liver glucose fatty acids ketone bodies vldl glycerol glucose fed fasting tca cycle glucose can can...
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LIVER
Glucose
Fatty acids
Ketone bodies
VLDL
Glycerol
Glucose
FED FASTING
TCA cycleGlucose can
can NOT be made from fatty acids
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Roles of Various Tissues in TG metabolism:
MUSCLE
Fatty acids Ketone bodiesGlucose
FED FASTING
Acetyl-CoA
TCA cycle (aerobic)
Lactate(anaerobic)
Glucose
Not possible
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Glucose
Fatty acids Fatty acids
Triacylglycerol
Glycerol
FED FASTING
VLDL Chylomicrons(liver) (intestine)
L.P.Lipase
Control byHormone sensitive lipase
Insulin mobilization
Control by GLUT-4 & L.P.Lipase
Insulin uptake
Albumin
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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.
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INTESTINE
Fatty acidsOther lipids2-Monoacylglycerol
Triacylglycerol
Chylomicrons
Lymph
Food & Bile salts
Pancreatic LipaseBile salts
Apolipoprotein B-48
Acly-CoA
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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:
From Shelness & Sellers (2001) Curr Opin Lipidology 12:151-157
chylomicron
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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
UAA
B100 (made in liver)
B48 (made in intestine)
mRNA editingStop
codon
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BRAIN
Fatty acids
Ketone bodiesGlucose
FED FASTING
Acetyl-CoA
TCA cycle
Glucose
Not metabolized
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Lipid Transport
• Three Major Lipoprotein Pathways– 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
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Lipoprotien Structure Typical of Chylomicron or VLDL
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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
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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
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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
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VLDL Pathway
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VLDL
TGPL, Ch, ChE
B-100Liver Blood
VLDL
B-100 - Apolipoprotein B-100TG - TriagylglycerolPL - PhospholipidCh - CholesterolChE - Cholesterol ester
Cholesterol Cholesterol ester
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VLDL
E
C HDLE
TGPL, Ch, ChE
B-100
TGPL, Ch, ChE
B-100
C
Liver Blood
VLDL
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VLDL
E
Fatty Acid + Glycerol
C HDLE
TGPL, Ch, ChE
B-100
TGPL, Ch, ChE
B-100
Adipose
Muscle
C
Endo Ct eh le llial
Liver Blood
VLDL
Lipoprotein Lipase
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VLDL
E
Fatty Acid + Glycerol
C HDLE
TGPL, Ch, ChE
B-100
TGPL, Ch, ChE
B-100
Adipose
Muscle
C
Endo Ct eh le llial
C
HDL
Liver Blood
TG,PL Ch, ChE
B-100
E
IDL
VLDL
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VLDL
E
Fatty Acid + Glycerol
C HDLE
TGPL, Ch, ChE
B-100
TGPL, Ch, ChE
B-100
Adipose
Muscle
C
Endo Ct eh le llial
C
HDL TG,PL Ch, ChE
B-100
Liver Blood
E
TG,PL Ch, ChE
B-100
E
ChE
IDL
LDL
VLDL
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VLDL
E
Fatty Acid + Glycerol
C HDLE
TGPL, Ch, ChE
B-100
TGPL, Ch, ChE
B-100
Adipose
Muscle
C
Endo Ct eh le llial
C
HDL TG,PL Ch, ChE
B-100
Liver
Lysosomaldegredation
Ch F.A. A.A.ChE
Bile salts
Liver Blood
LDL Receptor
E
TG,PL Ch, ChE
B-100
E
ChE
IDL
LDL
VLDL
Most cells have LDL receptors
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VLDL
E
Fatty Acid + Glycerol
C HDLE
TGPL, Ch, ChE
B-100
TGPL, Ch, ChE
B-100
Adipose
Muscle
C
Endo Ct eh le llial
C
HDL TG,PL Ch, ChE
B-100
Liver
Lysosomaldegredation
Ch F.A. A.A.ChE
Bile salts
Liver Blood
LDL Receptor
E
TG,PL Ch, ChE
B-100
E
ChE
IDL
LDL
VLDL
B-100
E
TG,PL Ch, ChE
LDL Receptor
Most cells have LDL receptors
E
TG,PL Ch, ChE
B-100
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Intracellular Cholesterol Metabolism
LDLLDL receptor
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Intracellular Cholesterol Metabolism
LDL
Lysosome
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Intracellular Cholesterol Metabolism
LDL
Lysosome
Amino acids
Fatty acids + Glycerol
Cholesterol
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Liver Cholesterol Metabolism
Cholesterol
Bile saltsCholesterol ester
Acyl-CoAHMG-CoA
HMG-CoA reductase
20 grams/day
19.5 grams/day
0.5 grams/day
VLDLLDL, chylomicron remnants
Bile
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Liver Cholesterol Metabolism
Cholesterol
Bile salts
HMG-CoAHMG-CoA reductase
DNA Tran
scrip
tion
Cholesterol ester
Acyl-CoA
Inhibition of HMG-CoA reductace and Bile saltreadsorption are important therapeutic targets.
VLDL
Cholesterol inhibits
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Periperal Cholesterol Metabolism
CholesterolHMG-CoAHMG-CoA reductase
DNA Tran
scrip
tion
Cholesterol ester
Inhibition of HMG-CoA reductace is an important therapeutic target.
ABC-A1transporter
HDL
Tangier Disease:a lack of ABC-A1
Ch to HDL
Cholesterol inhibits
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LDL receptor
Lysozyme
Cholesterol
LDL
LDL receptor
LDL receptor
LDL receptor
LDL
LDL
LDL
LDL receptor
LDL
Nucleus
-
LDL receptor
LDL
LDL
LDL
Lysozyme
Lysozyme
Nucleus
De novoCholesterol
synthesis
NORMAL FAMILIAL HYPERCHOLESTEROLEMIA
LDL LDL
To blood
Remains in blood To blood
Cholesterol export
Cholesterol export
Cholesterol
Remains in blood
Cholesterol synthesis is limited Cholesterol synthesis
is not as limited
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Chylomicron Pathway
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Chylomicrons
Chylomicron
Intestine Lymph TGPL, Ch, ChE
B-48 B-48 - Apolipoprotein B-48
TG - TriagylglycerolPL - PhospholipidCh - CholesterolChE - Cholesterol ester
Cholesterol Cholesterol ester
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Chylomicrons
CE
C HDLE TG
PL, Ch, ChE
B-48
TGPL, Ch, ChE
B-48
Intestine Lymph Blood
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Chylomicrons
E
Fatty Acid + Glycerol
C HDLE TG
PL, Ch, ChE
B-48
TGPL, Ch, ChE
B-48
Intestine Lymph Blood
Adipose
Muscle
C
Endo Ct eh le llial
Lipoprotein Lipase
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Chylomicrons
E
Fatty Acid + Glycerol
C HDLE TG
PL, Ch, ChE
B-48
TGPL, Ch, ChE
B-48
Intestine Lymph Blood
Adipose
Muscle
C
Endo Ct eh le llial
C
HDLE
B-48
TG,PL Ch, ChE
ChylomicronRemnant
Chylomicron
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Chylomicrons
E
Fatty Acid + Glycerol
C HDLE TG
PL, Ch, ChE
B-48
TGPL, Ch, ChE
B-48
Intestine Lymph Blood
Adipose
Muscle
C
Endo Ct eh le llial
C
HDLE
TG,PL Ch, ChE
B-48
LRP (LDL receptor-related protein)Liver
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Chylomicrons
E
Fatty Acid + Glycerol
C HDLE TG
PL, Ch, ChE
B-48
TGPL, Ch, ChE
B-48
Intestine Lymph Blood
Adipose
Muscle
C
Endo Ct eh le llial
C
HDL
E
TG,PL Ch, ChE
B-48
LRP (LDL receptor-related protein)Liver
Lysosomaldegradation
Ch F.A. A.A.ChE
Bile salts
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HDL Pathway
Reverse Cholesterol Transport Pathway
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HDL
PL,Ch
Intestine Lymph Blood
Liver
A
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HDL
PL,Ch
Intestine Lymph Blood
TISSUE
Liver
A
AB
C-A
1tr
ansp
orte
r
Ch
ChE
TG,PL Ch, ChE
B-100
E
LDL
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HDL
PL,Ch
E
Intestine Lymph Blood
TISSUE
C
Liver
A
AB
C-A
1tr
ansp
orte
r
Ch
ChE
B-100
Ch
PL,ChEALCAT
Tangier Disease:a lack of ABC-A1
Lecithin:cholesterol acyl transferase
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HDL
E
Intestine Lymph Blood
C
Liver
PL,ChE, TGA LCAT
CETP
TG, PL
Ch, ChE
B-100
E
ChE TG
PL,Ch
A
Cholesterol ester transfer protein
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HDL
E
Intestine Lymph Blood
C
Liver
A
TG,PL Ch, ChE
B-100
E
H.L.
F.A. + Glycerol
Hepatic Lipase
PL,Ch
A
PL,ChE, TG LCAT
CETP
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HDL
E
Intestine Lymph Blood
C
Liver
PL,ChEALCAT
CETP
H.L.
SR-B-1(Scavenger Receptor)
PL,Ch
A
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Macrophages to “foam cells”
SR-A(Scavenger Receptor A)
TG,PL Ch, ChE
B-100
E
Oxidized LDL (not recognized by LDL receptor)
Cholesterol
ABC-A-1transporter
Intracellular accumulationleading to “foam cell”
(atherogenic)
Export is limited
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Disorders of Lipid metabolismType 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.
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Dyslipidemias• Hypercholesterolemia
– High LDL cholesterol
• Hypertirgliceridemia– High blood triglycerides
• Combined hyperlipidemia– High blood triglycerides and cholesterol
• Hypoalphalipoproteinemia– Low HDL
• Hypobetalipoproteinemia– Low VLDL & chylomicrons
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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
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Disorders of Lipid metabolism
AtheroschlerosisImportant 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
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From: Durrington (2003) Lancet 362:717-731
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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
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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