Ursodeoxycholic acid induces glutathione synthesis through activation of PI3K/Akt pathway in HepG2 cells

Arisawa, Sakiko; Ishida, Kumiki; Kameyama, Natsumi; Ueyama, Jun; Hattori, Ai; Tatsumi, Yasuaki; Hayashi, Hisao; Yano, Motoyoshi; Hayashi, Kazuhiko; Katano, Yoshiaki; Goto, Hidemi; Takagi, Kenji; Wakusawa, Shinya

doi:10.1016/j.bcp.2008.11.012

Cited by 59 publications

(40 citation statements)

References 43 publications

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“…Several compounds such as brazilin, ursodeoxycholic acid, kahweol, and capsaicin have been reported to promote translocation of Nrf2 and reduced glutathione synthesis through an activation of the PI3=Akt=Nrf2 pathway. [29][30][31][32] Furthermore, the PI3K=Akt=mammalian target of rapamycin (mTOR) signaling pathway could be, in part, involved in the nuclear translocation of Nrf2 as inhibitors of Akt (FPA-124, KP372-1) and mTOR (rapamycin) suppressed the isoalantolactoneinduced accumulation of Nrf2 in the nucleus (Figs. 7 and 8).…”

Section: Discussionmentioning

confidence: 98%

Isoalantolactone fromInula heleniumCaused Nrf2-Mediated Induction of Detoxifying Enzymes

Seo

Park

Kim

et al. 2009

Journal of Medicinal Food

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Our previous study demonstrated that methanolic extract of Inula helenium (Elecampane) has the potential to induce detoxifying enzymes such as NAD(P)H:(quinone acceptor) oxidoreductase 1 (EC 1.6.99.2) (NQO1, QR) activity and glutathione S-transferase (GST) and found isoalantolactone and alantolactone as the active components. In this study we investigated the detoxifying enzyme-inducing potential of isoalantolactone, which is present in I. helenium and has a structure similar to that of alantolactone. The compound induced QR in a dose-dependent manner in both Hepa1c1c7 cells and its mutant BPRc1 cells lacking the arylhydrocarbon receptor translocator. Like with most phase 2 enzyme inducers, other phase 2 detoxifying enzymes, including GST, glutathione reductase, gamma-glutamylcysteine synthetase, and heme oxygenase-1, were also induced by isoalantolactone in a dose-dependent manner in the cultured cells. Furthermore, isoalantolactone caused a proportionate increase in luciferase activity depending upon concentration and exposure time in the reporter assay in which HepG2-C8 cells, transfectants carrying antioxidant response element-luciferase gene, were used. The nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) was stimulated by the compound and attenuated by phosphatidylinositol 3-kinase inhibitors such as LY294002 and wortmannin. In conclusion, isoalantolactone is a candidate for chemoprevention and acts as potent phase 2 enzyme inducer by stimulating the accumulation of Nrf2 in the nucleus.

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Section: Discussionmentioning

confidence: 98%

Isoalantolactone fromInula heleniumCaused Nrf2-Mediated Induction of Detoxifying Enzymes

Seo

Park

Kim

et al. 2009

Journal of Medicinal Food

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“…9A). We postulate that that the latter pathway involves the transcription factor nuclear factor E2-related factor 2 (Nrf2), as previous studies have shown that bile acids stimulate Nrf2 activity via a PI3K/Akt-dependent mechanism and that Nrf2 induction stimulates hepatic FGF21 expression in diabetic mice (45,46). The ability of CDCA to act through multiple signaling pathways to induce FGF21 gene expression provides a means through which CDCA can finely control FGF21 production during different conditions.…”

Section: Discussionmentioning

confidence: 99%

Glucagon and Insulin Cooperatively Stimulate Fibroblast Growth Factor 21 Gene Transcription by Increasing the Expression of Activating Transcription Factor 4

Alonge

Meares

Hillgartner

2017

Journal of Biological Chemistry

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Edited by John M. DenuPrevious studies have shown that glucagon cooperatively interacts with insulin to stimulate hepatic FGF21 gene expression. Here we investigated the mechanism by which glucagon and insulin increased FGF21 gene transcription in primary hepatocyte cultures. Transfection analyses demonstrated that glucagon plus insulin induction of FGF21 transcription was conferred by two activating transcription factor 4 (ATF4) binding sites in the FGF21 gene. Glucagon plus insulin stimulated a 5-fold increase in ATF4 protein abundance, and knockdown of ATF4 expression suppressed the ability of glucagon plus insulin to increase FGF21 expression. In hepatocytes incubated in the presence of insulin, treatment with a PKA-selective agonist mimicked the ability of glucagon to stimulate ATF4 and FGF21 expression. Inhibition of PKA, PI3K, Akt, and mammalian target of rapamycin complex 1 (mTORC1) suppressed the ability of glucagon plus insulin to stimulate ATF4 and FGF21 expression. Additional analyses demonstrated that chenodeoxycholic acid (CDCA) induced a 6-fold increase in ATF4 expression and that knockdown of ATF4 expression suppressed the ability of CDCA to increase FGF21 gene expression. CDCA increased the phosphorylation of eIF2␣, and inhibition of eIF2␣ signaling activity suppressed CDCA regulation of ATF4 and FGF21 expression. These results demonstrate that glucagon plus insulin increases FGF21 transcription by stimulating ATF4 expression and that activation of cAMP/PKA and PI3K/Akt/mTORC1 mediates the effect of glucagon plus insulin on ATF4 expression. These results also demonstrate that CDCA regulation of FGF21 transcription is mediated at least partially by an eIF2␣-dependent increase in ATF4 expression.FGF21 is an atypical member of the fibroblast growth factor family that lacks the ability to bind to heparin sulfate proteoglycans, allowing it to escape the extracellular matrix and function in an endocrine manner (1-3). Studies investigating the biological action of FGF21 have shown that starvation and other nutritional stresses (e.g. dietary protein restriction, consumption of a high-fat, low-carbohydrate ketogenic diet, and consumption of a high-fat obesogenic diet) stimulate an increase in the expression and secretion of FGF21 by the liver, the predominant site of FGF21 production in the body (4 -10). FGF21 signals through FGF receptor 1c (FGFR1c) linked to the co-receptor ␤-klotho to increase food intake, energy expenditure, gluconeogenesis, and insulin sensitivity and inhibit growth and female fertility in response to nutritional stress (1-6, 11).Several signaling pathways have been identified that mediate the effects of nutritional stress on FGF21 expression. One such pathway involves the activation of the nuclear receptor peroxisome proliferator-activated receptor ␣ (PPAR␣).2 A PPAR␣ response element (PPRE) has been identified in the 5Ј-flanking region of the murine and human FGF21 genes (8, 12). Ablation of the PPAR␣ gene suppresses the ability of starvation and ketogenic diet consumption to incr...

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“…Previous reports have demonstrated that UDCA activates p38 MAPK, extracellular signal-regulated protein kinase (ERK), and PI3K pathways (25,40). In addition, CDCA also activates the p38 MAPK, c-Jun N-terminal kinase, and ERK pathways but not the PI3K pathway (31).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, UDCA has beneficial effects on cholestatic disorders due to its anti-apoptotic, anti-fibrotic, and cytoprotective effects (24). UDCA treatment increases glutathione synthesis by activating the PI3K/Akt/Nrf2 pathway (25) and have beneficial effects on hepatic steatosis and insulin resistance (26,27). Other bile acids such as cholic acid (CA) and chenodeoxycholic acid (CDCA) prevent hepatic TG accumulation (28).…”

Section: Small Heterodimer Partner Interacting Leucine Zipper Proteinmentioning

confidence: 99%

Ursodeoxycholic Acid Inhibits Liver X Receptor α-mediated Hepatic Lipogenesis via Induction of the Nuclear Corepressor SMILE

Lee

Gang

Kim

et al. 2014

Journal of Biological Chemistry

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Background: Small heterodimer partner interacting leucine zipper protein (SMILE) is a nuclear corepressor of the nuclear receptor family. Results: Ursodeoxycholic acid (UDCA) increases SMILE gene expression, which contributes to inhibiting liver X receptor ␣ (LXR␣)-mediated hepatic lipogenesis. Conclusion: UDCA-induced SMILE inhibits LXR␣-mediated hepatic lipogenic gene expression. Significance: SMILE improves hepatic lipid metabolism.

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Ursodeoxycholic acid induces glutathione synthesis through activation of PI3K/Akt pathway in HepG2 cells

Cited by 59 publications

References 43 publications

Isoalantolactone fromInula heleniumCaused Nrf2-Mediated Induction of Detoxifying Enzymes

Isoalantolactone fromInula heleniumCaused Nrf2-Mediated Induction of Detoxifying Enzymes

Glucagon and Insulin Cooperatively Stimulate Fibroblast Growth Factor 21 Gene Transcription by Increasing the Expression of Activating Transcription Factor 4

Ursodeoxycholic Acid Inhibits Liver X Receptor α-mediated Hepatic Lipogenesis via Induction of the Nuclear Corepressor SMILE

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