Dataset Information

Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells.

ABSTRACT: Activation of hepatic stellate cells (HSCs) in response to injury is a key step in hepatic fibrosis, and is characterized by trans-differentiation of quiescent HSCs to HSC myofibroblasts, which secrete extracellular matrix proteins responsible for the fibrotic scar. There are currently no therapies to directly inhibit hepatic fibrosis. We developed a small molecule screen to identify compounds that inactivate human HSC myofibroblasts through the quantification of lipid droplets. We screened 1600 compounds and identified 21 small molecules that induce HSC inactivation. Four hits were tricyclic antidepressants (TCAs), and they repressed expression of pro-fibrotic factors Alpha-Actin-2 (ACTA2) and Alpha-1 Type I Collagen (COL1A1) in HSCs. RNA sequencing implicated the sphingolipid pathway as a target of the TCAs. Indeed, TCA treatment of HSCs promoted accumulation of ceramide through inhibition of acid ceramidase (aCDase). Depletion of aCDase also promoted accumulation of ceramide and was associated with reduced COL1A1 expression. Treatment with B13, an inhibitor of aCDase, reproduced the antifibrotic phenotype as did the addition of exogenous ceramide. Our results show that detection of lipid droplets provides a robust readout to screen for regulators of hepatic fibrosis and have identified a novel antifibrotic role for ceramide.

SUBMITTER: Chen JY

PROVIDER: S-EPMC5359599 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells.

Chen Jennifer Y JY Newcomb Benjamin B Zhou Chan C Pondick Joshua V JV Ghoshal Sarani S York Samuel R SR Motola Daniel L DL Coant Nicolas N Yi Jae Kyo JK Mao Cungui C Tanabe Kenneth K KK Bronova Irina I Berdyshev Evgeny V EV Fuchs Bryan C BC Hannun Yusuf Y Chung Raymond T RT Mullen Alan C AC

Scientific reports 20170321

Activation of hepatic stellate cells (HSCs) in response to injury is a key step in hepatic fibrosis, and is characterized by trans-differentiation of quiescent HSCs to HSC myofibroblasts, which secrete extracellular matrix proteins responsible for the fibrotic scar. There are currently no therapies to directly inhibit hepatic fibrosis. We developed a small molecule screen to identify compounds that inactivate human HSC myofibroblasts through the quantification of lipid droplets. We screened 1600 ...[more]

PMID: 28322247

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Project description:BackgroundMigraine, ranked as the 7th-highest specific cause of disability worldwide, has caused an enormous burden on the economy and society. Tricyclic antidepressant (TCA) is one of the most commonly drugs for migraine prevention. However, evidence about the efficacy and tolerability of TCAs in the prophylaxis of migraine in adults is somewhat confusing.MethodsA computerized literature search of the PubMed, Embase, Cochrane, and Web of Science databases from inception to July 2016 was conducted. We reviewed all randomized controlled trials that assigned adults with a clinical diagnosis of migraine to TCAs or other treatments (placebo or other antidepressants). Reduction in migraine frequency or index and response rates to treatment were defined as the efficacy outcomes. Rates of dropout due to adverse effects were defined as the tolerability outcomes.ResultsIn total 12 trials consisting of 1006 participants were identified: 9 trials compared TCAs with placebo, and the other 3 compared amitriptyline with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). A significant advantage of TCAs compared with placebo in the prevention of migraine in adults was observed (standardized mean difference [SMD] = -.75; 95% confidence interval [CI] = -1.05 to -.46; P?<?.00001). Participants receiving TCAs were more likely to experience an ?50% reduction in their headache burden than those receiving placebo (risk ratio [RR] =1.40; 95% CI = 0.89-2.20; P?=?.14). In addition, the efficacy between amitriptyline and SSRIs or SNRIs did not differ for migraine prevention in adults (SMD = -.01; 95% CI = -0.31 to 0.28; P?=?.94) based on the available limited trials. However, TCAs were less well tolerated than placebo (RR = 1.73; 95% CI = 1.00-2.99; P?=?.05) and SSRI or SNRI (RR = 2.85; 95% CI = 0.97-8.41; P?=?.06) on account of adverse events.ConclusionsThis research reveals that TCAs were more effective than placebo, but no more than SSRI or SNRI in ameliorating the headache burden in adults with migraine. However, TCAs appeared to be less tolerated than placebo and SSRIs or SNRIs for some side effects.

Project description:Inflammation has an important role in the development of liver fibrosis in general and the activation of hepatic stellate cells (HSCs) in particular. It is known that HSCs are themselves able to produce cytokines and chemokines, and that this production may be a key event in the initiation of fibrogenesis. However, the direct involvement of cytokines and chemokines in HSC (self-)activation remains uncertain. In this study, the effects of pro-inflammatory cytokines IL-1? and ?, TNF-?, and IL-8 on the activation state of HSCs were examined, in comparison to the pro-fibrogenic mediator TGF-?1. LX-2 cells were stimulated for 24 or 48 hours with recombinant human form of the pro-inflammatory cytokines IL-1? and ?, TNF-?, and IL-8, and also the pro-fibrogenic mediator TGF-?1. Two drugs were also evaluated, the anti-TNF-? monoclonal antibody infliximab and the IL-1 receptor antagonist anakinra, regarding their inhibitory effects. In LX-2 human HSC, treatment with TGF-?1 are associated with downregulation of the metalloproteinase (MMP)-1 and MMP-3, with upregulation of tissue inhibitor of metalloproteinase (TIMP)-1, collagen type I ?1, collagen type IV ?1, ?-SMA, endothelin-1 and PDGF-BB. Cytokines and chemokines expression were found to be downregulated, excepting IL-6. In contrast, we observed that LX-2 exposure to IL-1, TNF-? and IL-8 can reverse the phenotype of pro-fibrogenic activated cells. Indeed, MMP-1, MMP-3 and MMP-9 were found elevated, associated with downregulation of ?-SMA and/or PDGF-BB, and a greater expression of IL-1?, IL-6, IL-8, CXCL1 and CCL2. Lastly, we found that infliximab and anakinra successfully inhibits effects of TNF-? and IL-1 respectively in LX-2 cells. Infliximab and anakinra may be of value in preclinical trials in chronic liver disease. Overall, our results suggest that (i) pro-inflammatory mediators exert complex effects in HSCs via an MMP/TIMP imbalance, and (ii) targeting IL-1 signaling may be a potentially valuable therapeutic strategy in chronic liver diseases.

Dataset Information

Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells.

Publications

Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells.

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