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Biochemical Profiling of Lipids: Applications to Drug Development and Toxicology
Steven M. Watkins, Ph.D. President/CSO
Scientific Approach
• Building technology for understanding lipid metabolism in global and molecular detail. – Lipid metabolism in disease – Effects of foods and drugs on lipid metabolism – Lipids as central components of individual
health status
Metabolomics Integrates
MetabolismDrugs
Nutrition Health
Exercise Disease
Environment
Genes
Metabolic Assessment
• High-content analyses provide individual context
• Context allows interpretation
Metabolomics provides both
Tools for Enabling Metabolic Assessment
• High-content, quantitative analysis of metabolites
• Analysis of flux through metabolic pathways
Metabolomics provides both
Quantitative Analysis
PATIENT
Lipid Extract
SAMPLE
CLINICAL / HEALTH INFORMATION
Phosphatidylcholine
Phosphatidylserine
Phosphatidylethanolamine
Cardiolipin
Sphingomyelin
Phosphatidylinositol
Lyso-PLCholine
Triglycerides
Diacylglycerides
Monoacylglycerides
Free Fatty Acids
Cholesterol Esters
Sterols
DATABASE
Surveyor® Data Visualization
Steady-State Flux Analyses
ƒFlux
Experimental Quantitative Map Against Flux Models Analysis Pathway Signature
Building Diagnostics for Metabolic Disease Therapy
Edward Leiter The Jackson Laboratory
Profiling the Effects of Insulin-Sensitizing Drugs
• Investigated the effects of two diabetes drugs on lipid metabolism in a obese-diabetic model
• PPARγ agonist: Rosiglitazone • β-3 adrenergic agonist: CL316,243
PPAR-γ β3-Adrenergic 450 350
400 300
350
250 300
L 250 L 200
r d r de 200 e p p 150 s s
mg 150
mg
100 100
50 50
0 0 Cholesterol Glucose Triglycerides Cholesterol Glucose Triglycerides
Control Treatment
Clinical Biomarkers
PPAR-γ β3-Adrenergic 90 50
80 45
4070
3560
30
30 15
20 10
10 5
Gra
ms
0 0
Gra
ms 50
25 40
20
Body Weight post-treatment Body Weight post-treatment
Control Treatment
Body Weight Following Treatment
PPAR-γ Treatment
Hepatic Lipid Accumulation
PPAR-γ Treatment
β3-Adrenergic Agonist
Hepatic Lipid Synthesis
PPAR-γ β-3 Agonist
-100%
200%
-150% 150%
Hyp
o -lip
idem
icD
rug
A
-100%
200%
-150% 150%
Hyp
o -lip
idem
icD
rug
A
-100%
200%
-150% 150%
Hyp
o -lip
idem
icD
rug
AH
ypo -
lipid
emic
Dru
g A
De
De
De
Decccc
rrrreeeeaaaassss
eeeedddd w www
iiiitttthhhhIIIInnnn
crcrcrcreaeaeaea
sssseeeedddd
wwwwiiiitttthhhh
d dddrrrruuuu
gggg A AAA
drdrdrdrugugugug
A AAA
Plasma Metabolome Reveals Mechanism
Signature of lipogenesis
PPA
R-γ
Increased with drug BDecreased with drug B Increased with drug BDecreased with drug Increased with drug BDecreased with drug B
-100%
200%
-150% 150%
Increased with drug BDecreased with drug
All other metabolites
β3-Adrenergic 0
50
100
150
200
250
300
350
Cholesterol Glucose Triglycerides
mgs
per
dL
0
50
100
150
200
250
300
350
400
450
Cholesterol Glucose Triglycerides
mgs
per
dL
Must know both the identity and quantity of each metabolite
Metabolic Assessment
• High-content assays are required to elucidate metabolic basis for phenotype
• Want data on both metabolite concentrations and metabolic flux
Must know both the identity and quantity of each metabolite
Building Diagnostics
• Single chronic diseases have more than one metabolic (or environmental) cause
• Next generation diagnostics need to provide actionable information. – What dysregulation needs treatment?
• Metabolic assessment enables actionable, individual-specific diagnoses.
Delivering Health to the Individual
Individual Dx Map to Pathway Action
Biochemical Profiling of Lipids: Applications to Drug Development and Toxicology
Steven M. Watkins, Ph.D. President/CSO