Farnesoid X receptor signaling activates the hepatic X‐box binding protein 1 pathway in vitro and in mice

Li, Xiaoying; Guo, Grace L.; Kong, Bo; Hilburn, David B.; Hubchak, Susan; Park, Seong; LeCuyer, Brian; Hsieh, Antony; Wang, Li; Fang, Deyu; Green, Richard M.

doi:10.1002/hep.29815

Cited by 34 publications

(36 citation statements)

References 53 publications

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“…Furthermore, several studies have demonstrated amelioration of maladaptive ER signalling via FXR agonism in the kidney (Gai et al, ; Marquardt et al, ). These observations support the notion that FXR agonism may be involved in hepatic ER stress alleviation, although a recent study indicated that FXR activation induces hepatic ER stress via targeting XBP1/IRE1α signalling (Liu et al, ).…”

Section: Discussionsupporting

confidence: 76%

“…These findings suggest that FXR activation could reduce hepatic ER stress, and this effect may be involved in the anti‐NAFLD effect of FXR agonists. In contrast, in a recent article it was suggested that hepatic FXR activation exacerbates ER stress (Liu et al, ). Thus, the role of hepatic FXR activation in regulating the ER stress process remains to be clarified.…”

Section: Introductionmentioning

confidence: 92%

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Betulinic acid alleviates endoplasmic reticulum stress‐mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice

Ping

Zhang

et al. 2019

British J Pharmacology

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Background and Purpose: The molecular mechanism for the pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains elusive. Both farnesoid X receptor (FXR) signalling and endoplasmic reticulum (ER) stress contribute to the progression of NAFLD; however, it is not clear whether the actions of these two pathways are dependent on each other. Moreover, the pharmacological benefits and mechanism of betulinic acid (BA) in controlling metabolic syndrome and NAFLD are largely unknown.Experimental Approach: A reporter assay and a time-resolved FRET assay were used to identify BA as an agonist of the FXR. NAFLD was induced by a methionine and choline-deficient L-amino acid diet (MCD) and high-fat diet (HFD). The pharmacological effects of BA (100 mg·kg −1 ·day −1 ) and potential interactions between hepatic FXR activation and ER stress pathways were evaluated by FXR silencing, Western blot and RT-PCR analyses using control and FXR −/− mice.Key Results: Activation of the FXR inhibited intracellular PERK/EIF2α/ATF4 and CHOP signalling, thereby alleviating hepatic ER stress, whereas FXR silencing resulted in an opposite effect. Furthermore, we identified BA as an FXR agonist that effectively attenuated the progression of NAFLD and metabolic disorders in both HFD-and MCD diet-fed mice and restored the hepatocellular ER homeostasis by stimulating the FXR signalling pathway and blocking PERK/EIF2α signalling. In contrast, the effects of BA were attenuated in FXR −/− mice. Conclusions and Implications:Our data demonstrate that pharmacological activation of the FXR by BA reduces hepatocellular ER stress and attenuates NAFLD in an animal model of hepatic steatosis.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 92%

Betulinic acid alleviates endoplasmic reticulum stress‐mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice

Ping

Zhang

et al. 2019

British J Pharmacology

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“…A recent report suggests that FXR signaling modulates ER stress via activation of the IRE/XBP1 pathway (11). Our findings show that mice lacking FXR resulted in reduced expression of GRP94, ATF4, EDEM, XBP1 (including total, spliced and unconventional spliced XBP1) in the liver when suffering from IRI, suggesting that the absence of FXR forfeits protection of hepatocytes from apoptosis, contributing to the susceptibility to liver IRI.…”

Section: Discussionsupporting

confidence: 55%

“…Activation of the BA membrane receptor, G protein-coupled BA receptor 1 (TGR5), by TGR5 agonists inhibits inflammatory responses and attenuates liver IRI by suppressing the Toll like receptor 4 (TLR4)-NF-B mediated pathway (10). Recent experimental data suggest that activation of BA nuclear receptor, farnesoid X receptor (FXR), stimulates the IRE/XBP1 pathway and may be protective during liver injury (11). Similarly, administration of the FXR-agonist obeticholic acid (OCA) improves survival in a rodent model of intestinal IRI, through gut barrier preservation and mitigated inflammation (12).…”

Section: Introductionmentioning

confidence: 99%

Mice Lacking FXR Are Susceptible to Liver Ischemia-Reperfusion Injury

Rao

et al. 2019

Preprint

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Activation of bile acid (BA) receptor, farnesoid X receptor (FXR) has been shown to inhibit inflammatory responses and improve tissue ischemia-reperfusion injury (IRI). This study investigated the effect of FXR deficiency on liver IRI, using a liver warm IRI mouse model. We demonstrate that liver IRI resulted in decreased FXR expression in the liver of WT mice. FXR -/mice displayed greater liver damage and inflammatory responses than WT mice, characterized by significant increases in liver weight, serum AST and ALT, hepatocyte apoptosis and liver inflammatory cytokines. Liver IRI increased expression of X box binding protein 1 (XBP1) and FGF21 in WT liver, but not in FXR -/liver, which conversely increased CHOP expression, suggesting a loss of ER stress protection in the absence of FXR. FXR deficiency increased circulating total BAs and altered BA composition with reduced TUDCA and hepatic BA synthesis markers. FXR deficiency also reshaped gut microbiota composition with increased Bacteroidetes and Proteobacteria and decreased Firmicutes. Curiously, Bacteroidetes were positively and Firmicutes were negatively correlated with serum ALT levels. Administration of FXR agonist CDCA inhibited NF-B activity and TNFα expression in vitro and improved liver IRI in vivo. Our findings demonstrate that FXR signaling plays an important role in the modulation of liver IRI.

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“…A potential additional level of complexity arose from a recent study showing that FXR can activate the IRE/XBP1 pathway . That study notably suggests a role for FXR in XBP1 activation in the early stages of cholestasis, using a mouse bile duct ligation model.…”

Section: Discussionmentioning

confidence: 99%

Calnexin Depletion by Endoplasmic Reticulum Stress During Cholestasis Inhibits the Na+‐Taurocholate Cotransporting Polypeptide

et al. 2018

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Cholestasis‐induced accumulation of bile acids in the liver leads to farnesoid X receptor (FXR)‐mediated transcriptional down‐regulation of the bile acid importer Na+‐taurocholate cotransporting protein (NTCP) and to induction of endoplasmic reticulum (ER) stress. However, whether ER stress affects bile acid uptake is largely unknown. Here, we investigated the role of ER stress on the regulation and function of the bile acid transporter NTCP. ER stress was induced using thapsigargin or subtilase cytotoxin in human osteosarcoma (U2OS) and human hepatocellular carcinoma (HepG2) cells stably expressing NTCP. Cellular bile acid uptake was determined using radiolabeled taurocholate (TCA). NTCP plasma membrane expression was determined by cell surface biotinylation. Mice received a single injection of thapsigargin, and effects of ER stress on NTCP messenger RNA (mRNA) and protein were measured by reverse‐transcription polymerase chain reaction (RT‐PCR) and western blot analysis. Effects of cholestasis on NTCP and ER stress were assessed in response to 3, 5‐diethoxycarbonyl‐1, 4‐dihydrocollidine (DDC) feeding or bile duct ligation in FXR–/– mice after 7 or 3 days, respectively. Novel NTCP‐interacting proteins were identified by mass spectrometry (MS), interaction verified, and assessed by co‐immunoprecipitation and TCA uptake for functional relevance in relation to ER stress. ER stress induction strongly reduced NTCP protein expression, plasma membrane abundance, and NTCP‐mediated bile acid uptake. This was not controlled by FXR or through a single unfolded protein response (UPR) pathway but mainly depended on the interaction of NTCP with calnexin, an ER chaperone. In mice, expression of both NTCP and calnexin was reduced by thapsigargin or cholestasis‐induced ER stress. Calnexin down‐regulation in vitro recapitulated the effect of ER stress on NTCP. Conclusion: ER stress‐induced down‐regulation of calnexin provides an additional mechanism to dampen NTCP‐mediated bile acid uptake and protect hepatocytes against bile acid overload during cholestasis.

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Farnesoid X receptor signaling activates the hepatic X‐box binding protein 1 pathway in vitro and in mice

Cited by 34 publications

References 53 publications

Betulinic acid alleviates endoplasmic reticulum stress‐mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice

Betulinic acid alleviates endoplasmic reticulum stress‐mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice

Mice Lacking FXR Are Susceptible to Liver Ischemia-Reperfusion Injury

Calnexin Depletion by Endoplasmic Reticulum Stress During Cholestasis Inhibits the Na+‐Taurocholate Cotransporting Polypeptide

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