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Anti- Lipemic Mechanism of (R) -α- Lipoic Acid (LA)

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

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Anti- Lipemic Mechanism of (R) -α- Lipoic Acid (LA)

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  1. Anti-Lipemic Mechanism of (R)-α-Lipoic Acid (LA) Regis Moreau, Ph.D.Assistant ProfessorDepartment of Nutrition and Health SciencesUniversity of Nebraska-Lincoln LA ZuckerDiabetic Fatty(ZDF) rats,model of hypertriglyceridemia

  2. 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 ZuckerDiabetic Fatty(ZDF) rats,model of hypertriglyceridemia

  3. 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

  4. Novel Molecular Targets of LA LA TSC1/2 FGF21 LA X6 β-Klotho mTORC1 Rheb FGFR1 SREBP1c Tf ChREBP Tf β-oxidationgenes X5 Lipogenic genesACC, FAS, GPAT1, DGAT2 Fgf21 Liver Liver Muscle 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)

  5. Preliminary Studies C A B D A) Feeding LA to obese rats corrects hypertriglyceridemia (–70%). B) Feeding LA to obese rats increases blood FGF21levels (+600%). 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. Butler et al. 2009 ABB; Finlay et al. 2011 AJP

  6. Experimental Models • Fgfr1f/f/Cremice lacking fibroblast growth factor-21 (FGF21) receptor • Tsc1f/f/Cre mice constitutively expressing mammalian target of rapamycin complex 1 (mTORC1) Cre/ESR +Tamoxifen Fgfr1 Gt(ROSA)26Sor Cre ESR loxP loxP Fgfr1 KO Cre/ESR +Tamoxifen Tsc1 Gt(ROSA)26Sor Cre ESR loxP loxP Tsc1 KO

  7. 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

  8. 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 LA 2A. 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

  9. 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

  10. 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

  11. NPOD Scientific Collaborations • Dr. Dmitri Fomenko (Project Leader 2) • Thiol disulfide exchange between LA and protein sulfhydryls(COBRE-supported Redox Biology Center) • Dr. SaraswathiViswanathan (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/Cremice

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