipose
Fatty Acid +
Glycerol
Lipoprotein Lipase

18. VLDL Liver Blood M HDL u s c l VLDL e IDL Adipose HDL Fatty Acid +n d
o C
t e
h l
e l l i a M u s c l e TG
PL, Ch, ChE C
HDL E
VLDL
B-100
B-100
TG,PL
Ch, ChE TG
PL, Ch, ChE E E C
IDL
Adipose C
Fatty Acid +
Glycerol
HDL

19. VLDL Liver Blood M HDL u s c l VLDL e IDL Adipose HDL LDL ChEn d
o C
t e
h l
e l l i a M u s c l e TG
PL, Ch, ChE C
HDL E
VLDL
B-100
B-100
IDL
TG,PL
Ch, ChE TG
PL, Ch, ChE E E C
Adipose C
ChE
Fatty Acid +
Glycerol
B-100
HDL
TG,PL
Ch, ChE E
LDL

20. VLDL Liver Blood Liver M HDL u s c l VLDL e IDL LDL Receptor LDLn d
o C
t e
h l
e l l i a M u s c l e TG
PL, Ch, ChE C
HDL E
VLDL
B-100
B-100
IDL
TG,PL
Ch, ChE TG
PL, Ch, ChE E E
LDL Receptor C
Adipose
LDL C
ChE
Fatty Acid +
Glycerol
B-100
HDL
TG,PL
Ch, ChE
Lysosomal
degredation E
ChE
Ch F.A A.A.
Liver
Most cells have LDL receptors
Bile salts

21. VLDL Liver Blood Liver LDL Receptor M HDL u s c l VLDL e IDL
TG,PL
Ch, ChE
Liver Blood
B-100 E n d
o C
t e
h l
e l l i a M u s c l e E TG
PL, Ch, ChE C
HDL E
VLDL
B-100 E
B-100
IDL
TG,PL
Ch, ChE
TG,PL
Ch, ChE TG
PL, Ch, ChE E
B-100 E
LDL Receptor C
Adipose
LDL C
ChE
Fatty Acid +
Glycerol
B-100
HDL
TG,PL
Ch, ChE
Lysosomal
degredation E
ChE
Ch F.A A.A.
Most cells have LDL receptors
Liver
Bile salts

22. Intracellular Cholesterol Metabolism
LDL receptor
LDL

23. Intracellular Cholesterol Metabolism
Lysosome
LDL

24. Intracellular Cholesterol Metabolism
Lysosome
Amino acids
LDL
Fatty acids + Glycerol
Cholesterol

25. Liver Cholesterol Metabolism
LDL, chylomicron remnants
VLDL
HMG-CoA
reductase
HMG-CoA
Cholesterol
Acyl-CoA
19.5 grams/day
Bile salts
Cholesterol ester
20 grams/day
0.5 grams/day
Bile

26. Liver Cholesterol Metabolism
Inhibition of HMG-CoA reductace and Bile salt
readsorption are important therapeutic targets.
VLDL
Cholesterol inhibits
Transcription
DNA
HMG-CoA reductase
Acyl-CoA
HMG-CoA
Cholesterol
Bile salts
Cholesterol ester

27. Periperal Cholesterol Metabolism
Tangier Disease:
a lack of ABC-A1
HDL
Ch to HDL
Inhibition of HMG-CoA reductace
is an important therapeutic target.
ABC-A1
transporter
Cholesterol inhibits
Transcription
DNA
HMG-CoA reductase
HMG-CoA
Cholesterol
Cholesterol ester

28. - Remains in blood To blood Remains in blood
NORMAL FAMILIAL
HYPERCHOLESTEROLEMIA
Remains in blood
To blood
To blood
LDL
LDL
LDL
LDL
LDL receptor
Lysozyme
LDL
LDL receptor
Lysozyme
Cholesterol
export
LDL
LDL receptor
Lysozyme
Cholesterol
export
LDL
LDL receptor
LDL
Cholesterol
LDL receptor
Cholesterol
De novo
Cholesterol
synthesis
Nucleus
Nucleus -
LDL
LDL
LDL receptor
Remains in blood
Cholesterol synthesis is limited
Cholesterol synthesis is not as limited

29. Chylomicron Pathway

30. Chylomicrons B-48 - Apolipoprotein B-48 TG - Triagylglycerol
Intestine Lymph
B-48
B-48 - Apolipoprotein B-48
TG - Triagylglycerol
PL - Phospholipid
Ch - Cholesterol
ChE - Cholesterol ester TG
PL, Ch, ChE
Chylomicron
Cholesterol
Cholesterol ester

31. Chylomicrons HDL Intestine Lymph Blood B-48 B-48 TG PL, Ch, ChE TG

32. Chylomicrons M u HDL s c l e Adipose Lipoprotein Lipase
o C
t e
h l
e l l i a
Intestine Lymph Blood M u s c l e
B-48
HDL C TG
PL, Ch, ChE E
B-48 TG
PL, Ch, ChE E C
Adipose
Fatty Acid +
Glycerol
Lipoprotein Lipase

33. Chylomicrons M u HDL s c l e Adipose HDL Intestine Lymph Blood
o C
t e
h l
e l l i a
Intestine Lymph Blood M u s c l e
B-48
HDL C TG
PL, Ch, ChE E
B-48
Chylomicron TG
PL, Ch, ChE E C
Adipose
B-48
Fatty Acid +
Glycerol
TG,PL
Ch, ChE C E
HDL
Chylomicron
Remnant

34. (LDL receptor-related protein)
Chylomicrons E n d
o C
t e
h l
e l l i a
Intestine Lymph Blood M u s c l e
B-48
HDL C TG
PL, Ch, ChE E
B-48 TG
PL, Ch, ChE E C
Adipose
B-48
Fatty Acid +
Glycerol
TG,PL
Ch, ChE C E
HDL
LRP
(LDL receptor-related protein)
Liver

35. (LDL receptor-related protein)
Chylomicrons E n d
o C
t e
h l
e l l i a
Intestine Lymph Blood M u s c l e
B-48
HDL C TG
PL, Ch, ChE E
B-48 TG
PL, Ch, ChE E C
Adipose
B-48
Fatty Acid +
Glycerol
TG,PL
Ch, ChE C E
Lysosomal
degradation
HDL
ChE
Ch F.A A.A.
LRP
(LDL receptor-related protein)
Liver
Bile salts

36. HDL Pathway Reverse Cholesterol Transport Pathway

37. HDL
Intestine Lymph Blood A
PL,Ch
Liver

38. HDL T I S U E LDL A Ch ABC-A1 transporter ChE Liver
Intestine Lymph Blood
LDL A
PL,Ch
B-100
TG,PL
Ch, ChE E Ch
ABC-A1
transporter
ChE
Liver

39. HDL T I S U E A Lecithin:cholesterol acyl transferase Ch A LCAT Ch
Intestine Lymph Blood A
PL,Ch
Lecithin:cholesterol acyl transferase
B-100 E C Ch A
PL,ChE
LCAT Ch
ABC-A1
transporter
ChE
Tangier Disease:
a lack of ABC-A1
Liver

40. HDL A A LCAT CETP Cholesterol ester transfer protein ChE TG Liver
Intestine Lymph Blood A
PL,Ch E C A
PL,ChE, TG
LCAT
CETP
Cholesterol ester transfer protein
ChE TG
TG, PL
Ch, ChE E
B-100
Liver

41. HDL A A LCAT CETP Hepatic Lipase H.L. F.A. + Glycerol Liver
Intestine Lymph Blood A
PL,Ch E C A
PL,ChE, TG
LCAT
CETP
Hepatic Lipase
H.L.
F.A. + Glycerol
TG,PL
Ch, ChE E
B-100
Liver

42. HDL A A LCAT CETP H.L. SR-B-1 (Scavenger Receptor) Liver
Intestine Lymph Blood A
PL,Ch E C A
PL,ChE
LCAT
CETP
H.L.
SR-B-1
(Scavenger Receptor)
Liver

43. Macrophages to “foam cells”
Oxidized LDL (not recognized by LDL receptor)
Export is limited
B-100
TG,PL
Ch, ChE
SR-A
(Scavenger Receptor A) E
ABC-A-1
transporter
Cholesterol
Intracellular accumulation
leading to “foam cell”
(atherogenic)

44. Disorders of Lipid metabolism
Type I diabetes:
Very low insulin: cells act as if starving even though blood glucose is high.
Adipose:
Fatty acid mobilization up
Triacylglycerol synthesis is down
Liver:
Fatty acid synthesis is down (low glycolysis; low citrate) yet VLDL production is up.
Fatty acid oxidation is up
Ketone body formation is up: severe ketosis
Excess fatty acids go to VLDL formation: high blood lipid.

45. Dyslipidemias Hypercholesterolemia Hypertirgliceridemia
High LDL cholesterol
Hypertirgliceridemia
High blood triglycerides
Combined hyperlipidemia
High blood triglycerides and cholesterol
Hypoalphalipoproteinemia
Low HDL
Hypobetalipoproteinemia
Low VLDL & chylomicrons

46. Disorders of Lipid metabolism
Type II diabetes:
Cells have a greatly reduced sensitivity to the effects of insulin
Molecular basis is poorly understood
Numerous hormones produced by adipocytes may play a role
Effects of obesity
PPAR modulates expression of important proteins

47. Disorders of Lipid metabolism
Atheroschlerosis
Important risk factors include:
High LDL/ HDL ratio
High concentration of small dense LDL particles
not efficiently taken up by liver
targets for oxidation
taken up by macrophage
Uptake of oxidized lipids by macrophages
Cholesterol processing by macrophages

48. From: Durrington (2003) Lancet 362:717-731

49. Predisposing alleles and therapeutic targets:
Apolipoprotein B
VLDL/chylomicron metabolism
Apolipoproteins CII & CIII
rate of clearance of VLDL
Lipoprotein Lipase
Rate of clearance of VLDL
Apolipoprotein E
uptake of chylomicron remnants; LDL uptake
Three common Alleles
E2/E2 risk factor for hyperlipidemia
E4 risk factor for Alzheimer

50. Predisposing alleles and therapeutic targets:
LDL receptor
Rate of clearance of LDL
Familial hypercholesteolemia
Apolipoprotein A1
low HDL
Cholesterol ester transfer protein (CETP)
HDL stability; LDL metabolism
ABC-A1 protein
Cholesterol export from cells, particularly macrophage
PPARα PPARγ PPARδ