Caffeine protects against alcohol-induced liver fibrosis by dampening the cAMP/PKA/CREB pathway in rat hepatic stellate cells

Wang, Qi; Dai, Xuefei; Yang, Won‐Kyung; Wang, He; Zhao, Han; Yang, Feng; Yang, Yan; Li, Jun; Lv, Xiongwen

doi:10.1016/j.intimp.2015.02.012

Cited by 80 publications

(53 citation statements)

References 53 publications

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“…Our study is consistent with the findings of a recent study, which reported that the expression of p-CREB-1 was downregulated by caffeine through its blockade of adenosine A2A receptor and the cAMP/PKA/CREB signaling pathway, thereby inhibiting the activation of HSCs and liver fibrogenesis (19). Taken together, our findings provide evidence for the pro-fibrotic role of p-CREB-1 in liver fibrogenesis.…”

Section: Discussionsupporting

confidence: 92%

“…In the present study, we examined the expression level of activated CREB-1 and showed that p-CREB-1 expression was markedly upregulated in a rat model of CCl 4 -induced liver fibrosis, indicating that p-CREB-1 may play an important role in liver fibrogenesis. Our study is consistent with a recent study, which reported a similar finding; namely that CREB phosphorylation was significantly increased in alcoholic liver fibrosis (19). Furthermore, we examined the underlying regulatory mechanism as well as the role of upregulated p-CREB-1 in liver fibrosis.…”

Section: Discussionsupporting

confidence: 92%

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p-CREB-1 promotes hepatic fibrosis through the transactivation of transforming growth factor-β1 expression in rats

Wang

Deng

Zhuang

et al. 2016

International Journal of Molecular Medicine

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Abstract. Phosphorylated cAMP-responsive element binding protein-1 (p-CREB-1) is an important transcription factor which has been reported to be implicated in fibrogenesis. However, the association between p-CREB-1 and transforming growth factor-β1 (TGF-β1)-mediated liver fibrogenesis remains poorly understood. In the present study, exogenous TGF-β1 recombinant protein was used to activate hepatic stellate cells (HSCs), and we established a rat model of tetrachloromethane (CCl 4 )-induced liver fibrosis. Loss-and gain-of-function studies were performed to examine the role of p-CREB-1 in liver fibrogenesis, and the detailed mechanism responsible for these effects was further explored using chromatin immunoprecipitation and luciferase reporter gene assays. We found that p-CREB-1 expression was significantly upregulated in a rat model of hepatic fibrosis. We also demonstrated that p-CREB-1 increased TGF-β1 expression and auto-induction in HSCs, through directly binding to the CRE site within the TGF-β1 promoter in order to enhance its transcriptional activity. Moreover, lentivirus-mediated CREB-1 overexpression promoted hepatic fibrogenesis in rats. These findings suggest that p-CREB-1 may function as a potent profibrogenic factor through the transactivation of TGF-β1 expression in liver fibrosis. IntroductionHepatic fibrosis, characterized by the excessive production and deposition of the extracellular matrix (ECM), is a common pathologic change observed in the progression of various chronic liver diseases to cirrhosis (1-3). Transforming growth factor-β1 (TGF-β1), the most potent profibrogenic cytokine currently known, stimulates the activation and transformation of hepatic stellate cells (HSCs) into myofibroblasts producing abnormal and abundant ECM (4,5). It has been reported that TGF-β1 binds to TGF-β type II receptors on the cell surface, and then recruits type I receptors; as a consequence, the type II receptor kinase phosphorylates the type I receptors and intracellular signal molecules such as Smads. Phosphorylated (p-)Smad2 and/or p-Smad3 form heteroligomers with Smad4, which translocate into the nucleus to control the ECM gene transcription (6-7). On the contrary, blocking TGF-β1 signaling may inhibit collagen production and promote the degradation of collagen (8,9). The roles of TGF-β1 in HSCs activation and liver fibrosis have been intensively studied; however, the transcriptional regulation of TGF-β1 remains poorly understood.Cyclic adenosine 3' ,5'-monophosphate (cAMP)-responsive element (CRE) binding protein-1 (CREB-1), a eukaryotic transcription factor, binds to CRE sites in the promoters of various cytokines to widely regulate gene transcription (10,11). The role of CREB-1 in fibrogenesis remains controversial. Several studies have reported that CREB-1 exerts anti-fibrotic effects, such as in myocardial fibrosis and pulmonary fibrosis (12,13). On the contrary, CREB-1 facilitated high glucose induced renal tubulointerstitial fibrosis in diabetic nephropathy (14). Currently, there limited research r...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

p-CREB-1 promotes hepatic fibrosis through the transactivation of transforming growth factor-β1 expression in rats

Wang

Deng

Zhuang

et al. 2016

International Journal of Molecular Medicine

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“…Among 17 NMNAT2 positive modulators confirmed by Western analysis, 5 compounds are known to increase cAMP signaling. These include 8-Br-cAMP, Ro20–17243940, caffeine41, the caffeine analog dipropyl-7-methylxanthine42, and rolipram4344. Both caffeine and rolipram act as phosphodiesterase inhibitors to reduce cAMP degradation and thus increase cAMP concentrations.…”

Section: Discussionmentioning

confidence: 99%

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

Ali

Bradley

2017

Sci Rep

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Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer’s, Huntington’s, Parkinson’s diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds. This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modulators identified. Western analysis was conducted to validate and determine the dose-dependency of identified modulators. Caffeine, one identified NMNAT2 positive-modulator, when systemically administered restored NMNAT2 expression in rTg4510 tauopathy mice to normal levels. We confirmed in a cell culture model that four selected positive-modulators exerted NMNAT2-specific neuroprotection against vincristine-induced cell death while four selected NMNAT2 negative modulators reduced neuronal viability in an NMNAT2-dependent manner. Many of the identified NMNAT2 positive modulators are predicted to increase cAMP concentration, suggesting that neuronal NMNAT2 levels are tightly regulated by cAMP signaling. Taken together, our findings indicate that the NMNAT2-MSD platform provides a sensitive phenotypic screen to detect NMNAT2 in neurons.

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“…25,26) In agreement with these findings, Shim et al reported that caffeine decreased fibrosis and α-SMA expression in human HSC line LX-2 cells cultured in DMEM supplemented with FBS, and that these decreases were accompanied by an elevation in cAMP level. 27) However, other studies have reported contradictory results: The inhibition by caffeine of acetaldehyde-induced activation of HSC-T6 cell lines 28) and rat HSCs 29) was accompanied by a decrease in cAMP level by antagonizing Gs-coupled adenosine A 2A receptors. Therefore, the involvement of cAMP in the caffeine effect on HSC activation is still controversial.…”

Section: Discussionmentioning

confidence: 97%

Caffeine Suppresses the Activation of Hepatic Stellate Cells cAMP-Independently by Antagonizing Adenosine Receptors

Yamaguchi

Nishiyama

Nakamura

et al. 2017

Biological & Pharmaceutical Bulletin

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During liver injury, hepatic stellate cells (HSCs) are activated by various cytokines and transdifferentiated into myofibroblast-like activated HSCs, which produce collagen, a major source of liver fibrosis. Therefore, the suppression of HSC activation is regarded as a therapeutic target for liver fibrosis. Several epidemiological reports have revealed that caffeine intake decreases the risk of liver disease. In this study, therefore, we investigated the effect of caffeine on the activation of primary HSCs isolated from mice. Caffeine suppressed the activation of HSC in a concentration-dependent manner. BAPTA-AM, an intracellular Ca 2 chelator, had no effect on the caffeine-induced suppression of HSC activation. None of the isoformselective inhibitors of phosphodiesterase1 to 5 affected changes in the morphology of HSC during activation, whereas CGS-15943, an adenosine receptor antagonist, inhibited them. Caffeine had no effect on intracellular cAMP level or on the phosphorylation of extracellular signal-regulated kinase (ERK)1/2. In contrast, caffeine significantly decreased the phosphorylation of Akt1. These results suggest that caffeine inhibits HSC activation by antagonizing adenosine receptors, leading to Akt1 signaling activation.

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Caffeine protects against alcohol-induced liver fibrosis by dampening the cAMP/PKA/CREB pathway in rat hepatic stellate cells

Cited by 80 publications

References 53 publications

p-CREB-1 promotes hepatic fibrosis through the transactivation of transforming growth factor-β1 expression in rats

p-CREB-1 promotes hepatic fibrosis through the transactivation of transforming growth factor-β1 expression in rats

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

Caffeine Suppresses the Activation of Hepatic Stellate Cells cAMP-Independently by Antagonizing Adenosine Receptors

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