Metabolic Dyslipidemia

1
Metabolic Dyslipidemia in Insulin Resistant
States Pathobiology Molecular Mechanisms
Khosrow Adeli Ph.D., FCACB, DABCC, NACB Head
Professor, Clinical Biochemistry
Laboratory Medicine and Pathobiology Hospital
for Sick Children University of Toronto Toronto,
CANADA
2
Summary of Presentation

• Introduction
• Insulin Resistance/Metabolic Dyslipidemia
• Recent Observations
• Animal Model of Insulin Resistance
• (Fructose-Fed Syrian Golden Hamster)
• Evidence for Hepatic VLDL Overproduction
• Evidence for Hepatic Insulin Resistance
• Evidence for Intestinal Lipoprotein Overproduction

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Insulin Resistance
The diverse biological manifestations of the
insulin resistant state arise as a consequence of
both a blunted insulin action as well as the
compensatory hyperinsulinemia per se.
Insulin
Insulin resistant peripheral tissues
Increased insulin action in more sensitive
tissues or biochemical pathways
Pancreas
4
Clinical spectrum of insulin resistant states

• Rare (genetic) forms of insulin resistance
• Obesity (central, abdominal, visceral, android)
• Fasting hyperglycemia/Impaired glucose tolerance
• Type 2 diabetes mellitus

5
Putative Candidate Gene Mutations in
Putative Candidate Gene Mutations in
Insulin Resistance
Insulin Resistance
Glucose Metabolism
Insulin Sensitization/
Glucose Metabolism
Insulin Sensitization/
desensitization
desensitization


Glut 1
Glut 1
Lipid Metabolism
Lipid Metabolism


Glut 4
Glut 4


Hormone Sensitive Lipase
Hormone Sensitive Lipase

PPAR
g
g

PPAR


Hexokinase
Hexokinase
II
II


ISPK-1
ISPK-1
Insulin Action
Obesity
Insulin Action
Obesity

GSK-3(
a
a
,
b
b
)

GSK-3(
,
)


Insulin Receptor
Insulin Receptor


Leptin
Leptin

PPIC (
a
a
,
b
b
,
g
g
)

PPIC (
,
,
)


IRS-1/2
IRS-1/2


Leptin
Leptin
Receptor
Receptor


PPIG
PPIG


Shc
Shc


b2-
b2-
adrenergic
adrenergic
receptor
receptor


Glycogen
Glycogen
Synthase
Synthase


PI3-
PI3-
kinase
kinase


UCP-1
UCP-1

GS-inhibitor-2

GS-inhibitor-2
a
b

UCP-2

Protein
Kinase
B (
a
,
b
)

UCP-2

Protein
Kinase
B (
,
)

Glycogenin

Glycogenin

NPY

NPY

Phosphofructokinase

Phosphofructokinase

NPY receptor
isoforms

NPY receptor
isoforms
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Disorders associated with insulin resistance

• Dyslipidemia
• Hypertension
• Polycystic ovarian disease
• Hyperuricemia
• Thrombogenic/fibrinolytic abnormalities
• Atherosclerosis

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Features of Metabolic Dyslipidemia




Hypertriglyceridemia
Hypertriglyceridemia
TG,
TG,
ApoB
ApoB
VLDL-TG and VLDL-apoB secretion
VLDL-TG and VLDL-apoB secretion
Small Dense LDL
Small Dense LDL
( LDL particle density)
( LDL particle density)

Reduced HDL-C

Reduced HDL-C


Increase FFA
Increase FFA
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Mechanisms of VLDL overproduction in Insulin
Resistance
Intestine
Adipose tissue
Hepatic Insulin Resistance
LPL
FFA
TG mobilization by tissue lipases
Liver
DNL
FA
Oxidation
Muscle
ApoB
TG, CE
Lipases
Cytosolic TG stores
Adeli K. et al. (2000) J. Biol. Chem. 275
8416-8425. Adeli K. et al. (2002) J. Biol. Chem.
277793-803.
VLDL