Caffeine mitigates experimental nonalcoholic steatohepatitis and the progression of thioacetamide-induced liver fibrosis by blocking the MAPK and TGF-β/Smad3 signaling pathways

Vargas-Pozada, Eduardo E.; Ramos‐Tovar, Erika; Acero-Hernández, Consuelo; Cardoso-Lezama, Irina; Galindo-Gómez, Silvia; Tsutsumi, Vı́ctor; Muriel, Pablo

doi:10.1016/j.aohep.2022.100671

Cited by 19 publications

(7 citation statements)

References 45 publications

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“…In the present study, caffeine prevented HFSCD+CCl 4 -induced JNK, ERK, and p38 phosphorylation. These results are consistent with those of previous studies using different experimental models and tissues [ 52 , 53 , 54 ]. Furthermore, caffeine prevents the increase in TGF-β, an efficient activator of the profibrogenic HSCs and the main inducer of ECM-exacerbated deposition [ 4 , 7 ], thereby inhibiting α-SMA protein elevation, an indicator of HSC activation.…”

Section: Discussionsupporting

confidence: 94%

Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model

Vargas-Pozada

Ramos‐Tovar²,

Rodríguez-Callejas

et al. 2022

IJMS

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Caffeine elicits protective effects against liver diseases, such as NASH; however, its mechanism of action involving the pyrin domain-containing-3 (NLRP3) inflammasome signaling pathway remains to be elucidated. This study aimed to evaluate the effect of caffeine on the NLRP3 inflammasome signaling pathway in a rat model of NASH. NASH was induced by feeding rats a high-fat, -sucrose, and -cholesterol diet (HFSCD) for 15 weeks along with a weekly low dose (400 mg/kg, i.p.) of CCl4. Caffeine was administered at 50 mg/kg p.o. The effects of HFSCD+CCl4 and caffeine on the liver were evaluated using biochemical, ultrastructural, histological, and molecular biological approaches. The HFSCD+CCl4-treated rats showed fat accumulation in the liver, elevated levels of inflammatory mediators, NLRP3 inflammasome activation, antioxidant dysregulation, and liver fibrosis. Caffeine reduced necrosis, cholestasis, oxidative stress, and fibrosis. Caffeine exhibited anti-inflammatory effects by attenuating NLRP3 inflammasome activation. Moreover, caffeine prevented increases in toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) protein levels and mitigated the phosphorylation of mitogen-activated protein kinase (MAPK). Importantly, caffeine prevented the activation of hepatic stellate cells. This study is the first to report that caffeine ameliorates NASH by inhibiting NLRP3 inflammasome activation through the suppression of the TLR4/MAPK/NF-κB signaling pathway.

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Section: Discussionsupporting

confidence: 94%

Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model

Vargas-Pozada

Ramos‐Tovar²,

Rodríguez-Callejas

et al. 2022

IJMS

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“…TGFβ signaling pathway has been established as an essential profibrogenic factor that induces the transdifferentiation of HSCs to myofibroblasts and ECM accumulation in the liver 31–33 . TGFβ binds to its receptor and phosphorylates SMAD3 and triggers the transcription of target genes, including αSMA 34–36 . Our data showed that PTH activates TGFβ/smad3 signaling in HSCs.…”

Section: Discussionmentioning

confidence: 56%

“…[31][32][33] TGFβ binds to its receptor and phosphorylates SMAD3 and triggers the transcription of target genes, including αSMA. [34][35][36] Our data showed that PTH activates TGFβ/smad3 signaling in HSCs. However, TGFβ production was remarkably attenuated in PTH1R KO mice treated with CCl 4 .…”

Section: Discussionmentioning

confidence: 60%

Parathyroid hormone receptor-1 signaling aggravates hepatic fibrosis through upregulating cAMP response element-binding protein-like 2

et al. 2023

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Background and Aims: Parathyroid hormone receptor-1 (PTH1R) is a class B G protein–coupled receptor central to skeletal development, bone turnover, and calcium homeostasis. However, the role of PTH1R signaling in liver fibrosis is largely unknown. Here, the role of PTH1R signaling in the activation of HSCs and hepatic fibrosis was examined. Approach and Results: PTH1R was highly expressed in activated HSCs and fibrotic liver by using human liver specimens or carbon tetrachloride (CCl4)-treated or methionine and choline-deficient diet (MCD)-fed C57/BL6 mice. The mRNA level of hepatic PTH1R was positively correlated to α-smooth muscle actin in patients with liver cirrhosis. Mice with HSCs-specific PTH1R deletion were protected from CCl4, MCD, or western diet, plus low-dose CCl4-induced liver fibrosis. Conversely, parathyroid hormone (PTH) aggravated liver fibrosis in CCl4-treated mice. Mouse primary HSCs and LX2 cell lines were used for in vitro experiments. Molecular analyses by luciferase reporter assays and chromatin immunoprecipitation assays in combination with mRNA sequencing in HSCs revealed that cAMP response element-binding protein-like 2 (Crebl2), a novel regulator in HSCs treated by PTH that interacted with mothers against decapentaplegic homolog 3 (SMAD3) and increased the transcription of TGFβ in activating HSCs and collagen deposition. In agreement, HSCs-specific Crebl2 deletion ameliorated PTH-induced liver fibrosis in CCl4-treated mice. Conclusions: In both mouse and human models, we found that PTH1R was highly expressed in activated HSCs and fibrotic liver. PTH1R signaling regulated collagen production in the HSCs through Crebl2/SMAD3/TGFβ regulatory circuits. Blockade of PTH1R signaling in HSCs might help mitigate the development of liver fibrosis.

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“…5053, IN, USA), the HFSCD group was fed an HFSCD ad libitum, the HFSCD + caffeine group received an ad libitum HFSCD and 50 mg of caffeine/kg body weight by gavage daily, and the caffeine-only group received an ad libitum control diet and 50 mg of caffeine/kg body weight by gavage daily (Scheme 1). The 50 mg/kg dose of caffeine has been used by our research group (Arauz et al 2014;Vargas-Pozada et al 2022a, 2022b, with good results and no adverse effects reported. Previous observations showed that lower doses were ineffective, while larger ones afforded no further protection in other experimental models.…”

Section: Nonalcoholic Steatohepatitis Induction and Caffeine Treatmentmentioning

confidence: 99%

“…The caffeine-only group received 50 mg of caffeine/kg body weight by gavage daily for 3 weeks (Scheme 2). The 200 mg/kg dose of TAA has been used by several research groups, including ours, to cause liver damage (Ramos-Tovar et al 2018a;Vargas-Pozada et al 2022a), generating a well-characterized liver damage model. The animals had free access to food (Labdiet No.…”

Section: Thioacetamide-induced Liver Damage and Caffeine Treatmentmentioning

confidence: 99%

The antioxidant and anti-inflammatory activities of caffeine effectively attenuate nonalcoholic steatohepatitis and thioacetamide-induced hepatic injury in male rats

Vargas-Pozada

Ramos‐Tovar²,

Acero-Hernández

et al. 2023

Can. J. Physiol. Pharmacol.

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The antioxidant effect of caffeine, associated with its ability to upregulate the nuclear factor-E2-related factor-2 (Nrf2)-signaling pathway, was explored as a possible mechanism for the attenuation of liver damage. Nonalcoholic steatohepatitis (NASH) was induced in rats by the administration of a high-fat, high-sucrose, high-cholesterol diet (HFSCD) for 15 weeks. Liver damage was induced in rats by intraperitoneal administration of thioacetamide (TAA) for six weeks. Caffeine was administered orally at a daily dose of 50 mg/kg body weight during the period of NASH induction to evaluate its ability to prevent disease development. Meanwhile, rats received TAA for three weeks, after which 50 mg/kg caffeine was administered daily for three weeks with TAA to evaluate its capacity to interfere with the progression of hepatic injury. HFSCD administration induced hepatic steatosis, decreased Nrf2 levels, increased oxidative stress, induced the activation of nuclear factor-κB (NF-κB), and elevated proinflammatory cytokine levels, leading to hepatic damage. TAA administration produced similar effects, excluding steatosis. Caffeine increased Nrf2 levels; attenuated oxidative stress markers, including malondialdehyde and 4-hydroxynonenal; restored normal, reduced glutathione levels; and reduced NF-κB activation, inflammatory cytokine levels, and damage. Our findings suggest that caffeine may be useful in the treatment of human liver diseases.

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Caffeine mitigates experimental nonalcoholic steatohepatitis and the progression of thioacetamide-induced liver fibrosis by blocking the MAPK and TGF-β/Smad3 signaling pathways

Cited by 19 publications

References 45 publications

Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model

Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model

Parathyroid hormone receptor-1 signaling aggravates hepatic fibrosis through upregulating cAMP response element-binding protein-like 2

The antioxidant and anti-inflammatory activities of caffeine effectively attenuate nonalcoholic steatohepatitis and thioacetamide-induced hepatic injury in male rats

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