• The Korean Journal of Physiology and Pharmacology
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• v.25 no.2
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• pp.111-118
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• 2021

27-Hydroxycholesterol (27OHChol) exhibits agonistic activity for liver X receptors (LXRs). To determine roles of the LXR agonistic activity in macrophage gene expression, we investigated the effects of LXR inhibition on the 27OHChol-induced genes. Treatment of human THP-1 cells with GSK 2033, a potent cell-active LXR antagonist, results in complete inhibition in the transcription of LXR target genes (such as LXRα and ABCA1) induced by 27OHChol or a synthetic LXR ligand TO 901317. Whereas expression of CCL2 and CCL4 remains unaffected by GSK 2033, TNF-α expression is further induced and 27OHChol-induced CCL3 and CXCL8 genes are suppressed at both the transcriptional and protein translation levels in the presence of GSK 2033. This LXR antagonist downregulates transcript levels and surface expression of CD163 and CD206 and suppresses the transcription of CD14, CD80, and CD86 genes without downregulating their surface levels. GSK 2033 alone had no effect on the basal expression levels of the aforementioned genes. Collectively, these results indicate that LXR inhibition leads to differential regulation of 27-hydroxycholesterol-induced genes in macrophages. We propose that 27OHChol induces gene expression and modulates macrophage functions via LXR-dependent and -independent mechanisms.

• Food Science of Animal Resources
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• v.31 no.3
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• pp.398-404
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• 2011

TR4 has been suggested to play an important role in lipid metabolism in adipocytes. Although TR4 facilitates lipid accumulation during adipogenesis, the regulatory effect of TR4 on lipid storage in mature adipocytes remains unclear. We showed that TR4 inhibited the LXR agonist GW3965-mediated decrease of lipid accumulation in 3T3-L1 adipocytes. A reporter gene analysis revealed that TR4 suppressed LXR${\alpha}$ transcriptional activity, although LXR${\alpha}$ was unable to affect TR4 transcriptional activity. Moreover, adding TR4 resulted in reduced LXR${\alpha}$ binding to the LXR responsive element in a gel shift assay. Additionally, the suppressive effect of GW3965 on perilipin expression and lipid accumulation in 3T3-L1 adipocytes was abolished by TR4 overexpression. Taken together, our data demonstrate that TR4 plays an inhibitory role in LXR${\alpha}$-mediated suppression of lipid accumulation in 3T3-L1 adipocytes. This TR4 protective effect is mediated, in part, y blocking the suppressive effect of GW3965 on perilipin gene expression.

• Herbal Formula Science
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• v.30 no.3
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• pp.137-143
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• 2022

Objectives : Brain-Liver axis is an important target of the chronic human diseases. Hepatic steatosis is one of the most famous disorders in the chronic diseases. This study investigated the moderating effect of beneficial herbs on the fat accumulation, which is mediated by the LXR alpha-SREBP-1c signaling pathway. Methods : In order to confirm the SREBP-1c inhibitory effect, we performed immonoblotting ananlysis using HepG2 cells and Huh 7 cells treated by T0901317, the ligand of LXRα. Results : Forsythiae suspensa water extract (FSE) was not cytotoxicity in cell lines. FSE inhibited SREBP-1c protein expression in HepG2 and Huh7 cells induced by T0901317. In addition, FSE increased the phosphorylation of LKB1, which is associated with LXR-related pathway in HepG2 and Huh 7 cells. Conclusions : These results showed that FSE activated LKB1 to suppress SREBP-1c, which protects the cells against oxidative stress.

• Journal of Life Science
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• v.21 no.4
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• pp.481-485
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• 2011

T0901317 is a potent synthetic ligand for liver X receptor (LXR, NR1H2/3), a member of the nuclear receptor superfamily that functions as a transcription factor. However, T0901317 has been also reported to modulate the activity at least four other nuclear receptors (NRs), acting as agonists for farnesoid X receptor (FXR, NR1H4) and pregnane X receptor (PXR, NR1I2) and as antagonists for androgen receptor (AR, NR3C4) and retinoid-related orphan receptor-${\alpha}$ (ROR-${\alpha}$, NR1F1). We report here that T0901317 can also function as an inhibitor for constitutive androstane receptor (CAR, NR1I3). Since CAR is a major player of xenobiotic and cholesterol metabolism in the liver, along with PXR, FXR and LXR, which are reported to be regulated by T0901317, this further complicates the interpretation of potential results with T0901317 in liver cells.

• Molecules and Cells
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• v.26 no.4
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• pp.409-414
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• 2008

The cholesteryl ester transfer protein (CETP), a key player in cholesterol metabolism, has been shown to promote the transfer of triglycerides from very low density lipoprotein (VLDL) and low density lipoprotein (LDL) to high density lipoprotein (HDL) in exchange for cholesterol ester. Here we demonstrate that farnesoid X receptor ${\alpha}$ ($FXR{\alpha}$; NR1H4) down-regulates CETP expression in HepG2 cells. A $FXR{\alpha}$ ligand, chenodeoxycholic acid (CDCA), suppressed basal mRNA levels of the CETP gene in HepG2 cells in a dose-dependent manner. Using gel shift and chromatin immunoprecipitation (ChIP) assays, we found that $FXR{\alpha}$ could bind to the liver X receptor ${\alpha}$ ( $LXR{\alpha}$; NR1H3) binding site (LXRE; DR4RE) located within the CETP 5' promoter region. $FXR{\alpha}$ suppressed $LXR{\alpha}$-induced DR4RE-luciferase activity and this effect was mediated by a binding competition between $FXR{\alpha}$ and $LXR{\alpha}$ for DR4RE. Furthermore, the addition of CDCA together with a $LXR{\alpha}$ ligand, GW3965, to HepG2 cells was shown to substantially decrease mRNA levels of hepatic CETP gene, which is typically induced by GW3965. Together, our data demonstrate that $FXR{\alpha}$ down-regulates CETP gene expression via binding to the DR4RE sequence within the CETP 5' promoter and this $FXR{\alpha}$ binding is essential for $FXR{\alpha}$ inhibition of $LXR{\alpha}$-induced CETP expression.

• Korean Journal of Food Science and Technology
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• v.51 no.6
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• pp.558-564
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• 2019

Hypertriglyceridemia is one of the metabolic syndrome that is often observed as a result of lipid abnormalities. It is associated with other lipids, metabolic disorders, cardiovascular disease and liver disease. Korean red ginseng is known to affect obesity, dyslipidemia, liver disease and liver function, but the mechanism of its effect is not clear. This study examined the beneficial effects of hypertriglyceridemia and the mechanism of action of Jinan red ginseng extract (JRG) in hepatoma cells. To measure the levels of triglyceride accumulation, we studied the expression of proteins and mRNAs related to lipidogenesis in hepatoma cells (Huh7 and HepG2). JRG decreases the lipidogenic markers, peroxisome proliferator-activated receptor γ (PPARγ), CCAAT-enhancer-binding proteins α (C/EBPα) and C/EBPβ which are major regulators of triglyceride synthesis in hepatoma cells. We also found that JRG reduced sterol regulatory element binding proteins 1c (SREBP-1c), C/EBPα and C/EBPβ by regulating liver X receptor (LXR) and stearoyl CoA desaturase (SCD) expressions. In addition, the first-limited step of synthesis triglyceride (TG), glycerol-3-phosphate (G3P) is decreased by JRG. These results suggest that the anti-hypertriglyceride effect of JRG in hepatoma cells could be accompanied with the inhibition of lipidogenic transcription factors by regulating LXR and SCD expression.

• Food Science of Animal Resources
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• v.30 no.5
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• pp.787-794
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• 2010

Calcium plays a role as a signaling molecule in various cellular events. It has been reported that calcium suppresses adipocyte differentiation only in the early phase of adipogenesis. Herein, we demonstrate that treatment of A23187, a mobilizer of intracellular calcium, on day 4 post adipocyte differentiation could still reduce lipid accumulation in differentiating 3T3-L1 cells for 48 h. In addition, luciferase reporter gene and RT-Q-PCR assays demonstrate that A23187 can selectively inhibit transcriptional activities and expression of PPAR$\gamma$ and LXR$\alpha$, suggesting that A23187 may reduce lipid accumulation in the late phase of adipogenesis via downregulation of PPAR$\gamma$ and LXR$\alpha$ expression and transactivation. Moreover, inhibition of HDAC activity by trichostatin A (TSA) partially blocked A23187-mediated downregulation of transcriptional activities of PPAR$\gamma$ and LXR$\alpha$. Together, our data demonstrate that calcium mobilization inhibits expression and transcriptional activities of PPAR$\gamma$ and LXR$\alpha$, resulting in reduced lipid accumulation in differentiating adipocytes, and thus, mobilization of intracellular calcium in adipocytes may serve as a new preventive and therapeutic approach for obesity.

• Journal of the Society of Cosmetic Scientists of Korea
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• v.34 no.1
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• pp.1-8
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• 2008

Epidermis is one of the most dynamic organs in the human body. Multiple layers of keratinocytes in the epidermis continuously undergo proliferation, differentiation, and desquamation cycles, which is the bases of maintaining the epidermal homeostasis. Epidermal homeostasis eventually leads to establish and maintain permeability barrier homeostasis, the most important function of the epidermis. The permeability barrier is located in the stratum corneum. Tightly coordinated regulations are required for the sustained normal barrier function. Extensive studies have established that several nuclear hormone liposensors, including peroxisome proliferator-activated receptor a PPARa, PPARb/d, PPARg and LXRs are expressed in keratinocyte. Activation of PPARs and LXRs could provide a mechanism to coordinate the formation of the corneocytes and extracellular lipid membranes that constitute the stratum corneum. Topical application of PPAR/LXR ligands to murine skin results in the increased expression of keratinocyte differentiation-related proteins, such as involucrin, loricrin, profilaggrin, and trans-glutaminase 1, which would stimulate cornified envelope formation. In conclusion, topical application of ligands or activators of PPAR/LXR as an epidermotherapy would be a promising option to deal dry skin conditions such as atopy.

• Journal of Ginseng Research
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• v.48 no.1
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• pp.89-97
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• 2024

Background: Ginsenoside F2 (GF2), the protopanaxadiol-type constituent in Panax ginseng, has been reported to attenuate metabolic dysfunction-associated steatotic liver disease (MASLD). However, the mechanism of action is not fully understood. Here, this study investigates the molecular mechanism by which GF2 regulates MASLD progression through liver X receptor (LXR). Methods: To demonstrate the effect of GF2 on LXR activity, computational modeling of protein-ligand binding, Time-resolved fluorescence resonance energy transfer (TR-FRET) assay for LXR cofactor recruitment, and luciferase reporter assay were performed. LXR agonist T0901317 was used for LXR activation in hepatocytes and macrophages. MASLD was induced by high-fat diet (HFD) feeding with or without GF2 administration in WT and LXRα^-/- mice. Results: Computational modeling showed that GF2 had a high affinity with LXRα. LXRE-luciferase reporter assay with amino acid substitution at the predicted ligand binding site revealed that the S264 residue of LXRα was the crucial interaction site of GF2. TR-FRET assay demonstrated that GF2 suppressed LXRα activity by favoring the binding of corepressors to LXRα while inhibiting the accessibility of coactivators. In vitro, GF2 treatments reduced T0901317-induced fat accumulation and pro-inflammatory cytokine expression in hepatocytes and macrophages, respectively. Consistently, GF2 administration ameliorated hepatic steatohepatitis and improved glucose or insulin tolerance in WT but not in LXRα^-/- mice. Conclusion: GF2 alters the binding affinities of LXRα coregulators, thereby interrupting hepatic steatosis and inflammation in macrophages. Therefore, we propose that GF2 might be a potential therapeutic agent for the intervention in patients with MASLD.

• Molecules and Cells
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• v.39 no.11
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• pp.797-806
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• 2016

Lipogenesis is under the concerted action of ChREBP, SREBP-1c and other transcription factors in response to glucose and insulin. The isolated porcine preadipocytes were differentiated into mature adipocytes to investigate the roles and interrelation of these transcription factors in the context of glucose- and insulin-induced lipogenesis in pigs. In ChREBP-silenced adipocytes, glucose-induced lipogenesis decreased by ~70%, however insulin-induced lipogenesis was unaffected. Moreover, insulin had no effect on ChREBP expression of unperturbed adipocytes irrespective of glucose concentration, suggesting ChREBP mediate glucose-induced lipogenesis. Insulin stimulated SREBP-1c expression and when SREBP-1c activation was blocked, and the insulin-induced lipogenesis decreased by ~55%, suggesting SREBP-1c is a key transcription factor mediating insulin-induced lipogenesis. $LXR{\alpha}$ activation promoted lipogenesis and lipogenic genes expression. In ChREBP-silenced or SREBP-1c activation blocked adipocytes, $LXR{\alpha}$ activation facilitated lipogenesis and SREBP-1c expression, but had no effect on ChREBP expression. Therefore, $LXR{\alpha}$ might mediate lipogenesis via SREBP-1c rather than ChREBP. When ChREBP expression was silenced and SREBP-1c activation blocked simultaneously, glucose and insulin were still able to stimulated lipogenesis and lipogenic genes expression, and $LXR{\alpha}$ activation enhanced these effects, suggesting $LXR{\alpha}$ mediated directly glucose- and insulin-induced lipogenesis. In summary, glucose and insulin stimulated lipogenesis through both dissimilar and identical regulation pathway in porcine adipocytes.