Journal ArticleDOI
Role of Fatty Acid Binding Proteins and Long Chain Fatty Acids in Modulating Nuclear Receptors and Gene Transcription
Friedhelm Schroeder,Anca D. Petrescu,Huan Huang,Barbara P. Atshaves,Avery L. McIntosh,Gregory G. Martin,Heather A. Hostetler,Aude Vespa,Danilo Landrock,Kerstin K. Landrock,H. Ross Payne,Ann B. Kier +11 more
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TLDR
The hypothesis that cytoplasmic lipid binding proteins transfer and channel lipidic ligands into nuclei for initiating nuclear receptor transcriptional activity to provide new lipid nutrient signaling pathways that affect lipid and glucose catabolism and storage is proposed.Abstract:
Abnormal energy regulation may significantly contribute to the pathogenesis of obesity, diabetes mellitus, cardiovascular disease, and cancer. For rapid control of energy homeostasis, allosteric and posttranslational events activate or alter activity of key metabolic enzymes. For longer impact, transcriptional regulation is more effective, especially in response to nutrients such as long chain fatty acids (LCFA). Recent advances provide insights into how poorly water-soluble lipid nutrients [LCFA; retinoic acid (RA)] and their metabolites (long chain fatty acyl Coenzyme A, LCFA-CoA) reach nuclei, bind their cognate ligand-activated receptors, and regulate transcription for signaling lipid and glucose catabolism or storage: (i) while serum and cytoplasmic LCFA levels are in the 200 μM–mM range, real-time imaging recently revealed that LCFA and LCFA-CoA are also located within nuclei (nM range); (ii) sensitive fluorescence binding assays show that LCFA-activated nuclear receptors [peroxisome proliferator-activated receptor-α (PPARα) and hepatocyte nuclear factor 4α (HNF4α)] exhibit high affinity (low nM Kds) for LCFA (PPARα) and/or LCFA-CoA (PPARα, HNF4α)—in the same range as nuclear levels of these ligands; (iii) live and fixed cell immunolabeling and imaging revealed that some cytoplasmic lipid binding proteins [liver fatty acid binding protein (L-FABP), acyl CoA binding protein (ACBP), cellular retinoic acid binding protein-2 (CRABP-2)] enter nuclei, bind nuclear receptors (PPARα, HNF4α, CRABP-2), and activate transcription of genes in fatty acid and glucose metabolism; and (iv) studies with gene ablated mice provided physiological relevance of LCFA and LCFA-CoA binding proteins in nuclear signaling. This led to the hypothesis that cytoplasmic lipid binding proteins transfer and channel lipidic ligands into nuclei for initiating nuclear receptor transcriptional activity to provide new lipid nutrient signaling pathways that affect lipid and glucose catabolism and storage.read more
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Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events.
TL;DR: Overall, current data provide strong concordant evidence that n-3 PUFA are bioactive compounds that reduce risk of cardiac death.
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Triglyceride Metabolism in the Liver
TL;DR: The current understanding of fatty acid and triglyceride metabolism in the liver and its regulation in health and disease is described, identifying potential directions for future research.
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Metabolic functions of FABPs--mechanisms and therapeutic implications.
TL;DR: The roles and regulation of both intracellular and extracellular FABP actions are discussed, highlighting new insights that might direct drug discovery efforts and opportunities for management of chronic metabolic diseases.
Journal ArticleDOI
Cellular Fatty Acid Uptake: A Pathway Under Construction
Xiong Su,Nada A. Abumrad +1 more
TL;DR: The contribution of CD36 to pathophysiology in rodents and humans is highlighted and variants in the CD36 gene were shown recently to influence susceptibility for the metabolic syndrome, which greatly increases the risk of diabetes and heart disease.
Journal ArticleDOI
Retinoic acid receptors: from molecular mechanisms to cancer therapy.
Alessandra di Masi,Loris Leboffe,Elisabetta De Marinis,Francesca Pagano,Laura Cicconi,Cécile Rochette-Egly,Francesco Lo-Coco,Paolo Ascenzi,Clara Nervi +8 more
TL;DR: An overview of the biochemical and molecular mechanisms that regulate the RA and retinoid signaling pathways is provided and mechanisms through which deregulation of RA signaling pathways ultimately impact on cancer are examined.
References
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Journal ArticleDOI
Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ
TL;DR: It is shown here that specific FAs, eicosanoids, and hypolipidemic drugs are ligands for PPARα or PPARδ, and a novel conformation-based assay is developed that screens activators for their ability to bind to PPAR α/δ and induce DNA binding.
Journal ArticleDOI
Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ
Steven A. Kliewer,Scott S. Sundseth,Stacey A. Jones,Peter Brown,G. Bruce Wisely,Cecilia S. Koble,Pallavi R. Devchand,Walter Wahli,Timothy M. Willson,James M. Lenhard,Jürgen M. Lehmann +10 more
TL;DR: Evidence that PPARs serve as physiological sensors of lipid levels is provided and a molecular mechanism whereby dietary fatty acids can modulate lipid homeostasis is suggested.
Journal ArticleDOI
Roles of PPARs in health and disease.
TL;DR: The latest developments in the PPAR field are presented, with particular emphasis on the physiological function ofPPARs during various nutritional states, and the possible role of PPARs in several chronic diseases.
Journal ArticleDOI
Convergence of 9- cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors
TL;DR: The coupling of the peroxisome proliferator and retinoid signalling pathways is demonstrated and evidence for a physiological role for 9-cis retinoic acid in modulating lipid metabolism is provided.
Journal ArticleDOI
Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators.
Susanna S.T. Lee,Thierry Pineau,John Drago,Eric J. Lee,Jennie W. Owens,Deanna L. Kroetz,Pedro M. Fernández-Salguero,Heiner Westphal,Frank J. Gonzalez +8 more
TL;DR: It is demonstrated that mPPAR alpha is the major isoform required for mediating the pleiotropic response resulting from the actions of peroxisome proliferators.