Anti- Lipemic Mechanism of (R) -α- Lipoic Acid (LA)
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Anti-Lipemic Mechanism of (R)-α-Lipoic Acid (LA) Regis Moreau, Ph.D. Assistant Professor Department of Nutrition and Health Sciences University of Nebraska-Lincoln LA Zucker Diabetic Fatty (ZDF) rats, model of hypertriglyceridemia
description
Anti- Lipemic Mechanism of (R) -α- Lipoic Acid (LA). Regis Moreau, Ph.D. Assistant Professor Department of Nutrition and Health Sciences University of Nebraska-Lincoln. LA. Zucker Diabetic Fatty (ZDF) rats, model of hypertriglyceridemia. Fit with the COBRE Theme - PowerPoint PPT Presentation
Transcript of Anti- Lipemic Mechanism of (R) -α- Lipoic Acid (LA)
Anti-Lipemic Mechanism of (R)-α-Lipoic Acid (LA)
Regis Moreau, Ph.D.
Assistant ProfessorDepartment of Nutrition and Health Sciences
University of Nebraska-Lincoln
LA
Zucker Diabetic Fatty (ZDF) rats,
model of hypertriglyceridemia
Fit with the COBRE Theme• Controlling blood lipid abnormalities is a major public health challenge
• Hypertriglyceridemia affects 65 million Americans
• Major risk factor for cardiovascular disease and type-2 diabetes
• Dietary molecule: (R)-a-lipoic acid (LA)– Naturally occurring molecule synthesized by plants and animals
– Used therapeutically in diabetics
– Safe in humans
– Lipid-lowering properties have recently been recognized
LA
Zucker Diabetic Fatty (ZDF) rats,
model of hypertriglyceridemia
Goals of the Project• Identify the molecular targets and signaling mechanism of LA
• Generate interest in the therapeutic use of LA
Central Hypothesis• LA corrects hypertriglyceridemia by the combined stimulation of triglyceride
(TG) clearance mediated by FGF21 and inhibition of hepatic TG synthesis mediated by mTORC1
Novel Molecular Targets of LA
Fibroblast growth factor-21 (FGF21) mediates the lipolytic properties of LA(Tf = Transcription factor)
LA downregulates SREBP1c-mediated transcription of lipogenic genes through inactivation mTORC1 (mammalian target of rapamycin complex 1)
β-oxidationgenes
Tf
FGFR
1 β-K
loth
o
Fgf21
Tf
X5
FGF21LA
Liver Muscle
X6
SREBP1c
LA
ChREBP
Lipogenic genesACC, FAS, GPAT1, DGAT2
mTORC1 Rheb
TSC1/2
Liver
Preliminary Studies
A) Feeding LA to obese rats corrects hypertriglyceridemia (–70%).B) Feeding LA to obese rats increases blood FGF21 levels (+600%).
A B
C) LA (50 µM) added to liver cells inactivates mTORC1 via dephosphorylation of mTOR and loss of Raptor. Ctl = vehicle control.D) LA lowers hepatic levels of transcription factors SREBP1c and ChREBP downstream of mTORC1.
C
D
Butler et al. 2009 ABB; Finlay et al. 2011 AJP
Experimental Models
• Fgfr1f/f/Cre mice lacking fibroblast growth factor-21 (FGF21) receptor
• Tsc1f/f/Cre mice constitutively expressing mammalian target of rapamycin complex 1 (mTORC1)
Gt(ROSA)26Sor Cre ESR Fgfr1
loxPloxP
Cre/ESR+
Tamoxifen
Fgfr1 KO
Gt(ROSA)26Sor Cre ESR Tsc1
loxPloxP
Cre/ESR+
Tamoxifen
Tsc1 KO
Innovation• Shift from the current paradigm that LA acts as an antioxidant
• Novel lipid-lowering mechanisms of LA– Stimulation of lipid clearance (FGF21)
– Downregulation of triglyceride synthesis (mTORC1)
Outcome• Safe and economical alternative to current lipid-lowering therapies
• Mechanism-based rationale for clinical trials with LA
Timetable of the Proposed Studies• The project will span 3 years
• Two Specific Aims– Specific Aim 1. Define the role of FGF21 in the mechanism of LA
1A. Elucidate the mechanism by which LA up-regulates FGF21 gene expression
1B. Assess the FGF21 sensitizing properties of LA and consequences on lipolysis
– Specific Aim 2. Define the role of mTORC1 in the mechanism of LA2A. Elucidate the mechanism by which LA represses mTORC1 activity
2B. Ascertain SREBP1c requirement in mTORC1 repression by LA
2C. Evaluate the consequences of mTORC1 repression by LA on lipogenesis
• Year 1: Initiate Specific Aims 1A, 1B and 2A, complete Specific Aim 1A
• Year 2: Complete Specific Aims 1B and 2A, initiate Specific Aims 2C
• October of Year 2: Submission date for an R01 (NHLBI, NIDDK, NCCAM)
• Year 3: Complete Specific Aims 2B and 2C
Mentorship Work Plan• Primary mentor
– Dr. Janos Zempleni (NHS, UNL)• Published work on LA
• Collection of chemically defined LA metabolites (structure-function studies)
• Secondary mentors– Dr. Edgar Cahoon (Biochemistry, UNL)
• Expert in secondary plant metabolites
• Strategies to increase LA content in plants
– Dr. Mark Wilson (Biochemistry, UNL)• Expert in X-ray crystallography
• Structure-signaling relationships of LA and signaling protein
Use of UNL Core Research Facilities• NPOD Epigenetics Core
– Chromatin immunoprecipitation (ChIP) assay
– Antibody validation
• NPOD Computational and Data Sharing Core– Statistical data analysis
• Genomics Core– DNA sequencing
– Primer validation
– RNA integrity
• Animal Research Facility– Breeding colonies
– Feeding trials
NPOD Scientific Collaborations• Dr. Dmitri Fomenko (Project Leader 2)
– Thiol disulfide exchange between LA and protein sulfhydryls (COBRE-supported Redox Biology Center)
• Dr. Saraswathi Viswanathan (Project Leader 5)– LA-omega 3 fatty acids synergies
Existing Collaborations• Dr. Qingsheng Li (COBRE-supported Nebraska Center for Virology)
– Recombinant lentivirus gene knockdown
• Dr. David Wasserman (Vanderbilt-NIDDK Mouse Metabolic Phenotyping Center)
– Metabolic studies in Fgfr1f/f/Cre mice
