cyp7b1 catalyses the 7α-hydroxylation of dehydroepiandrosterone and25-hydroxycholesterol in rat prostate

Martin, Cécile; Bean, Rhona; Rose, Ken; Habib, Fouad K.

doi:10.1042/bj3550509

Cited by 26 publications

(12 citation statements)

References 30 publications

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“…Data from mouse studies indicate some fundamental interaction between PPARa and sex hormones. It has been shown in mice that PPARa is involved in estrogen signaling and reproduction (30)(31)(32). Conversely, female rats treated with testosterone and male rats treated with estrogen altered their mRNA concentration of PPARa (33).…”

Section: Discussionmentioning

confidence: 99%

Men and women differ in their diurnal expression of monocyte peroxisome proliferator‐activated receptor‐α in the fed but not in the fasted state

et al. 2015

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Peroxisome proliferator-activated receptor-a (PPARa) plays a pivotal role in regulating metabolic response to fasting and is an inhibitor of inflammatory pathways in immune cells. It represents a therapeutic target for treatment of several diseases, mainly hyperlipidemia. To shed light on PPARa expression changes in response to fasting, young healthy male and female volunteers were fed or fasted for 24 hours. Monocytes were analyzed every 2 hours to compile both profiles of mRNA and protein expression of PPARa and its interactive partner, the circadian pacemaker brain and muscle aryl hydrocarbon receptor nuclear translocator like-1 (BMAL1). We found that women change their diurnal expression profiles of PPARa and BMAL1 when switching from the fed to the fasted state, whereas men do not. Interestingly, the PPARa and BMAL1 profiles of men and women in the fed state are different, whereas the profiles in the fasted state are virtually identical. The finding of diametrically opposite responses of male and female PPARa expression in the fed state might have practical implication in human medicine as PPARa activators like fibrates are used for the therapy of chronic lymphocytic leukemia, microvascular complications in diabetes, and kidney diseases.-Wege, N., Schutkowski, A., Boenn, M., Bialek, J., Schlitt, A., Noack, F., Grosse, I., Stangl, G. I. Men and women differ in their diurnal expression of monocyte peroxisome proliferator-activated receptor-a in the fed but not in the fasted state. FASEB J. 29, 2905-2911 (2015). www.fasebj.org Key Words: caloric intake • nuclear receptor • circadian pacemaker FOOD SHORTAGE IS A FREQUENT phenomenon in nature. Hence, organisms have evolved a metabolic program to survive periods of food shortage. During fasting, organisms suspend growth and reproduction, induce defense molecules, and shift whole-body fuel utilization from both carbohydrates and fat to almost exclusively fat (1). This metabolic flexibility is vital to survival. Adaptations to fasting are mediated by peroxisome proliferator-activated receptor-a (PPARa), a nuclear hormone receptor, which plays a pivotal role as a nutritional state sensor and key regulator in the mediation of metabolic responses to fasting (2, 3). Besides its pivotal role in fasting adaptation, there is emerging evidence that PPARa exerts antiinflammatory effects in cells and animals (4-6) and that it mediates the delay of aging and the extension of lifespan in response to caloric restriction (7). It further serves as receptor for therapeutic PPARa agonists such as fibrates that have been widely used as drugs to reduce high lipid levels in plasma (8). Human PPARa is expressed among various tissues with high expression levels in immune cells (4). Its expression is, among other factors, regulated by brain and muscle aryl hydrocarbon receptor nuclear translocator like-1 (BMAL1), a basic helix-loop-helix protein that functions as circadian pacemaker (9, 10) and that is involved in regulation of energy homeostasis (11).Despite the significant phys...

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Section: Discussionmentioning

confidence: 99%

Men and women differ in their diurnal expression of monocyte peroxisome proliferator‐activated receptor‐α in the fed but not in the fasted state

et al. 2015

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“…Though most pronounced in rat and mouse liver, sex differences in CYP expression also occur in humans (16). A prominent member of the CYP superfamily, oxysterol 7α-hydroxylase (CYP7B1), is enriched in male compared with female liver (17)(18)(19)(20)(21). The CYP7B1 protein represses androgen biosynthesis by modulating the availability of dehydroepiandrosterone (DHEA), the main precursor of the male hormone testosterone (18).…”

Section: Introductionmentioning

confidence: 99%

“…A prominent member of the CYP superfamily, oxysterol 7α-hydroxylase (CYP7B1), is enriched in male compared with female liver (17)(18)(19)(20)(21). The CYP7B1 protein represses androgen biosynthesis by modulating the availability of dehydroepiandrosterone (DHEA), the main precursor of the male hormone testosterone (18). In contrast to its negative effect on androgen production, CYP7B1 promotes estrogen receptor (ER) activity by catalyzing the clearance of 27-hydroxycholesterol, which functions as a competitive ER antagonist (22).…”

Section: Introductionmentioning

confidence: 99%

Sumoylated PPARα mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice

Leuenberger¹,

Pradervand²,

Wahli³

2009

J. Clin. Invest.

102

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As most metabolic studies are conducted in male animals, understanding the sex specificity of the underlying molecular pathways has been broadly neglected; for example, whether PPARs elicit sex-dependent responses has not been determined. Here we show that in mice, PPARα has broad female-dependent repressive actions on hepatic genes involved in steroid metabolism and immunity. In male mice, this effect was reproduced by the administration of a synthetic PPARα ligand. Using the steroid oxysterol 7α-hydroxylase cytochrome P450 7b1 (Cyp7b1) gene as a model, we elucidated the molecular mechanism of this sex-specific PPARα-dependent repression. Initial sumoylation of the ligand-binding domain of PPARα triggered the interaction of PPARα with GA-binding protein α (GABPα) bound to the target Cyp7b1 promoter. Histone deacetylase and DNA and histone methylases were then recruited, and the adjacent Sp1-binding site and histones were methylated. These events resulted in loss of Sp1-stimulated expression and thus downregulation of Cyp7b1. Physiologically, this repression conferred on female mice protection against estrogen-induced intrahepatic cholestasis, the most common hepatic disease during pregnancy, suggesting a therapeutic target for prevention of this disease.

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“…Rose and coworkers (2001) also reported that expression of Cyp7b1 in the liver and kidney was greater in males compared with female mice. Little is known about the transcriptional regulation of Cyp7b1, however, this isoform contributes to bile acid synthesis through the 7␣-hydroxylation of 27-hydroxycholesterol (Schwarz et al, 1997;Martin et al, 2001;Memon et al, 2001). Because this isoform is important in cholesterol metabolism, it is interesting that a nonsignificant trend for a decrease in the levels of Cyp7b1 mRNA was observed in males with hyperinsulinemia and diabetes.…”

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confidence: 99%

Effect of Hyperinsulinemia and Type 2 Diabetes-Like Hyperglycemia on Expression of Hepatic Cytochrome P450 and GlutathioneS-Transferase Isoforms in a New Zealand Obese-Derived Mouse Backcross Population

Pass¹,

Becker²,

Kluge³

et al. 2002

J Pharmacol Exp Ther

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In subgroups of a New Zealand obese mouse-derived backcross population with defined aberrations of glucose homeostasis, a comprehensive study of the hepatic expression of cytochrome P450 and glutathione S-transferase was performed. Three patterns of alterations in response to insulin resistance (normoglycemia/hyperinsulinemia) or diabetes (hyperglycemia/hypoinsulinemia) were observed: mRNA levels of Cyp2b9, Cyp3a16, Cyp4a14, and Gstt2 as assessed by Northern-and dot-blot analysis were increased markedly in liver from diabetic mice with no or only a slight increase in insulin resistant mice. Western-blot analysis detected the corresponding changes of the CYP2B and CYP4A proteins. In contrast, expression of Cyp2c22, Cyp2c29, and Cyp2c40 was reduced in diabetic, but normal in insulin resistant mice. These alterations were correlated with changes in serum free fatty acid levels and, therefore, seem to be mediated by the peroxisome proliferator activated receptor-␣. Furthermore, expression of Cyp1a2, Cyp7b1, Gstm3, and Gstm6 was reduced in both diabetic and insulin resistant mice. Because this third pattern was not correlated with the alterations of serum free fatty acid levels, it seems to reflect an early alteration in the course of the disease, and may be related to the progression of the syndrome from insulin resistance to the type 2-like diabetes.New Zealand obese (NZO) mice exhibit a polygenic syndrome of obesity, insulin resistance, dyslipidemia, and hypertension that is similar to the human metabolic syndrome . Like other rodents with morbid obesity, the strain exhibits impaired glucose tolerance and eventually develops a type 2 diabetes-like hyperglycemia and hypoinsulinemia. Thus, the NZO mouse is a suitable model for the identification of obesity and diabetes genes and for the characterization of their interaction (Leiter et al., 1998;.We have recently established a backcross model of NZO mice with the lean and atherosclerosis-resistant SJL strain . The male NZO ϫ F1 (SJL ϫ NZO) backcross population (referred to as NSZO) is heterogeneous and includes normoglycemic/normoinsulinemic animals, insulin resistant animals with a compensatory hyperinsulinemia, and diabetic animals with hyperglycemia/hypoinsulinemia. This heterogeneity defines different stages in the development of diabetes and reflects the different genetic burden of the subgroups. A striking characteristic of the backcross is that only a few female mice develop hypoinsulinemia, despite a marked obesity and hyperinsulinemia. In a genome-wide scan of the NSZO backcross population, we identified a susceptibility locus for obesity/hyperinsulinemia and a separate locus for hyperglycemia/ hypoinsulinemia that was contributed by the SJL genome ; together, these loci are responsible for approximately 90% of the prevalence of diabetes in the backcross. In addition to the genome-wide search for disease susceptibility loci, we have used the NSZO backcross population for

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cyp7b1 catalyses the 7α-hydroxylation of dehydroepiandrosterone and25-hydroxycholesterol in rat prostate

Cited by 26 publications

References 30 publications

Men and women differ in their diurnal expression of monocyte peroxisome proliferator‐activated receptor‐α in the fed but not in the fasted state

Men and women differ in their diurnal expression of monocyte peroxisome proliferator‐activated receptor‐α in the fed but not in the fasted state

Sumoylated PPARα mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice

Effect of Hyperinsulinemia and Type 2 Diabetes-Like Hyperglycemia on Expression of Hepatic Cytochrome P450 and GlutathioneS-Transferase Isoforms in a New Zealand Obese-Derived Mouse Backcross Population

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