On the mechanism of bile acid inhibition of rat sterol 12alpha-hydroxylase gene (CYP8B1) transcription: roles of alpha-fetoprotein transcription factor and hepatocyte nuclear factor 4alpha.
Animals; Rats; Gene Expression Regulation; Base Sequence; Cattle; Cytochrome P-450 Enzyme System/*genetics; Hepatocyte Nuclear Factor 4; *DNA-Binding Proteins; Bile Acids and Salts/*pharmacology; Steroid Hydroxylases/*genetics; alpha-Fetoproteins/genetics/*physiology; DNA; Phosphoproteins/genetics/*physiology; Steroid 12-alpha-Hydroxylase; Transcription Factors/genetics/*physiology; Sprague-Dawley; RNA; Transcription; Genetic; Promoter Regions; Messenger/genetics; Enzymologic/*drug effects/physiology; Genetic/*drug effects
The sterol 12alpha-hydroxylase (CYP8B1) is a key enzyme of the bile acid biosynthetic pathway. It regulates the composition of bile acids in bile, i.e. ratio between cholic acid (CA) and chenodeoxycholic acid (CDCA). In similarity with cholesterol 7alpha-hydroxylase (CYP7A1), this enzyme is subjected to a negative feedback regulation by bile acids. It has been recently reported that bile acid-activated farnesoid X receptor (FXR) induces the small heterodimer partner (SHP) that interacts with alpha-fetoprotein transcription factor (FTF) and down-regulates CYP7A1 transcription. We studied whether the same mechanism also regulated rat CYP8B1 gene transcription. Feeding rats with CDCA caused a
Yang Yizeng; Zhang Ming; Eggertsen Gosta; Chiang John Y L
Biochimica et biophysica acta
2002
2002-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Black currant anthocyanins abrogate oxidative stress through Nrf2- mediated antioxidant mechanisms in a rat model of hepatocellular carcinoma.
Male; Animals; Rats; Diet; Signal Transduction; NF-E2-Related Factor 2/genetics/*metabolism; *Phytotherapy; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Alkylating Agents/toxicity; Anthocyanins/*therapeutic use; Antioxidants/therapeutic use; Diethylnitrosamine/toxicity; Glutathione Transferase; Immunoenzyme Techniques; Lipid Peroxidation/drug effects; Nitric Oxide Synthase Type II/genetics/metabolism; Oxidative Stress/*drug effects; Ribes/*chemistry; Tyrosine/analogs & derivatives/metabolism; Carcinoma; Sprague-Dawley; Blotting; Western; RNA; Liver Neoplasms; Messenger/genetics; Experimental/chemically induced/metabolism/*prevention & control; Hepatocellular/chemically induced/metabolism/*prevention & control
Hepatocellular carcinoma (HCC), considered to be one of the most lethal cancers with almost \textgreater 1 million deaths reported annually worldwide, remains a devastating disease with no known effective cure. Hence, chemopreventive strategies come into play, offering an effective and safe mode of treatment, ideal to ward off potential cancer risks and mortality. A major predisposing condition, pertinent to the development and progression of HCC is oxidative stress. We previously reported a striking chemopreventive effect of anthocyanin-rich black currant skin extract (BCSE) against diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats. The current study aims to elucidate the underlying antioxidant mechanisms of black currant anthocyanins implicated in the previously observed chemopreventive effects against experimental hepatocarcinogenesis. Dietary BCSE (100 and 500 mg/kg) administered four weeks before and 18 weeks after DENA challenge decreased abnormal lipid peroxidation, protein oxidation, and expression of inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in a dose-responsive fashion. Mechanistic studies revealed that BCSE upregulated the gene expression of a number of hepatic antioxidant and carcinogen detoxifying enzymes, such as NAD(P)H:quinone oxidoreductase, glutathione S-transferase, and uridine diphosphate-glucuronosyltransferase isoenzymes, in DENA-initiated animals. Protein and mRNA expressions of nuclear factor E2-related factor 2 (Nrf2) were substantially elevated with BCSE treatment, providing a direct evidence of a coordinated activation of the Nrf2-regulated antioxidant pathway, which led to the upregulation of a variety of housekeeping genes. The results of our study provide substantial evidence that black currant bioactive anthocyanins exert chemopreventive actions against DENA-inflicted hepatocarcinogenesis by attenuating oxidative stress through activation of Nrf2 signaling pathway.
Thoppil Roslin J; Bhatia Deepak; Barnes Kendra F; Haznagy-Radnai Erzsebet; Hohmann Judit; Darvesh Altaf S; Bishayee Anupam
Current cancer drug targets
2012
2012-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2174/156800912803987968" target="_blank" rel="noreferrer noopener">10.2174/156800912803987968</a>
The orphan nuclear receptor small heterodimer partner is required for thiazolidinedione effects in leptin-deficient mice.
Animals; Bile Acids and Salts/metabolism; Cytoplasmic and Nuclear/biosynthesis/*genetics/metabolism; Diabetes Mellitus/*drug therapy/genetics/metabolism; Gene Expression Regulation/drug effects; Glucose/metabolism; Hepatocytes/drug effects; Humans; Insulin Resistance/genetics; Insulin/*metabolism; Leptin/deficiency/genetics; Lipid Metabolism/drug effects; Messenger/genetics; Mice; Obese; PPAR gamma/*biosynthesis/genetics; Receptors; RNA; Thiazolidinediones/*administration & dosage
BACKGROUND: Small heterodimer partner (SHP, NR0B2) is involved in diverse metabolic pathways, including hepatic bile acid, lipid and glucose homeostasis, and has been implicated in effects on the peroxisome proliferator-activated receptor gamma (PPARgamma), a master regulator of adipogenesis and the receptor for antidiabetic drugs thiazolidinediones (TZDs). In this study, we aim to investigate the role of SHP in TZD response by comparing TZD-treated leptin-deficient (ob/ob) and leptin-, SHP-deficient (ob/ob;Shp(-/-)) double mutant mice. RESULTS: Both ob/ob and double mutant ob/ob;Shp(-/-) mice developed hyperglycemia, insulin resistance, and hyperlipidemia, but hepatic fat accumulation was decreased in the double mutant ob/ob;Shp(-/-) mice. PPARgamma2 mRNA levels were markedly lower in ob/ob;Shp(-/-) liver and decreased to a lesser extent in adipose tissue. The TZD troglitazone did not reduce glucose or circulating triglyceride levels in ob/ob;Shp(-/-) mice. Expression of the adipocytokines, such as adiponectin and resistin, was not stimulated by troglitazone treatment. Expression of hepatic lipogenic genes was also reduced in ob/ob;Shp(-/-) mice. Moreover, overexpression of SHP by adenovirus infection increased PPARgamma2 mRNA levels in mouse primary hepatocytes. CONCLUSIONS: Our results suggest that SHP is required for both antidiabetic and hypolipidemic effects of TZDs in ob/ob mice through regulation of PPARgamma expression.
Tseng Hsiu-Ting; Park Young Joo; Lee Yoon-Kwang; Moore David D
Journal of biomedical science
2015
2015-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s12929-015-0133-3" target="_blank" rel="noreferrer noopener">10.1186/s12929-015-0133-3</a>
Mechanism of vitamin D receptor inhibition of cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes.
Base Sequence; Calcitriol/drug effects/genetics/*physiology; Cell Line; Cells; Cholesterol 7-alpha-Hydroxylase/*genetics; Cultured; DNA Primers; Electrophoretic Mobility Shift Assay; Gene Knockdown Techniques; Genetic/*physiology; Hepatocytes/*drug effects/enzymology; Humans; Immunoprecipitation; Lithocholic Acid/pharmacology; Messenger/genetics; Polymerase Chain Reaction; Receptors; RNA; Small Interfering; Transcription; Tumor; Two-Hybrid System Techniques
Lithocholic acid (LCA) is a potent endogenous vitamin D receptor (VDR) ligand. In cholestasis, LCA levels increase in the liver and intestine. The objective of this study is to test the hypothesis that VDR plays a role in inhibiting cholesterol 7alpha-hydroxylase (CYP7A1) gene expression and bile acid synthesis in human hepatocytes. Immunoblot analysis has detected VDR proteins in the nucleus of the human hepatoma cell line HepG2 and human primary hepatocytes. 1alpha, 25-Dihydroxy-vitamin D(3) or LCA acetate-activated VDR inhibited CYP7A1 mRNA expression and bile acid synthesis, whereas small interfering RNA to VDR completely abrogated VDR inhibition of CYP7A1 mRNA expression in HepG2 cells. Electrophoretic mobility shift assay and mutagenesis analyses have identified the negative VDR response elements that bind VDR/retinoid X receptor alpha in the human CYP7A1 promoter. Mammalian two-hybrid, coimmunoprecipitation, glutathione
Han Shuxin; Chiang John Y L
Drug metabolism and disposition: the biological fate of chemicals
2009
2009-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1124/dmd.108.025155" target="_blank" rel="noreferrer noopener">10.1124/dmd.108.025155</a>
Interleukin-1beta induced Stress Granules Sequester COX-2 mRNA and Regulates its Stability and Translation in Human OA Chondrocytes.
*Protein Biosynthesis; Cells; Chondrocytes/drug effects/metabolism/pathology; Cultured; Cyclooxygenase 2/*genetics; Dinoprostone/genetics; Fluorescence; Gene Expression Regulation; Humans; Immunoprecipitation; In Situ Hybridization; Interleukin-1beta/administration & dosage/*genetics; Messenger/genetics; Nitric Oxide/metabolism; Osteoarthritis/drug therapy/*genetics/pathology; RNA
Enhanced and immediate expression of cyclooxygenase-2 (COX-2) mRNA is observed in
Ansari Mohammad Y; Haqqi Tariq M
Scientific reports
2016
2016-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/srep27611" target="_blank" rel="noreferrer noopener">10.1038/srep27611</a>
miR-139 modulates MCPIP1/IL-6 expression and induces apoptosis in human OA chondrocytes.
*Apoptosis; 3' Untranslated Regions; Aged; Chondrocytes/*metabolism/pathology; Down-Regulation; Female; Gene Expression Regulation; Humans; Interleukin-6/*genetics; Male; Messenger/genetics; MicroRNAs/*genetics; Middle Aged; Osteoarthritis/*genetics/pathology; Ribonucleases/*genetics; RNA; Transcription Factors/*genetics; Up-Regulation
IL-6 is an inflammatory cytokine and its overexpression plays an important role in osteoarthritis (OA) pathogenesis. Expression of IL-6 is regulated post-transcriptionally by MCPIP1. The 3' untranslated region (UTR) of MCPIP1 mRNA harbors a miR-139 'seed sequence', therefore we examined the post-transcriptional regulation of MCPIP1 by miR-139 and its impact on IL-6 expression in OA chondrocytes. Expression of miR-139 was found to be high in the damaged portion of the OA cartilage compared with unaffected cartilage from the same patient and was also induced by IL-1beta in OA chondrocytes. Inhibition of miR-139 decreased the expression of IL-6 mRNA by 38% and of secreted IL-6 protein by 40%. However, overexpression of miR-139 increased the expression of IL-6 mRNA by 36% and of secreted IL-6 protein by 56%. These data correlated with altered expression profile of MCPIP1 in transfected chondrocytes. Studies with a luciferase reporter construct confirmed the interactions of miR-139 with the 'seed sequence' located in the 3' UTR of MCPIP mRNA. Furthermore, miR-139 overexpression increased the catabolic gene expression but expression of anabolic markers remained unchanged. Overexpression of miR-139 also induced apoptosis in OA chondrocytes. Importantly, we also discovered that IL-6 is a potent inducer of miR-139 expression in OA chondrocytes. These findings indicate that miR-139 functions as a post-transcriptional regulator of MCPIP1 expression and enhances IL-6 expression, which further upregulates miR-139 expression in OA chondrocytes. These results support our hypothesis that miR-139-mediated downregulation of MCPIP1 promotes
Makki Mohammad Shahidul; Haqqi Tariq M
Experimental & molecular medicine
2015
2015-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/emm.2015.66" target="_blank" rel="noreferrer noopener">10.1038/emm.2015.66</a>