On the role of oxysterols in regulation of cholesterol homeostasis by nuclear receptors

2007 ◽  
pp. 80-87
Author(s):  
S. Meaney ◽  
I. Björkhem
Keyword(s):  
Nuclear Receptors ◽  
Cholesterol Homeostasis

W15-P-001 Role of nuclear receptors in the molecular regulation of cholesterol homeostasis in cultured human hepatocytes

2005 ◽  
Vol 6 (1) ◽  
pp. 96-97
Author(s):  
M. Bertolotti ◽  
C. Anzivino ◽  
C. Gabbi ◽  
E. Tenedini ◽  
E. Tagliafico ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Human Hepatocytes ◽  
Cholesterol Homeostasis ◽  
Molecular Regulation

The role of hepatic 11[b]-hydroxysteroid dehydrogenase type 1 in cholesterol homeostasis

2013 ◽  
pp. 1-1
Author(s):  
Kajal Manwani ◽  
Tak Y Man ◽  
Christopher J Kenyon ◽  
Ruth Andrew ◽  
Karen E Chapman ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Cholesterol Homeostasis

scholarly journals Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Vijay R. Varma ◽  
H. Büşra Lüleci ◽  
Anup M. Oommen ◽  
Sudhir Varma ◽  
Chad T. Blackshear ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Tissue ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Transcriptomic Data ◽  
Brain Cholesterol ◽  
Cholesterol Levels

AbstractThe role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

Role of nuclear receptors and hepatocyte-enriched transcription factors for Ntcp repression in biliary obstruction in mouse liver

2005 ◽  
Vol 289 (5) ◽  
pp. G798-G805 ◽  
Author(s):  
Gernot Zollner ◽  
Martin Wagner ◽  
Peter Fickert ◽  
Andreas Geier ◽  
Andrea Fuchsbichler ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Bile Acid ◽  
Dna Binding ◽  
Nuclear Receptors ◽  
Farnesoid X Receptor ◽  
Acid Uptake ◽  
Mrna Levels ◽  
Uptake System ◽  
Duct Ligation

Expression of the main hepatic bile acid uptake system, the Na+-taurocholate cotransporter (Ntcp), is downregulated during cholestasis. Bile acid-induced, farnesoid X receptor (FXR)-mediated induction of the nuclear repressor short heterodimer partner (SHP) has been proposed as a key mechanism reducing Ntcp expression. However, the role of FXR and SHP or other nuclear receptors and hepatocyte-enriched transcription factors in mediating Ntcp repression in obstructive cholestasis is unclear. FXR knockout (FXR−/−) and wild-type (FXR+/+) mice were subjected to common bile duct ligation (CBDL). Cholic acid (CA)-fed and LPS-treated FXR−/− and FXR+/+ mice were studied for comparison. mRNA levels of Ntcp and SHP and nuclear protein levels of hepatocyte nuclear factor (HNF)-1α, HNF-3β, HNF-4α, retinoid X receptor (RXR)-α, and retinoic acid receptor (RAR)-α and their DNA binding were assessed. Hepatic cytokine mRNA levels were also measured. CBDL and CA led to Ntcp repression in FXR+/+, but not FXR−/−, mice, whereas LPS reduced Ntcp expression in both genotypes. CBDL and LPS but not CA induced cytokine expression and reduced levels of HNF-1α, HNF-3β, HNF-4α, RXRα, and RARα to similar extents in FXR+/+ and FXR−/−. DNA binding of these transactivators was unaffected by CA in FXR+/+ mice but was markedly reduced in FXR−/− mice. In conclusion, Ntcp repression by CBDL and CA is mediated by accumulating bile acids via FXR and does not depend on cytokines, whereas Ntcp repression by LPS is independent of FXR. Reduced levels of HNF-1α, RXRα, and RARα in CBDL FXR−/− mice and reduced DNA binding in CA-fed FXR−/− mice, despite unchanged Ntcp levels, indicate that these factors may have a minor role in regulation of mouse Ntcp during cholestasis.

scholarly journals Role of nuclear receptors in neural stem cell biology of the mammalian central nervous system

2016 ◽  
Author(s):  
Αθανάσιος Στεργιόπουλος
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Stem Cell ◽  
Neural Stem Cell ◽  
Nuclear Receptors ◽  
Cell Biology ◽  
Stem Cell Biology ◽  
Mammalian Central Nervous System

Το δυναμικό και η ικανότητα αυτο-ανανέωσης και διαφοροποίησης των νευρικών βλαστικών κυττάρων (ΝΒΚ) ελέγχονται από τη δράση διαφόρων μεταγραφικών παραγόντων και πυρηνικών υποδοχέων, επηρεάζοντας μ ’αυτόν τον τρόπο την ανάπτυξη και τη λειτουργία του κεντρικού νευρικού συστήματος (ΚΝΣ). Στην παρούσα μελέτη χαρακτηρίσαμε τον ορφανό πυρηνικό υποδοχέα NR5A2 (LRH1), ως ένα νέο μόριο το οποίο κατέχει κεντρικό αναπτυξιακό ρόλο στο ΚΝΣ. Με πειράματα υπερ-έκφρασης και αποσιώπησης γονιδίων σε πρωτογενή ΝΒΚ καθώς και με ανάλυση εμβρύων ποντικών στα οποία έχει επιτραπεί η ιστο-ειδική και χρονική εξάλειψη του NR5A2, δείξαμε πως ο NR5A2 είναι ικανός να διακόπτει τον πολλαπλασιασμό των ΝΒΚ, οδηγώντας τα προς τη νευρωνική διαφοροποίηση με την παράλληλη απώλεια των αστροκυττάρων. Σε μηχανιστική βάση, ο NR5A2 ελέγχει αυτούς τους φαινοτύπους μέσω της άμεσης επίδρασής του στον γενετικό τόπο του Ink4/Arf, στο Prox1, το οποίο αποτελεί καθοδικό στόχο των προ-νευρικών γονιδίων, καθώς επίσης και στα σηματοδοτικά μονοπάτια του Notch1 και του JAK/STAT. Αντιθέτως, ο NR5A2 ρυθμίζεται ανοδικά από προ-νευρικά γονίδια και από τα Notch1 και JAK/STAT μονοπάτια. Συμπερασματικά, οι παρατηρήσεις μας προτείνουν τον NR5A2 σαν ένα νέο υποδοχέα-ρυθμιστή της ανάπτυξης του ΚΝΣ, και, σε συνδυασμό με την ανακάλυψη αγωνιστών/ανταγωνιστών του, τον καθιστούν υποψήφιο στόχο στην ανάπτυξη θεραπευτικών στρατηγικών αναγεννητικής ιατρικής του ΚΝΣ.

The Important Role of Lipids in Cognitive Impairment

2011 ◽  
pp. 206-211
Author(s):  
Yu Jia ◽  
Zheng Chen ◽  
Jiangyang Lu ◽  
Liu Tingting ◽  
Zhou Liang ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Memory Function ◽  
Pyramidal Cells ◽  
Cholesterol Homeostasis ◽  
Neonatal Lethality ◽  
Somatic Gene ◽  
Current Knowledge Base ◽  
Somatic Gene Transfer ◽  
The Brain

The current knowledge base on circulating serum and plasma risk factors of the cognitive decline of degenerative Alzheimer’s Disease is linked to cholesterol homeostasis and lipoprotein disturbances (i.e., total cholesterol, 24S-hydroxy-cholesterol, lipoprotein(a), or apolipoprotein E. Lipoprotein lipase (LPL) is also expressed in the brain, with the highest levels found in the pyramidal cells of the hippocampus, suggesting a possible role for LPL in the regulation of cognitive function. Little is currently known, however, about the specific role of LPL in the brain. The authors of this chapter have generated an LPL-deficient mouse model that was rescued from neonatal lethality by somatic gene transfer. The levels of the presynaptic marker synaptophysin were reduced in the hippocampus while the levels of the post-synaptic marker PSD-95 remained unchanged in the LPL-deficient mice. The decreased frequency of mEPSC in LPL-deficient neurons indicated that the number of presynaptic vesicles was decreased, which was consistent with the decreases observed in the numbers of total vesicles and docking vesicles. These findings indicate that LPL plays an important role in learning and memory function, possibly by influencing presynaptic function.

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