• The Korean Journal of Physiology and Pharmacology
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• v.25 no.5
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• pp.385-393
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• 2021

Tissue factor (TF) activates the coagulation system and has an important role in the pathogenesis of various diseases. Our previous study stated that retinoid receptors (RAR-α and RXR-α) are released as a lipid droplet in monocrotaline/lipopolysaccharide-induced idiosyncratic liver toxicity in mice. Herein, the interdependence between the release of retinoid receptors RAR-α and RXR-α and TF in N-acetyl-p-aminophenol (APAP)-induced mice liver toxicity, is investigated. Serum alanine transaminase (ALT) level, platelet and white blood cells (WBCs) counts, protein expression of fibrin, TF, cyclin D1 and cleaved caspase-3 in liver tissues are analyzed. In addition, histopathological evaluation and survival study are also performed. The results indicate that using of TF-antisense (TF-AS) deoxyoligonucleotide (ODN) injection (6 mg/kg), to block TF protein synthesis, significantly restores the elevated level of ALT and WBCs and corrects thrombocytopenia in mice injected with APAP. TF-AS prevents the peri-central overexpression of liver TF, fibrin, cyclin D1 and cleaved caspase-3. The release of RXR-α and RAR-α droplets, in APAP treated sections, is inhibited upon treatment with TF-AS. In conclusion, the above findings designate that the released RXR-α and RAR-α in APAP liver toxicity is TF dependent. Additionally, the enhancement of cyclin D1 to caspase-3-dependent apoptosis can be prevented by blocking of TF protein synthesis.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.120.2-120.2
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• 2003

Cytochrome P-450 3A4 (CYP3A4) is major enzyme in human liver, the role of this is detoxification and metabolizing more than 50% clinical drugs in use. Expression of CYP3A4 is transciptionally regulated by the Pregnenolone X receptor (PXR), of which human form is Steroid and Xenobiotics receptor (SXR). SXR is activated by wide range of endogenous and exogenous compounds, and then induces CYP3A4 gene expression. In the previous study, it has been known that proximal promoter (-864 to +64) does not response to chemical inducers such as pregnenolone 16a-carbonitrile (PCN), Rifampicin, Estrogen in terms of transcription of CYP 3A4 in cultured cells. (omitted)

• BMB Reports
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• v.46 no.6
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• pp.322-327
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• 2013

The ATP-binding cassette transporters ABCG5 and ABCG8 form heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion. To identify cis-regulatory elements of the two genes, we have cloned and analyzed twenty-three evolutionary conserved region (ECR) fragments using the CMV-luciferase reporter system in HepG2 cells. Two ECRs were found to be responsive to the Liver-X-Receptor (LXR). Through elaborate deletion studies, regions containing putative LXREs were identified and the binding of $LXR{\alpha}$ was demonstrated by EMSA and ChIP assay. When the LXREs were inserted upstream of the intergenic promoter, synergistic activation by $LXR{\alpha}/RXR{\alpha}$ in combination with GATA4, $HNF4{\alpha}$, and LRH-1, which had been shown to bind to the intergenic region, was observed. In conclusion, we have identified two LXREs in ABCG5/ABCG8 genes for the first time and propose that these LXREs, especially in the ECR20, play major roles in regulating these genes.

• Toxicological Research
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• v.30 no.1
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• pp.19-25
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• 2014

Licochalcone (LC), a major phenolic retrochalcone from licorice, has anti-inflammatory activity. This study investigated the effects of licochalcone A (LCA) and licochalcone E (LCE) on Liver X receptor-${\alpha}$ ($LXR{\alpha}$)-mediated lipogenic gene expression and the molecular mechanisms underlying those effects. LCA and LCE antagonized the ability of $LXR{\alpha}$ agonists (T0901317 or GW3965) to increase sterol regulatory element binding protein-1c (SREBP-1c) expression and thereby inhibited target gene expression (e.g., FAS and ACC) in HepG2 cells. Moreover, treatment with LCA and LCE impaired $LXR{\alpha}/RXR{\alpha}$-induced CYP7A1-LXRE-luciferase (CYP7A1) transactivation. The AMPK-Sirt1 signaling pathway is an important regulator of energy metabolism and, therefore, a potential therapeutic target for metabolic diseases, including hepatic steatosis. We found here that LCE increased AMPK phosphorylation and Sirt1 expression. We conclude that LC inhibits SREBP-1c-mediated hepatic lipogenesis via activation of the AMPK/Sirt1 signaling pathway.

• IMMUNE NETWORK
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• v.21 no.5
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• pp.37.1-37.17
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• 2021

Hepatitis B virus X (HBx) protein has been reported as a key protein regulating the pathogenesis of HBV-induced hepatocellular carcinoma (HCC). Recent evidence has shown that HBx is implicated in the activation of autophagy in hepatic cells. Nevertheless, the precise molecular and cellular mechanism by which HBx induces autophagy is still controversial. Herein, we investigated the molecular and cellular mechanism by which HBx is involved in the TRAF6-BECN1-Bcl-2 signaling for the regulation of autophagy in response to TLR4 stimulation, therefore influencing the HCC progression. HBx interacts with BECN1 (Beclin 1) and inhibits the association of the BECN1-Bcl-2 complex, which is known to prevent the assembly of the pre-autophagosomal structure. Furthermore, HBx enhances the interaction between VPS34 and TRAF6-BECN1 complex, increases the ubiquitination of BECN1, and subsequently enhances autophagy induction in response to LPS stimulation. To verify the functional role of HBx in liver cancer progression, we utilized different HCC cell lines, HepG2, SK-Hep-1, and SNU-761. HBx-expressing HepG2 cells exhibited enhanced cell migration, invasion, and cell mobility in response to LPS stimulation compared to those of control HepG2 cells. These results were consistently observed in HBx-expressed SK-Hep-1 and HBx-expressed SNU-761 cells. Taken together, our findings suggest that HBx positively regulates the induction of autophagy through the inhibition of the BECN1-Bcl-2 complex and enhancement of the TRAF6-BECN1-VPS34 complex, leading to enhance liver cancer migration and invasion.

• Animal Bioscience
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• v.35 no.1
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• pp.22-28
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• 2022

Objective: Endoplasmic reticulum (ER) stress engages the unfolded protein response (UPR) that serves as an important mechanism for modulating hepatic fatty acid oxidation and lipogenesis. Chronic fasting in mice induced the UPR activation to regulate lipid metabolism. However, there is no direct evidence of whether negative energy balance (NEB) induces ER stress in the liver of cows. This study aimed to elucidate the relationship between the NEB attributed to feed deprivation and ER stress in bovine hepatocytes. Methods: Blood samples and liver biopsy tissues were collected from 6 non-lactating cows before and after their starvation for 48 h. The blood non-esterified fatty acids (NEFA), β-hydroxybutyric acid (BHBA) and glucose level were analyzed. Real-time quantitative polymerase chain reaction and Western blotting were used to explore the regulation of genes associated with UPR and lipid metabolism. Results: The starvation increased the plasma BHBA and NEFA levels and decreased the glucose level. Additionally, the starvation caused significant increases in the mRNA expression level of spliced X-box binding protein 1 (XBP1s) and the protein level of phosphorylated inositol-requiring kinase 1 alpha (p-IRE1α; an upstream protein of XBP1) in the liver. The mRNA expression levels of peroxisome proliferator-activated receptor alpha and its target fatty acid oxidation- and ketogenesis-related genes were significantly upregulated by the starvation-mediated NEB. Furthermore, we found that the mRNA expression levels of lipogenic genes were not significantly changed after starvation. Conclusion: These findings suggest that in the initial stage of NEB in dairy cows, the liver coordinates an adaptive response by activating the IRE1 arm of the UPR to enhance ketogenesis, thereby avoiding a fatty liver status.

• Journal of Convergence Korean Medicine
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• v.5 no.1
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• pp.55-60
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• 2023

Objectives: This study was performed to investigate the effect of TJGB on the liver of high-fat diet (HFD)-fed mice and the cell viability of HepG2 cells. Methods: After a week adaptation, 8-week-old C57BL/6N mice were fed with a 45% HFD or normal diet for 3 weeks. For the next 9 weeks, the mice were divided into 6 groups: normal diet group; HFD group; HFD plus orlistat group; HFD plus Ephedra sinica Stapf (ES) group; HFD plus low dose of TJGB group; HFD plus high dose of TJGB group. To estimate the effect of TJGB in the liver of HFD-fed mice, the protein expressions of phospho-acetyl-CoA carboxylase (p-ACC) and liver X Receptor (LXR) were determined by Western blot assay. The cell viability of ES and TJG was also evaluated in HepG2 cells. Results: The administration of TJGB had little effect on the protein expressions of p-ACC and LXR in the liver of HFD-fed mice. And the cytotoxicity was showed above 7.8 ㎍/mL in HepG2 cells. Conclusion: Further research is needed to evaluate the mechanism of TJGB on hepatic steatosis and cytotoxicity in HepG2 cells.

• 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.

• Asian-Australasian Journal of Animal Sciences
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• v.20 no.10
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• pp.1606-1611
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• 2007

The experiment was conducted to investigate the effects of dihydropyridine on laying performance and fat metabolism of laying hens. Five hundred and forty laying hens, 40 weeks old, were randomly allotted to three groups, each of which included four replicates of 45 hens. The groups were given a basal corn-soybean meal diet supplemented with 0, 150 mg/kg and 300 mg/kg dihydropyridine. Results showed that compared with the control group (0 mg/kg dihydropyridine), supplements of 150 and 300 mg/kg dihydropyridine increased egg production rate by 9.39% (p<0.01) and 12.97% (p<0.01), increased mean egg weight by 3% (p>0.05) and 4.8% (p>0.05), and improved feed efficiency by 9.54% (p<0.05) and 7.25% (p<0.05), respectively; The addition of 150 and 300 mg/kg dihydropyridine decreased percentage of abdominal fat by 35.4% (p<0.05) and 46.9% (p<0.05), decreased liver fat content by 32.4% (p<0.05) and 10.5% (p<0.05), increased HSL activity of abdominal fat by 39.64% (p<0.05) and 48.48% (p<0.05), increased HSL activity of liver by 9.4% (p>0.05) and 47.34% (p<0.05) and increased the content of cAMP in adenohypophysis by 14.67% (p<0.05) and 10.91% (p<0.05), respectively; The inclusion of 150 mg/kg dihydropyridine increased liver superoxide dismutase activity by 69.61% (p<0.05), and increased hepatic apoB concentration by 53.96% (p<0.05); The supplementation of 150 or 300 mg/kg dihydropyridine decreased malondialdehyde concentration of hepatic mitochondria by 30.90% (p<0.01) and 10.39% (p<0.05), respectively; Supplemented dihydropyridine had no significant effects on TG, Ch HDL-C and VLDL-C concentrations in serum; addition of 150 or 300 mg/kg dihydropyridine increased T3 levels in serum by 15.34% (p<0.05) and 11.88% (p<0.05) and decreased insulin concentration by 40.44% (p<0.05) and 54.37% (p<0.05), respectively. The results demonstrated that adding dihydropyridine had the tendency of improving very low density lipoprotein receptor (VLDLR) content in the ovary. It was concluded that dihydropyridine could improve laying performance and regulate the fat metabolism of laying hens and that 150 mg/kg dihydropyridine is the optimum dose for laying birds in practical conditions.

• Journal of Life Science
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• v.32 no.3
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• pp.256-262
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• 2022

Oxysterols are oxygenated metabolites of cholesterol generated by serial enzymatic reactions during bile acid synthesis. Similar to cholesterol, oxysterols move rapidly to the intracellular region and modulate various cellular processes, such as immune cell responses, lipid metabolism, and cholesterol homeostasis. Different nuclear transcription factors, such as glucocorticoid, estrogen, and liver X receptors, can be modulated by oxysterols in multiple tissues. The most abundant oxysterol, 27-hydroxycholesterol (27-OHC), is a well-known selective modulator that can either activate or suppress estrogen receptor activity in a tissue-specific manner. The contribution of 27-OHC in atherosclerosis development is apparent because a large amount of it is found in atherosclerotic plaques, accelerating the transformation of macrophages into foam cells that uptake extracellular modified lipids. According to previous studies, however, there are opposing opinions about how 27-OHC affects lipid and cholesterol metabolism in metabolic organs, including the liver and adipose tissue. In particular, the effects of 27-OHC on lipid metabolism are entirely different between in vitro and in vivo conditions, suggesting that understanding the physiology of this oxysterol requires a sophisticated approach. This review summarizes the potential effects of 27-OHC in atherosclerosis and metabolic syndromes with a special discussion of its role in metabolic tissues.