SIRT1 activation synergizes with FXR agonism in hepatoprotection via governing nucleocytoplasmic shuttling and degradation of FXR

Cui, Shuang; Hu, Huijian; Chen, An; Cui, Ming; Pan, Xiaojie; Zhang, Pengfei; Wang, Guangji; Wang, Hong; Hao, Haiping

doi:10.1016/j.apsb.2022.08.019

Cited by 7 publications

(3 citation statements)

References 64 publications

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“…In the ER stress induced by tunicamycin, the expression of NLRP3 inflammasome related proteins increased, while the expression of FXR decreased in mouse liver or hepatocytes [ 15 ]. In various mouse models of liver injuries, including cholestasis induced by bile duct ligation, acute liver injury induced by intraperitoneal injection of CCl 4 , nonalcoholic steatohepatitis induced by high-fat high-cholesterol diet or methionine and choline-deficient diet, all the protein levels of FXR in the liver decreased [ 25 ]. They are in line with our study, with activation of the NLRP3 inflammasome, FXR expression was reduced in LX2 cells and in the liver of mice with CCl 4 -induced and GCDCA-induced hepatic fibrosis compared to the control mice (Figs.…”

Section: Discussionmentioning

confidence: 99%

Bile acids induce liver fibrosis through the NLRP3 inflammasome pathway and the mechanism of FXR inhibition of NLRP3 activation

Feng,

Xie,

et al. 2024

Hepatol Int

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Background Altered patterns of bile acids (BAs) are frequently present in liver fibrosis, and BAs function as signaling molecules to initiate inflammatory responses. Therefore, this study was conducted to uncover the notably altered components of BAs and to explore the pathway of altered BA induced inflammation in the development of liver fibrosis. Methods Bile acids were quantified by ultraperformance liquid chromatography coupled to mass spectrometry (UPLC‒MS/MS). Cell Counting Kit-8 assays were used to determine the proliferative capacity of HSCs. Transwell assays and wound healing assays were used to determine the migratory capacity of LX2 cells. Protein expression was evaluated by western blotting. Results Plasma bile acid analysis showed higher levels of GCDCA, TCDCA, GCA and TCA in patients with liver fibrosis than in normal controls. The AUC of GCDCA was the highest. Western blotting showed that GCDCA treatment increased the expression of NLRP3-related proteins and collagen1 in vitro and significantly increased LX2 cells proliferation and migration. Furthermore, knockdown of NLRP3 or overexpression of FXR in LX2 cells decreased the expression of the above proteins, and FXR inhibited NLRP3 (ser 295) phosphorylation in vitro and vivo. In vivo, HE, Masson’s trichrome, and Sirius Red staining showed that GCDCA increased collagen fibers in the mouse liver, and the expression of NLRP3-related proteins, collagen 1, and α-SMA in the liver increased significantly. However, the knockout of NLRP3 reversed these patterns. Conclusion (1) Primary conjugated bile acids increased in patients with liver fibrosis; (2) GCDCA induce hepatic fibrosis via the NLRP3 inflammasome pathway; (3) FXR inhibits NLRP3 activity by restraining its phosphorylation; (4) knockdown or knockout of NLRP3 may relieve the onset of hepatic fibrosis.

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Section: Discussionmentioning

confidence: 99%

Bile acids induce liver fibrosis through the NLRP3 inflammasome pathway and the mechanism of FXR inhibition of NLRP3 activation

Feng,

Xie,

et al. 2024

Hepatol Int

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“…[31,32] Further investigations uncovered modulatory effects of FXR on inflammation and oxidative stress, along with hepatoprotective ability. [33] The lysine 217 residue of FXR is the main deacetylation target of SIRT-1. [34] SIRT-1mediated deacetylation induces FXR activity, thereby promoting the phosphorylation of AMPK.…”

Section: Discussionmentioning

confidence: 99%

β‐lapachone protects against doxorubicin‐induced hepatotoxicity through modulation of NAD⁺/SIRT‐1/FXR/p‐AMPK/NF‐kB and Nrf2 signaling axis

Kalantary‐Charvadeh,

Nazari Soltan Ahmad,

Aslani

et al. 2023

J Biochem & Molecular Tox

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Doxorubicin (DOX) is a widely used antineoplastic drug, but its clinical use is limited by significant toxicities, such as hepatotoxicity. In this study, we evaluated the effects of β‐lapachone (β‐LAP), a natural quinone‐containing compound, in a mouse model of DOX‐induced hepatotoxicity. β‐LAP was orally administered at 1.25, 2.5, and 5 mg/kg for 4 days, and a single dose of DOX (20 mg/kg) was injected intraperitoneally on the second day. Histopathological changes, liver function markers, antioxidant and inflammatory markers were assessed. β‐LAP ameliorated liver injury and liver function markers evoked by DOX. β‐LAP also downregulated the mRNA expression of nuclear factor‐kB‐corresponding genes including interleukin‐6, interleukin‐1β, and tumor necrosis factor‐α. Moreover, β‐LAP increased the nuclear factor erythroid 2‐related factor 2 target genes heme oxygenase‐1 and NAD(P)H: quinone oxidoreductase 1, along with antioxidant enzymes including reduced glutathione, catalase, and superoxide dismutase with simultaneous reduction in the lipid peroxidation product malondialdehyde. Meanwhile, it recovered NAD+/NADH ratios and subsequently elevated the protein levels of sirtuin‐1 (SIRT‐1), farnesoid X receptor (FXR), and phosphorylated AMP‐activated protein kinase (p‐AMPK). Collectively, these findings suggest a protective role of β‐LAP against DOX‐induced hepatotoxicity by partly regulating the NAD+/SIRT‐1/FXR/p‐AMPK axis.

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“…Loss of FXR protein expression was observed in patients with NAFLD, PBC, and fibrosis 11,94,95 . SIRT1 activation has been demonstrated to be a valid way to prevent FXR degradation and enhance the hepatoprotection of FXR agonists by governing nucleocytoplasmic shuttling 96 . More novel methods, including stimulating its transcription by small activating RNAs and preventing its degradation by deubiquitinase‐targeting chimers, are expected to modulate its protein expression and synergize with FXR agonism for the purpose of hepatoprotection.…”

Section: Perspectives For All Fxr Agonistsmentioning

confidence: 99%

FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid

Wang,

Zhang,

Wang

et al. 2023

Medicinal Research Reviews

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Nonalcoholic fatty liver disease, also called metabolic dysfunction‐associated steatotic liver disease, is the most common liver disease worldwide and has no approved pharmacotherapy. Due to its beneficial effects on metabolic regulation, inflammation suppression, cell death prevention, and fibrogenesis inhibition, farnesoid X receptor (FXR) is widely accepted as a promising therapeutic target for nonalcoholic steatosis (NASH) or called metabolic dysfunction‐associated steatohepatitis (MASH). Many FXR agonists have been developed for NASH/MASH therapy. Obeticholic acid (OCA) is the pioneering frontrunner FXR agonist and the first demonstrating success in clinical trials. Unfortunately, OCA did not receive regulatory approval as a NASH pharmacotherapy because its moderate benefits did not outweigh its safety risks, which may cast a shadow over FXR‐based drug development for NASH/MASH. This review summarizes the milestones in the development of OCA for NASH/MASH and discuss its limitations, including moderate hepatoprotection and the undesirable side effects of dyslipidemia, pruritus, cholelithiasis, and liver toxicity risk, in depth. More importantly, we provide perspectives on FXR‐based therapy for NASH/MASH, hoping to support a successful bench‐to‐clinic transition.

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SIRT1 activation synergizes with FXR agonism in hepatoprotection via governing nucleocytoplasmic shuttling and degradation of FXR

Cited by 7 publications

References 64 publications

Bile acids induce liver fibrosis through the NLRP3 inflammasome pathway and the mechanism of FXR inhibition of NLRP3 activation

Bile acids induce liver fibrosis through the NLRP3 inflammasome pathway and the mechanism of FXR inhibition of NLRP3 activation

β‐lapachone protects against doxorubicin‐induced hepatotoxicity through modulation of NAD⁺/SIRT‐1/FXR/p‐AMPK/NF‐kB and Nrf2 signaling axis

FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid

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SIRT1 activation synergizes with FXR agonism in hepatoprotection via governing nucleocytoplasmic shuttling and degradation of FXR

Cited by 7 publications

References 64 publications

Bile acids induce liver fibrosis through the NLRP3 inflammasome pathway and the mechanism of FXR inhibition of NLRP3 activation

Bile acids induce liver fibrosis through the NLRP3 inflammasome pathway and the mechanism of FXR inhibition of NLRP3 activation

β‐lapachone protects against doxorubicin‐induced hepatotoxicity through modulation of NAD+/SIRT‐1/FXR/p‐AMPK/NF‐kB and Nrf2 signaling axis

FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid

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β‐lapachone protects against doxorubicin‐induced hepatotoxicity through modulation of NAD⁺/SIRT‐1/FXR/p‐AMPK/NF‐kB and Nrf2 signaling axis