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| (1) Nuclear receptors |
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| Protein | Model(s)/putative function |
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| ERα | Uterus, pituitary, kidney, and adrenal gland, HepG2 cell lines/biological effects of estrogens, LDL/HDL metabolism [134]. |
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| ERRα, β, γ | SHP promoter is activated by the ERRγ, while SHP inhibits ERRγ transactivation (autoregulatory loop). SHP and ERRγ coexpressed in several tissues (e.g., pancreas, kidney, and heart). Role in some forms of moderate obesity? SHP also physically interacts with ERR α and β isoforms (yeast two-hybrid and biochemical assays) [133]. |
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| FXR | Downregulation of CYP7A1-mediated bile acid biosynthesis by the FXR/SHP/LRH-1 cascade in the liver [64]. |
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| LXRα | Direct regulation of SHP and repression of CYP7A1-mediated bile acid biosynthesis (in humans not in rodents). Effect on cholesterol homeostasis [135]. |
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| LRH-1 | Liver/formation of heterodimeric SHP/LRH-1 complex > inactivation of LRH-1 > SHP repression (autoregulatory negative feedback) [64, 65, 136]. Also involved in the CLOCK-BMAL1 circadian activation of SHP [38]. |
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| PPARγ | Liver/PPARγ decreases gluconeogenic gene expression by the PPARγ/RXRα heterodimer binding to the PPRE in the human SHP promoter. A mechanism explaining the SHP-mediated acute antigluconeogenic effects of PPARγ [137]. |
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| SF-1 | At least five binding sites for SF-1 detected in the promoter region of SHP. Rat testis and adrenal glands, human fetal adrenal gland [136]. |
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| (2) Transcription factors |
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| Protein | Model(s)/putative function |
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| CLOCK-BMAL1 | Liver/SHP displays a circadian expression pattern involving CLOCK-BMAL1 (core circadian clock component). Regulation of SHP promoter together with LRH-1 and SHP. Relevance for circadian liver function? [38]. |
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| E2A proteins (E47, E12, E2/5) | HepG2, HeLa, and CV-1 cells/bHLH transcription factors, the E2A proteins activate human (not mouse) hSHP promoter. E47 and SF-1 stimulate cooperatively SHP promoter. The Id protein inhibits E47 binding to hSHP promoter. A role for tissue-specific gene regulation, B-cell differentiation, tumor suppression? [138]. |
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| HNF-1α | Liver/modulation of bile acid and liver cholesterol synthesis via the FXR/SHP/LRH-1 complex and effect on CYP7A1 [69]. |
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| HNF4α | Pancreatic β-cells/decreased expression of SHP may be indirectly mediated by a downregulation of HNF4α. SHP can repress its own transcriptional activation by inhibiting HNF4 α function (feedback autoregulatory loop) and, indirectly (via HNF4 α), HNF1α function. Relevance for pancreatic islet differentiation, insulin secretion, synthesis [116]. |
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| JNK/c-Jun/AP-1 | Primary rat hepatocytes/bile acid downregulation of CYP7A1-dependent bile acid biosynthesis via the JNK/cJun/AP1 pathway. SHP promoter is a direct target of activated c-Jun binding to AP-1 element [139]. Also, in HL-60 leukemia cells, c-Jun increases the transcriptional activation of the SHP promoter to activate the expression of Shp genes associated with the cascade regulation of monocytic differentiation [140]. |
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| SMILE | HEK-293T, HepG2, MCF-7, T47D, MDA-MB-435, HeLa, PC-3, C2C12, NIH 3T3, K28, Y-1, and TM4 cell lines/SMILE isoforms (SMILE-L and SMILE-S) regulate the SHP-driven inhibition of ERs transactivation in a cell-type-specific manner [25, 26, 39]. |
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| SREBP-1 | Liver/effect on human (not mouse) SHP promoter. Cholesterol and bile acid homeostasis, fatty acid synthesis [27]. |
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| USF-1 | HepG2, H4IIE, and AML12 cells/HGF activates AMPK signaling pathway in hepatocytes, E-box-binding transcription factor USF-1, and binding to the Shp gene promoter. SHP induction of gene expression leads to inhibition of hepatic gluconeogenesis due to SHP-repressed transcription factor HNF4α [28]. |
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| (3) Transcriptional coregulators |
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| Protein | Model(s)/putative function |
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| RNF31 | NCI-H295R (H295R) adrenocortical carcinoma cell line, COS-7 and HeLa cells/RNF31 interacts with SHP, stabilizes DAX-1, and is required for DAX-1-mediated repression of transcription. Relevant as coregulator of steroidogenic pathways [43]. |
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| SRC-1 | Murine macrophage cell line RAW 264.7, HeLa, and CV-1 cells/SHP interacts negatively with SRC-1 (a transcription coactivator of nuclear receptors and other transcription factors including NF-κB). See also oxLDL in this table [44]. |
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| (4) Other SHP inducers | |
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| Factor | Model(s)/putative function |
|
| Bile acids (final intermediates) | Experiments in HepG2 cells/treatment with chenodeoxycholic acid and late intermediates in the classic pathway of bile acid synthesis: 26-OH-THC (5β-cholestane-3α,7α,12α,26-tetrol), THCA (3α,7α,12α-trihydroxy-5 β-cholestanoic acid), 26-OHDHC (5β-cholestane-3α,7α,26-triol), DHCA (3α,7α-dihydroxy-5β-cholestanoic acid) resulted in 2.4-6.5-fold increase in SHP mRNA expression [132]. Confirmed by Ourlin et al. with the two FXR ligands chenodeoxycholic acid and cholic acid [1]. |
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| Guggulsterone (plant sterol) | Active extract from Commiphora Mukul. FXR antagonist. In Fisher rats, guggulsterone increased transcription of bile salt export pump (BSEP) mRNA and SHP expression [29]. |
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| GW4064 (ligand) | Synthetic FXR-selective agonist [29]. In primary cultured human hepatocytes, GW4064 treatment was associated with a marked induction of SHP (≈70-fold) and complete suppression of CYP7A1 [64, 65]. In HepG2 cells, GW4064 (1uM) induced a 3.9-fold increase in SHP mRNA expression. Confirmed by [30]. |
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| Interleukins (various) | IL-1Ra mice/high cytokine levels in IL-1Ra mice reduce mRNA expression of CYP7A1 with concurrent upregulation of SHP mRNA expression [31]. SHP significantly expressed in IFN-γ/CH11-resistant HepG2 cells [32]. |
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| PGC-1α (gene expression inducer) | COS-7 cell lines/PGC-1α mediates the ligand-dependent activation of FXR and transcription of Shp gene. Relevance in mitochondrial oxidative metabolism in brown fat, skeletal muscle, and liver gluconeogenesis [33]. |
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| PMRT1 (group of protein arginine methyltransferases) | Hepatic cell lines/PRMT1 functions as FXR coactivator and has a role in chromatin remodeling. PRMT1 induces BSEP and SHP and downregulation of NTCP and CYP7A1 (targets of SHP) [30]. |
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| Procyanidins (polyphenols) | Grape seed procyanidin extract is given orally in male Wistar rats. Increase of liver mRNA levels of small heterodimer partner (SHP) (2.4-fold), cholesterol 7α-hydroxylase (CYP7A1), and cholesterol biosynthetic enzymes with improved lipidogenic profile and atherosclerotic risk [34]. |
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| (5) Factors/conditions associated with SHP repression |
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| β Klotho (type I membrane protein) | In βKlotho mice: enhanced bile acid synthesis with attenuation of bile acid-mediated induction of Shp. βKlotho involved in CYP7A1 selective regulation [35]. |
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| IL-1β (interleukin) | SHP downregulation [36]. |
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| oxLDL (oxidized low density lipoprotein) | Murine macrophage cell line RAW 264.7, HeLa, and CV-1 cells/oxLDL decreased SHP expression. SHP transcription coactivator of NF-κB which became progressively inert in oxLDL-treated RAW 264.7 cells (see also Table 3). Relevance for differentiation mechanism of resting macrophage cells into foam cells and resulting atherogenesis [44]. |
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