Inhibitors of Fatty Acid Synthesis Induce PPARα-Regulated Fatty Acid β-Oxidative Genes: Synergistic Roles of L-FABP and GlucoseReport as inadecuate

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PPAR ResearchVolume 2013 2013, Article ID 865604, 22 pages

Research Article

Department of Physiology and Pharmacology, Texas A&M University, TAMU 4466, College Station, TX 77843-4466, USA

Department of Pathobiology, Texas A&M University, TAMU 4467, College Station, TX 77843-4467, USA

Received 13 November 2012; Accepted 21 December 2012

Academic Editor: Noa Noy

Copyright © 2013 Huan Huang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


While TOFA acetyl CoA carboxylase inhibitor and C75 fatty acid synthase inhibitor prevent lipid accumulation by inhibiting fatty acid synthesis, the mechanism of action is not simply accounted for by inhibition of the enzymes alone. Liver fatty acid binding protein L-FABP, a mediator of long chain fatty acid signaling to peroxisome proliferator-activated receptor-α PPARα in the nucleus, was found to bind TOFA and its activated CoA thioester, TOFyl-CoA, with high affinity while binding C75 and C75-CoA with lower affinity. Binding of TOFA and C75-CoA significantly altered L-FABP secondary structure. High 20 mM but not physiological 6 mM glucose conferred on both TOFA and C75 the ability to induce PPARα transcription of the fattyacid β-oxidative enzymes CPT1A, CPT2, and ACOX1 in cultured primary hepatocytes from wild-type WT mice. However, L-FABP gene ablation abolished the effects of TOFA and C75 in the context of high glucose. These effects were not associatedwith an increased cellular level of unesterified fatty acids but rather by increased intracellular glucose. These findings suggested that L-FABP may function as an intracellular fatty acid synthesis inhibitor binding proteinfacilitating TOFA and C75-mediated induction of PPARα in the context of high glucose at levels similar to those in uncontrolled diabetes.

Author: Huan Huang, Avery L. McIntosh, Gregory G. Martin, Anca D. Petrescu, Kerstin K. Landrock, Danilo Landrock, Ann B. Kier, and



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