SMILE, a new orphan nuclear receptor SHP-interacting protein, regulates SHP-repressed estrogen receptor transactivation

Xie, Yuanbin; Lee, Ok-Hee; Nedumaran, Balachandar; Seong, Hyun‐A; Lee, Kyeong-Min; Ha, Hyunjung; Lee, Inkyu; Yun, Yungdae; Choi, Hueng-Sik

doi:10.1042/bj20080782

Cited by 45 publications

(79 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our qRT-PCR experiment, however, revealed that NR0B1 mRNA expression is undetectable in mouse liver tissues (data not shown). Also, SHP-interacting leucine zipper protein (SMILE) [initially identified as an SHP-interacting protein (Xie et al, 2008)] has been shown to repress HNF4a transactivation of target genes in the absence of SHP . Our results showed, however, that the mRNA expression levels of SMILE did not differ between Shp(2/2);CYP2D6 and Shp (+/+);CYP2D6 male mice (data not shown; in female mice, SMILE mRNA expression was even lower in Shp(2/2);CYP2D6 mice as compared with Shp(+/+);CYP2D6 mice).…”

Section: Discussionmentioning

confidence: 99%

Farnesoid X Receptor Agonist Represses Cytochrome P450 2D6 Expression by Upregulating Small Heterodimer Partner

2015

View full text Add to dashboard Cite

Cytochrome P450 2D6 (CYP2D6) is a major drug-metabolizing enzyme responsible for eliminating approximately 20% of marketed drugs. Studies have shown that differential transcriptional regulation of CYP2D6 may contribute to large interindividual variability in CYP2D6-mediated drug metabolism. However, the factors governing CYP2D6 transcription are largely unknown. We previously demonstrated small heterodimer partner (SHP) as a novel transcriptional repressor of CYP2D6 expression. SHP is a representative target gene of the farnesoid X receptor (FXR). The objective of this study is to investigate whether an agonist of FXR, 3-(2,6-dichlorophenyl)-4-(39-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), alters CYP2D6 expression and activity. In CYP2D6-humanized transgenic mice, GW4064 decreased hepatic CYP2D6 expression and activity (by 2-fold) while increasing SHP expression (by 2-fold) and SHP recruitment to the CYP2D6 promoter. CYP2D6 repression by GW4064 was abrogated in Shp(2/2);CYP2D6 mice, indicating a critical role of SHP in CYP2D6 regulation by GW4064. Also, GW4064 decreased CYP2D6 expression (by 2-fold) in primary human hepatocytes, suggesting that the results obtained in CYP2D6-humanized transgenic mice can be translated to humans. This proof of concept study provides evidence for CYP2D6 regulation by an inducer of SHP expression, namely, the FXR agonist GW4064.

show abstract

Section: Discussionmentioning

confidence: 99%

Farnesoid X Receptor Agonist Represses Cytochrome P450 2D6 Expression by Upregulating Small Heterodimer Partner

2015

View full text Add to dashboard Cite

show abstract

“…The reporter plasmids LXRE-Luc, SREBP1c-Luc, and SMILE-Luc were described previously (12,17). pCMV-␤-gal, pcDNA3-HA-LXR␣, pcDNA3-HA-SRC-1, pcDNA3-ERR␥, pcDNA3-FLAG-SMILE, pGEX4T-1, pGEX4T-1-SMILE, pEBGempty, pEBG-SMILE, pSUPER-si-empty, and pSUPER-si-SMILE, FLAG-SMILE LXXLL mutants (m1, m2, m3, m4, and m5) were described previously (12,15,17). pEBG-LXR␣ WT, pEBG-LXR␣ C, pEBG-LXR␣ DE, and pEBG-LXR␣ AB were subcloned into the BamHI/KpnI sites of the pEBG vector.…”

Section: Methodsmentioning

confidence: 99%

“…SMILE has also been proposed as a coactivator of activating transcription factor 4 (14). Moreover, we have revealed that SMILE functions as a nuclear co-repressor of the estrogen receptor (ER), glucocorticoid receptor (GR), constitutive androstane receptor (CAR), hepatocyte nuclear factor 4␣, and estrogen receptor-related receptor ␥ (ERR ␥) (15)(16)(17). Moreover, we reported that curcumin induces SMILE gene expression through a liver kinase B1/adenosine monophosphate-activated kinase (AMPK) pathway and represses endoplasmic reticulum (ER) stress-responsive gene transcription (18).…”

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Small heterodimer partner-interacting leucine zipper protein (SMILE), including two alternative translation-derived isoforms, SMILE-L (CREBZF: long form of SMILE) and SMILE-S (Zhangfei: short form of SMILE), has been classified as a member of the CREB/ATF family of basic regionleucine zipper transcription factors. However, SMILE cannot bind to DNA as a homodimer (10)(11)(12). SMILE has also been reported to function as a coactivator of activating transcription factor 4 or as a corepressor of host cell factor-binding transcription factor (13,14).…”

mentioning

confidence: 99%

Insulin-Inducible SMILE Inhibits Hepatic Gluconeogenesis

et al. 2015

Self Cite

View full text Add to dashboard Cite

The role of a glucagon/cAMP-dependent protein kinaseinducible coactivator PGC-1a signaling pathway is well characterized in hepatic gluconeogenesis. However, an opposing protein kinase B (PKB)/Akt-inducible corepressor signaling pathway is unknown. A previous report has demonstrated that small heterodimer partner-interacting leucine zipper protein (SMILE) regulates the nuclear receptors and transcriptional factors that control hepatic gluconeogenesis. Here, we show that hepatic SMILE expression was induced by feeding in normal mice but not in db/db and high-fat diet (HFD)-fed mice. Interestingly, SMILE expression was induced by insulin in mouse primary hepatocyte and liver. Hepatic SMILE expression was not altered by refeeding in liver-specific insulin receptor knockout (LIRKO) or PKB b-deficient (PKBb 2/2 ) mice. At the molecular level, SMILE inhibited hepatocyte nuclear factor 4-mediated transcriptional activity via direct competition with PGC-1a. Moreover, ablation of SMILE augmented gluconeogenesis and increased blood glucose levels in mice. Conversely, overexpression of SMILE reduced hepatic gluconeogenic gene expression and ameliorated hyperglycemia and glucose intolerance in db/db and HFD-fed mice. Therefore, SMILE is an insulin-inducible corepressor that suppresses hepatic gluconeogenesis. Small molecules that enhance SMILE expression would have potential for treating hyperglycemia in diabetes.

show abstract

SMILE, a new orphan nuclear receptor SHP-interacting protein, regulates SHP-repressed estrogen receptor transactivation

Cited by 45 publications

References 52 publications

Farnesoid X Receptor Agonist Represses Cytochrome P450 2D6 Expression by Upregulating Small Heterodimer Partner

Farnesoid X Receptor Agonist Represses Cytochrome P450 2D6 Expression by Upregulating Small Heterodimer Partner

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

Insulin-Inducible SMILE Inhibits Hepatic Gluconeogenesis

Contact Info

Product

Resources

About