liver glucose fatty acids ketone bodies vldl glycerol glucose fed fasting tca cycle glucose can can...

LIVER

Glucose

Fatty acids

Ketone bodies

VLDL

Glycerol

Glucose

FED FASTING

TCA cycleGlucose can

can NOT be made from fatty acids

Roles of Various Tissues in TG metabolism:

MUSCLE

Fatty acids Ketone bodiesGlucose

FED FASTING

Acetyl-CoA

TCA cycle (aerobic)

Lactate(anaerobic)

Glucose

Not possible

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

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.

INTESTINE

Fatty acidsOther lipids2-Monoacylglycerol

Triacylglycerol

Chylomicrons

Lymph

Food & Bile salts

Pancreatic LipaseBile salts

Apolipoprotein B-48

Acly-CoA

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

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

BRAIN

Fatty acids

Ketone bodiesGlucose

FED FASTING

Acetyl-CoA

TCA cycle

Glucose

Not metabolized

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

Lipoprotien Structure Typical of Chylomicron or VLDL

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

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

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

VLDL Pathway

VLDL

TGPL, Ch, ChE

B-100Liver Blood

VLDL

B-100 - Apolipoprotein B-100TG - TriagylglycerolPL - PhospholipidCh - CholesterolChE - Cholesterol ester

Cholesterol Cholesterol ester

VLDL

E

C HDLE

TGPL, Ch, ChE

B-100

TGPL, Ch, ChE

B-100

C

Liver Blood

VLDL

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

VLDL

E


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

VLDL

E


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

VLDL

E


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

VLDL

E


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

Intracellular Cholesterol Metabolism

LDLLDL receptor


LDL

Lysosome


LDL

Lysosome

Amino acids

Fatty acids + Glycerol

Cholesterol

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

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

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

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

Chylomicron Pathway

Chylomicrons

Chylomicron

Intestine Lymph TGPL, Ch, ChE

B-48 B-48 - Apolipoprotein B-48

TG - TriagylglycerolPL - PhospholipidCh - CholesterolChE - Cholesterol ester

Cholesterol Cholesterol ester

Chylomicrons

CE

C HDLE TG

PL, Ch, ChE

B-48

TGPL, Ch, ChE

B-48

Intestine Lymph Blood

Chylomicrons

E


C HDLE TG

PL, Ch, ChE

B-48

TGPL, Ch, ChE

B-48


Adipose

Muscle

C

Endo Ct eh le llial

Lipoprotein Lipase

Chylomicrons

E


C HDLE TG

PL, Ch, ChE

B-48

TGPL, Ch, ChE

B-48


Adipose

Muscle

C

Endo Ct eh le llial

C

HDLE

B-48

TG,PL Ch, ChE

ChylomicronRemnant

Chylomicron

Chylomicrons

E


C HDLE TG

PL, Ch, ChE

B-48

TGPL, Ch, ChE

B-48


Adipose

Muscle

C

Endo Ct eh le llial

C

HDLE

TG,PL Ch, ChE

B-48

LRP (LDL receptor-related protein)Liver

Chylomicrons

E


C HDLE TG

PL, Ch, ChE

B-48

TGPL, Ch, ChE

B-48


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

HDL Pathway

Reverse Cholesterol Transport Pathway

HDL

PL,Ch


Liver

A

HDL

PL,Ch


TISSUE

Liver

A

AB

C-A

1tr

ansp

orte

r

Ch

ChE

TG,PL Ch, ChE

B-100

E

LDL

HDL

PL,Ch

E


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

HDL

E


C

Liver

PL,ChE, TGA LCAT

CETP

TG, PL

Ch, ChE

B-100

E

ChE TG

PL,Ch

A

Cholesterol ester transfer protein

HDL

E


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

HDL

E


C

Liver

PL,ChEALCAT

CETP

H.L.

SR-B-1(Scavenger Receptor)

PL,Ch

A

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

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.

Dyslipidemias• Hypercholesterolemia

– High LDL cholesterol

• Hypertirgliceridemia– High blood triglycerides

• Combined hyperlipidemia– High blood triglycerides and cholesterol

• Hypoalphalipoproteinemia– Low HDL

• Hypobetalipoproteinemia– Low VLDL & chylomicrons

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

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

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

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

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

liver glucose fatty acids ketone bodies vldl glycerol glucose fed fasting tca cycle glucose can can...

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