Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior

Huang, Fei; Wang, Tingting; Lan, Yunyi; Yang, Li; Pan, Weihong; Zhu, Yonghui; Lv, Boyang; Wei, Yinmao; Shi, Hailian; Wu, Hui; Zhang, Beibei; Wang, Jie; Duan, Xiaofeng; Zhi-bi, HU; Wu, Xiaojun

doi:10.3389/fnbeh.2015.00070

Cited by 79 publications

(60 citation statements)

References 50 publications

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“…Moreover, those changes were accompanied by reduced Fxr mRNA level in the brain and microglia of WD‐fed mice. FXR knockout mice have impaired memory and reduced motor coordination, based on behavioral studies (101). Together, it is likely that WD intake via deactivation of FXR‐ and TGR5‐regulated signaling affects cognition.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet–induced systemic inflammation, microglial activation, and reduced neuroplasticity

et al. 2018

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The goal of this study was to identify the intrinsic links that explain the effect of a Western diet (WD) on cognitive dysfunction. Specific pathogen-free, wild-type mice were fed either a control diet (CD) or a high-fat, high-sucrose WD after weaning and were euthanized at 10 mo of age to study the pathways that affect cognitive health. The results showed that long-term WD intake reduced hippocampal synaptic plasticity and the level of brain-derived neurotrophic factor mRNA in the brain and isolated microglia. A WD also activated ERK1/2 and reduced postsynaptic density-95 in the brain, suggesting postsynaptic damage. Moreover, WD-fed mice had increased inflammatory signaling in the brain, ileum, liver, adipose tissue, and spleen, which was accompanied by microglia activation. In the brain, as well as in the digestive tract, a WD reduced signaling regulated by retinoic acid and bile acids (BAs), whose receptors form heterodimers to control metabolism and inflammation. Furthermore, a WD intake caused dysbiosis and dysregulated BA synthesis with reduced endogenous ligands for BA receptors, i.e., farnesoid X receptor and G-protein-coupled bile acid receptor in the liver and brain. Together, dysregulated BA synthesis and dysbiosis were accompanied by systemic inflammation, microglial activation, and reduced neuroplasticity induced by WD.-Jena, P. K., Sheng, L., Di Lucente, J., Jin, L.-W., Maezawa, I., Wan, Y.-J. Y. Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet-induced systemic inflammation, microglial activation, and reduced neuroplasticity.

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Section: Discussionmentioning

confidence: 99%

Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet–induced systemic inflammation, microglial activation, and reduced neuroplasticity

et al. 2018

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“…Considering that Fxr-null mice had some unusual phenotypes, including disrupted multiple neurotransmitter systems and neurobehavior (46), impaired urine concentrating ability (47), and changed gut microbiota (48), FXR may affect various pathways in vivo. Liver-and intestine-specific Fxr-null mice were developed to show differential roles of this receptor (49 -51).…”

Section: Discussionmentioning

confidence: 99%

Celastrol Protects From Cholestatic Liver Injury Through Modulation of SIRT1-FXR Signaling

Zhao

Liu

Cheng

et al. 2019

Molecular & Cellular Proteomics

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The present study used metabolomics, transcriptomics, protein analysis by immunoblots, chemical inhibition and gene knockout mice to determine the effects of celastrol on cholestasis and its mechanisms. Samples from patients were used to validate our findings, and the data supported the conclusions that celastrol protected against cholestatic liver injury through modulation of the SIRT1 and FXR. Graphical Abstract Highlights• 1. Celastrol alleviated cholestatic liver injury.• 2. Celastrol inhibited the decrease of SIRT1 induced by deoxycholic acid.• 3. SIRT1-FXR signaling pathway mediated the effect of celastrol.Celastrol, derived from the roots of the Tripterygium Wilfordi, shows a striking effect on obesity. In the present study, the role of celastrol in cholestasis was investigated using metabolomics and transcriptomics. Celastrol treatment significantly alleviated cholestatic liver injury in mice induced by ␣-naphthyl isothiocyanate (ANIT) and thioacetamide (TAA). Celastrol was found to activate sirtuin 1 (SIRT1), increase farnesoid X receptor (FXR) signaling and inhibit nuclear factor-kappa B and P53 signaling. The protective role of celastrol in cholestatic liver injury was diminished in mice on co-administration of SIRT1 inhibitors. Further, the effects of celastrol on cholestatic liver injury were dramatically decreased in Fxr-null mice, suggesting that the SIRT1-FXR signaling pathway mediates the protective effects of celastrol. These observations demonstrated a novel role for celastrol in protecting against cholestatic liver injury through modulation of the SIRT1 and FXR.

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“…PAT was conducted in the shuttle boxes, as described previously (9). Briefly, on day 1, the mice were trained to learn to stay in the bright chamber with a criterion of 300 sec.…”

Section: Behavioral Tests Rotarod Test (Rrt) Rrt Was Carried Out Witmentioning

confidence: 99%

Qing'E formula alleviates the aging process in D-galactose-induced aging mice

et al. 2016

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Qing'E formula (QEF) is a clinically used prescription with four ingredients, ,, and, from the Song dynasty (10th century CE). The present study aimed to investigate the anti-aging effect and mechanisms of QEF on D-galactose-induced aging mice. A mouse subacute aging model was established by subcutaneous injection of D-galactose at the neck consecutively for 8 weeks. Motor activity and memory impairment of the mice were evaluated by the rotarod test and passive avoidance test, respectively. Serum and liver parameters were analyzed with biochemical kits. Hippocampal mRNA and protein expression levels were examined by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. QEF administration significantly ameliorated the impaired motor and memory of aging mice. In the serum, QEF reduced blood urea nitrogen, creatinine, nitric oxide (NO) and malondialdehyde (MDA) levels, and inhibited alanine aminotransferase and aspartate aminotransferase activities. In the liver, QEF increased the glutathione level, enhanced total antioxidant capacity and catalase activity, deceased NO and MDA production, and reduced NO synthase activity. In the hippocampus, QEF elevated gene expression levels of Klotho, sirtuin 1 (), forkhead box transcription factor O3, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), insulin-like growth factor-1 and peroxiredoxin-3. QEF increased protein expression levels of Klotho and SIRT1, and decreased that of PGC-1α in the hippocampus. In conclusion, QEF attenuated the aging process in D-galactose-treated mice, which may be mediated through enhancing the antioxidants in the body, protecting renal and hepatic health, and balancing hippocampal expression levels of the longevity-related genes.

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Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior

Cited by 79 publications

References 50 publications

Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet–induced systemic inflammation, microglial activation, and reduced neuroplasticity

Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet–induced systemic inflammation, microglial activation, and reduced neuroplasticity

Celastrol Protects From Cholestatic Liver Injury Through Modulation of SIRT1-FXR Signaling

Qing'E formula alleviates the aging process in D-galactose-induced aging mice

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