Regulation of aldo-keto reductases in human diseases.
aldo-keto reductase; human disease; regulation; response element; transcription factor
The aldo-keto reductases (AKRs) are a superfamily of NAD(P)H-linked oxidoreductases, which reduce aldehydes and ketones to their respective primary and secondary alcohols. AKR enzymes are increasingly being recognized to play an important role in the transformation and detoxification of aldehydes and ketones generated during drug detoxification and xenobiotic metabolism. Many transcription factors have been identified to regulate the expression of human AKR genes, which could have profound effects on the metabolism of endogenous mediators and detoxication of chemical carcinogens. This review summarizes the current knowledge on AKR regulation by transcription factors and other mediators in human diseases.
Chen Wei-Dong; Zhang Yanqiao
Frontiers in pharmacology
2012
1905-07
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/10.3389/fphar.2012.00035" target="_blank" rel="noreferrer noopener">10.3389/fphar.2012.00035</a>
An overlapping binding site in the CYP7A1 promoter allows activation of FXR to override the stimulation by LXR alpha
7-alpha-hydroxylase gene; activity; bile-acid biosynthesis; cholesterol; cholesterol 7 alpha-hydroxylase; dietary-cholesterol; down-regulation; farnesoid X; fetoprotein transcription factor; Gastroenterology & Hepatology; heterodimer partner; liver X receptor; LXR binding site; messenger-rna; metabolism; orphan nuclear receptor; Physiology; rat; receptor; regulation; short; transcriptional; x-receptor
An overlapping binding site in the CYP7A1 promoter allows activation of FXR to override the stimulation by LXR alpha. Am J Physiol Gastrointest Liver Physiol 293: G817-G823, 2007. First published August 9, 2007; doi:10.1152/ajpgi.00209.2007.-The aim of this study was to explore why in rabbits activation of farnesoid X receptor (FXR) is dominant over activated liver X receptor-alpha (LXR alpha) in the regulation of CYP7A1. We cloned the rabbit CYP7A1 promoter and found a fetoprotein transcription factor (FTF) binding element embedded within the LXR alpha binding site (LXRE). Gel shift assays demonstrated that FTF competes with LXR alpha for binding to LXRE. Short heterodimer partner (SHP) enhances the competitive ability of FTF. Studies in HepG2 cells showed that SHP combined with FTF had more powerful effect to offset the stimulation of CYP7A1 by LXR alpha. Gel shift and chromatin immunoprecipitation assays demonstrated that SHP with FTF diminished LXR alpha\binding to the CYP7A1 promoter. In vivo studies in rabbits fed cholesterol for 10 days showed that hepatic expression of SHP but not FTF rose and LXR alpha-bound LXRE decreased. We propose that the SHP/FTF heterodimer occupies LXRE via the embedded FTF binding element and blocks LXR alpha from recruiting to LXRE. Therefore, activation of FXR, which upregulates SHP expression, will eliminate the stimulatory effect of LXR alpha on the CYP7A1 promoter because increased levels of SHP combined with FTF diminish the recruitment of LXR alpha to CYP7A1 promoter.
Shang Q; Pan L X; Saumoy M; Chiang J Y L; Tint G S; Salen G; Xu G R
American Journal of Physiology-Gastrointestinal and Liver Physiology
2007
2007-10
Journal Article
<a href="http://doi.org/10.1152/ajpgi.00209.2007" target="_blank" rel="noreferrer noopener">10.1152/ajpgi.00209.2007</a>
Hormonal regulation of cholesterol 7 alpha-hydroxylase specific activity, mRNA levels, and transcriptional activity in vivo in the rat
bile-acid biosynthesis; Biochemistry & Molecular Biology; cholesterol; cholesterol 7 alpha-hydroxylase; cultures; gene; gene cyp7; glucocorticoid; hepatic cholesterol; hepatocyte cultures; liver; messenger-rna levels; monolayer-cultures; primary; protein-kinase-c; regulation; sterol 27-hydroxylase; thyroid; thyroid-hormone
In primary cultures of rat hepatocytes, transcription of the cholesterol 7 alpha-hydroxylase gene is induced synergistically by glucocorticoid and thyroid hormones. The objective of the present study was to evaluate the role of glucocorticoid and thyroid hormones in the maintenance of cholesterol 7 alpha-hydroxylase gene expression in vivo. Male Sprague-Dawley rats underwent adrenalectomy (A), thyroidectomy (T), adrenalectomy + thyroidectomy (A + T), hypophysectomy (H), or sham surgery (paired controls). Ten days post surgery, livers were harvested and cholesterol 7 alpha-hydroxylase specific activity, steady-state mRNA levels, and transcriptional activity were determined. Serum corticosterone levels were <2% of paired controls in A, A + T and H rats. Free thyroxine index was <32% of paired controls in rats with T and H. When compared to sham-operated controls, A + T and H led to decreases in cholesterol 7 alpha-hydroxylase specific activities of 44 +/- 8% and 57 +/- 3%, respectively (P < 0.03 and < 0.05). Similar changes were observed in cholesterol 7 alpha-hyroxylase steady-state mRNA levels, which decreased by 43 +/- 10% (P < 0.001) and 56 +/- 19% (P < 0.05), respectively. Cholesterol 7 alpha-hydroxylase transcriptional activity in A + T and H rats decreased by 34 +/- 11% (P < 0.01) and 61 +/- 4% (P < 0.001), respectively. The observed decreases were greater after H than after A + T, suggesting the possibility that another pituitary hormone plays a role in regulation of cholesterol 7 alpha-hydroxylase. Thyroidectomy alone led to a decrease in cholesterol 7 alpha-hydroxylase specific activity of 37 +/- 7% (P < 0.05) and a trend toward decreased steady-state mRNA levels (21 +/- 12%; P = ns). Adrenalectomy did not significantly decrease cholesterol 7 alpha-hydroxylase specific activity or mRNA levels. Neither thyroidectomy nor adrenalectomy alone affected transcriptional activity. We conclude that under physiologic circumstances, full expression of the cholesterol 7 alpha-hydroxylase gene requires synergistic action of glucocorticoids and thyroid hormone.
Pandak W M; Heuman D M; Redford K; Stravitz R T; Chiang J Y L; Hylemon P B; Vlahcevic Z R
Journal of Lipid Research
1997
1997-12
Journal Article
n/a
Growth And Repair Factors, Osteoactivin, Matrix Metalloproteinase And Heat Shock Protein 72, Increase With Resolution Of Inflammation In Musculotendinous Tissues In A Rat Model Of Repetitive Grasping
carpal-tunnel-syndrome; disorders; endothelial-cells; extracellular-matrix; gene-expression; Heat shock protein; human fibroblasts; Metalloproteinases; muscle; musculoskeletal; Orthopedics; Osteoactivin; Overuse; posttranscriptional; regulation; Restorative repair; Rheumatology; skeletal-muscle regeneration; Tendon; transgenic expression; upper extremity
Frara N; Abdelmagid S M; Tytell M; Amin M; Popoff S N; Safadi F F; Barbe M F
Bmc Musculoskeletal Disorders
2016
2016-01
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1186/s12891-016-0892-3" target="_blank" rel="noreferrer noopener">10.1186/s12891-016-0892-3</a>