Journal ArticleDOI
Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis
Spyridon Theofilopoulos,Yuqin Wang,Satish Srinivas Kitambi,Paola Sacchetti,Paola Sacchetti,Kyle M. Sousa,Kyle M. Sousa,Karl Bodin,Jayne Kirk,Carmen Saltó,Magnus Gustafsson,Enrique M. Toledo,Kersti Karu,Jan-Åke Gustafsson,Knut R. Steffensen,Patrik Ernfors,Jan Sjövall,William J. Griffiths,Ernest Arenas +18 more
TLDR
Cholic acid was identified as a new Lxr ligand and 24(S),25-epoxycholesterol (24,25-EC) was found to be the most potent and abundant LxR ligand in the developing mouse midbrain, suggesting that L xr ligands may contribute to the development of cell replacement and regenerative therapies for Parkinson's disease.Abstract:
Liver X receptors (Lxrα and Lxrβ) are ligand-dependent nuclear receptors critical for ventral midbrain neurogenesis in vivo. However, no endogenous midbrain Lxr ligand has so far been identified. Here we used LC/MS and functional assays to identify cholic acid as a new Lxr ligand. Moreover, 24(S),25-epoxycholesterol (24,25-EC) was found to be the most potent and abundant Lxr ligand in the developing mouse midbrain. Both Lxr ligands promoted neural development in an Lxr-dependent manner in zebrafish in vivo. Notably, each ligand selectively regulated the development of distinct midbrain neuronal populations. Whereas cholic acid increased survival and neurogenesis of Brn3a-positive red nucleus neurons, 24,25-EC promoted dopaminergic neurogenesis. These results identify an entirely new class of highly selective and cell type-specific regulators of neurogenesis and neuronal survival. Moreover, 24,25-EC promoted dopaminergic differentiation of embryonic stem cells, suggesting that Lxr ligands may thus contribute to the development of cell replacement and regenerative therapies for Parkinson's disease.read more
Citations
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Journal ArticleDOI
Liver X receptors in lipid metabolism: opportunities for drug discovery
Cynthia Hong,Peter Tontonoz +1 more
TL;DR: New strategies for the pharmacological manipulation of LXRs and their target genes offer promise for the treatment of human diseases in which lipids have a central role, including atherosclerosis and Alzheimer's disease.
Journal ArticleDOI
Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming
Susan Gascon,Elisa Murenu,Giacomo Masserdotti,Felipe Ortega,Felipe Ortega,Felipe Ortega,Gianluca Luigi Russo,David Petrik,Aditi Deshpande,Christophe Heinrich,Marisa Karow,Stephen P. Robertson,Timm Schroeder,Johannes Beckers,Martin Irmler,Carsten Berndt,José Pedro Friedmann Angeli,Marcus Conrad,Benedikt Berninger,Benedikt Berninger,Magdalena Götz +20 more
TL;DR: Co-expression of Bcl-2 and anti-oxidative treatments leads to an unprecedented improvement in glial-to-neuron conversion after traumatic brain injury in vivo, underscoring the relevance of these pathways in cellular reprograming irrespective of cell type in vitro and in vivo.
Journal ArticleDOI
How to make a midbrain dopaminergic neuron
TL;DR: This Primer summarises recent efforts to generate human midbrain dopaminergic neurons in vitro, from pluripotent stem cells or from somatic cells via direct reprogramming.
Journal ArticleDOI
Oxysterols: From cholesterol metabolites to key mediators
TL;DR: The complex metabolism and molecular targets (including binding properties) of these bioactive lipids in human and mice are discussed and the genetic mouse models currently available to interrogate their effects in pathophysiological settings are discussed.
Journal ArticleDOI
The Role of Lipids in Parkinson’s Disease
TL;DR: The authors' review corroborates a central role for most lipid classes, but the available information is fragmented, not always reproducible, and sometimes differs by sex, age or PD etiology of the patients, hinders drawing firm conclusions about causal or associative effects of dietary lipids or defects in specific steps of lipid metabolism in PD.
References
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Journal ArticleDOI
Identification of a Nuclear Receptor for Bile Acids
Makoto Makishima,Arthur Y. Okamoto,Joyce J. Repa,Hua Tu,R. Marc Learned,Alvin Luk,Mitchell V. Hull,Kevin D. Lustig,David J. Mangelsdorf,Bei Shan +9 more
TL;DR: Results presented here show that bile acids are physiological ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor, which demonstrates a mechanism by which bile acid transcriptionally regulate their biosynthesis and enterohepatic transport.
Journal ArticleDOI
Bile Acids: Natural Ligands for an Orphan Nuclear Receptor
Derek J. Parks,Steven G. Blanchard,Randy K. Bledsoe,Gyan Chandra,Thomas G. Consler,Steven A. Kliewer,Julie B. Stimmel,Timothy M. Willson,Ann Marie Zavacki,David D. Moore,Jürgen M. Lehmann +10 more
TL;DR: Results provide evidence for a nuclear bile acid signaling pathway that may regulate cholesterol homeostasis and modulated interaction of FXR with a peptide derived from steroid receptor coactivator 1.
Journal ArticleDOI
Nuclear receptors and lipid physiology: opening the X-files.
TL;DR: Some general principles that govern the actions of this class of bioactive lipids and their nuclear receptors are considered here, and the scheme that emerges reveals a complex molecular script at work.
Journal ArticleDOI
An oxysterol signalling pathway mediated by the nuclear receptor LXRα
TL;DR: The results demonstrate the existence of a nuclear receptor signalling pathway for oxysterols and suggest that LXRα may be important as a sensor of cholesterol metabolites.
Journal ArticleDOI
Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.
TL;DR: It is suggested that FXR (BAR) is the endogenous biliary component that selectively activates the orphan nuclear receptor, FXR, and thus an important regulator of cholesterol homeostasis.
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