Dopamine Burden Triggers Cholesterol Overload Following Disruption of Synaptogenesis in Minimal Hepatic Encephalopathy

Zhuge, Weishan; Wen, Fangfang; Ni, Zhihui; Zhao, Zheng; Zhu, Xiaohong; Lin, Jianting; Wang, Jian; Zhuge, Qichuan; Ding, Saidan

doi:10.1016/j.neuroscience.2019.04.056

Cited by 9 publications

(9 citation statements)

References 42 publications

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“…Several studies have demonstrated that hepatic encephalopathy is accompanied by increased levels of dopamine in brain (Ding et al, 2013, 2016, 2017; Ding, Huang, et al, 2014; Rai & Dhiman, 2013; Zhuge et al, 2019). In thioacetamide (TAA)‐induced acute liver failure rats it was found that levels of 5‐hydroxyindoleacetic acid and dopamine in the prefrontal cortex and the hippocampus, as well as 5‐hydroxytryptamine (5‐HT; serotonin) levels in the prefrontal cortex were significantly higher than those in control rats (Yurdaydin et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Bile duct ligation increased dopamine levels in the cerebral cortex of rats partly due to induction of tyrosine hydroxylase

Kong

Sun

et al. 2023

British J Pharmacology

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Background and Purpose Liver failure is associated with psychiatric alterations, partly resulting from the increased brain dopamine levels. We investigated the relationship between increased dopamine levels and mental abnormalities using bile duct ligation (BDL) rats and the mechanism by which liver failure increased dopamine levels in SH‐SY5Y cells. Behavioural tests were carried out on day 13 and 27 following BDL, along with measurements of dopamine and metabolites, expressions of enzymes and transporters related to dopamine metabolism, and its transport into the cortex and the hippocampus. SH‐SY5Y cells were used to investigate whether NH4Cl, bile acids and bilirubin affected expression of tyrosine hydroxylase or not. Tyrosine hydroxylase (TH) expression in SH‐SY5Y cells co‐incubated with bilirubin and signal pathway inhibitors was measured. Key Results Open‐field test results demonstrated BDL rats showed anxiety‐like behaviour, accompanied by increased dopamine levels and expression of TH protein in the cortex. Membrane bound long form (MB)‐COMT, slightly but significantly decreased. SH‐SY5Y cells indicated that increased bilirubin levels was a factor in inducing TH expression. Both inhibitor of NF‐κB pathway BAY 11‐7082 and silencing NF‐κB p65 reversed bilirubin‐induced upregulation of TH protein. NF‐κB activator TNF‐α increased expression of TH protein. Roles of bilirubin in increases of TH protein expressions and dopamine levels were measured using hyperbilirubinemia rats. Anxiety‐like behaviour, was associated with increased dopamine levels and TH protein expressions in hyperbilirubinemia rats. Conclusion and Implications BDL significantly increased dopamine levels in rat cortex partly due to bilirubin‐mediated TH induction. Increased bilirubin induced TH expression via activating NF‐κB signalling pathway.

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Section: Introductionmentioning

confidence: 99%

Bile duct ligation increased dopamine levels in the cerebral cortex of rats partly due to induction of tyrosine hydroxylase

Kong

Sun

et al. 2023

British J Pharmacology

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“…Lipid accumulation in glial cells due to reactive oxygen species production and mitochondrial damage leads to further neuronal damage and degeneration ( Ioannou et al, 2019 ). Moderate cholesterol homeostasis maintains the structure of α-synuclein; however, excess cholesterol promotes the local deposition of α-synuclein and the formation of Lewy vesicles with aggregated α-synuclein, which in turn affects the function of DATs and dopaminergic neurons ( van Maarschalkerweerd et al, 2015 ; Zhuge et al, 2019 ). Furthermore, the cholesterol metabolite 27-OHC decreases TH activity and causes oxidative stress and apoptosis ( Dai et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Proteomic profiling reveals the potential mechanisms and regulatory targets of sirtuin 4 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s mouse model

Weng

Song

et al. 2023

Front. Neurosci.

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IntroductionParkinson’s disease (PD), as a common neurodegenerative disease, currently has no effective therapeutic approaches to delay or stop its progression. There is an urgent need to further define its pathogenesis and develop new therapeutic targets. An increasing number of studies have shown that members of the sirtuin (SIRT) family are differentially involved in neurodegenerative diseases, indicating their potential to serve as targets in therapeutic strategies. Mitochondrial SIRT4 possesses multiple enzymatic activities, such as deacetylase, ADP ribosyltransferase, lipoamidase, and deacylase activities, and exhibits different enzymatic activities and target substrates in different tissues and cells; thus, mitochondrial SIRT4 plays an integral role in regulating metabolism. However, the role and mechanism of SIRT4 in PD are not fully understood. This study aimed to investigate the potential mechanism and possible regulatory targets of SIRT4 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice.MethodsThe expression of the SIRT4 protein in the MPTP-induced PD mouse mice or key familial Parkinson disease protein 7 knockout (DJ-1 KO) rat was compared against the control group by western blot assay. Afterwards, quantitative proteomics and bioinformatics analyses were performed to identify altered proteins in the vitro model and reveal the possible functional role of SIRT4. The most promising molecular target of SIRT4 were screened and validated by viral transfection, western blot assay and reverse transcription quantitative PCR (RT-qPCR) assays.ResultsThe expression of the SIRT4 protein was found to be altered both in the MPTP-induced PD mouse mice and DJ-1KO rats. Following the viral transfection of SIRT4, a quantitative proteomics analysis identified 5,094 altered proteins in the vitro model, including 213 significantly upregulated proteins and 222 significantly downregulated proteins. The results from bioinformatics analyses indicated that SIRT4 mainly affected the ribosomal pathway, propionate metabolism pathway, peroxisome proliferator-activated receptor (PPAR) signaling pathway and peroxisome pathway in cells, and we screened 25 potential molecular targets. Finally, only fatty acid binding protein 4 (FABP4) in the PPAR signaling pathway was regulated by SIRT4 among the 25 molecules. Importantly, the alterations in FABP4 and PPARγ were verified in the MPTP-induced PD mouse model.DiscussionOur results indicated that FABP4 in the PPAR signaling pathway is the most promising molecular target of SIRT4 in an MPTP-induced mouse model and revealed the possible functional role of SIRT4. This study provides a reference for future drug development and mechanism research with SIRT4 as a target or biomarker.

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“…It is worth noting that the relationship between cholesterol and DA is not one-sided. Excess DA is responsible for the increase in cholesterol synthesis by activating the c-Jun N-terminal kinase (JNK3)/sterol regulatory element-binding protein 2 (SREBP2) signaling pathway in astrocyte colonies [ 44 ].…”

Section: Statins and Dopaminergic Neurotransmissionmentioning

confidence: 99%

The Effects of Statins on Neurotransmission and Their Neuroprotective Role in Neurological and Psychiatric Disorders

et al. 2021

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Statins are among the most widely used drug classes in the world. Apart from their basic mechanism of action, which is lowering cholesterol levels, many pleiotropic effects have been described so far, such as anti-inflammatory and antiatherosclerotic effects. A growing number of scientific reports have proven that these drugs have a beneficial effect on the functioning of the nervous system. The first reports proving that lipid-lowering therapy can influence the development of neurological and psychiatric diseases appeared in the 1990s. Despite numerous studies about the mechanisms by which statins may affect the functioning of the central nervous system (CNS), there are still no clear data explaining this effect. Most studies have focused on the metabolic effects of this group of drugs, however authors have also described the pleiotropic effects of statins, pointing to their probable impact on the neurotransmitter system and neuroprotective effects. The aim of this paper was to review the literature describing the impacts of statins on dopamine, serotonin, acetylcholine, and glutamate neurotransmission, as well as their neuroprotective role. This paper focuses on the mechanisms by which statins affect neurotransmission, as well as on their impacts on neurological and psychiatric diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), vascular dementia (VD), stroke, and depression. The pleiotropic effects of statin usage could potentially open floodgates for research in these treatment domains, catching the attention of researchers and clinicians across the globe.

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Dopamine Burden Triggers Cholesterol Overload Following Disruption of Synaptogenesis in Minimal Hepatic Encephalopathy

Cited by 9 publications

References 42 publications

Bile duct ligation increased dopamine levels in the cerebral cortex of rats partly due to induction of tyrosine hydroxylase

Bile duct ligation increased dopamine levels in the cerebral cortex of rats partly due to induction of tyrosine hydroxylase

Proteomic profiling reveals the potential mechanisms and regulatory targets of sirtuin 4 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s mouse model

The Effects of Statins on Neurotransmission and Their Neuroprotective Role in Neurological and Psychiatric Disorders

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