Jean-Marc A Lobaccaro

French National Centre for Scientific Research, Lutetia Parisorum, Île-de-France, France

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Publications (63)299.95 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To determine whether the transcription factors liver X receptors (LXRs) and their downstream genes, which are involved in the regulation of several testicular functions in mouse models, are differentially expressed in testes of men with nonobstructive azoospermia (NOA) or obstructive azoospermia (OA).
    Fertility and sterility. 05/2014;
  • Jean-Marc A Lobaccaro, Amalia Trousson
    Endocrinology 03/2014; 155(3):656-8. · 4.72 Impact Factor
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    ABSTRACT: Liver X Receptors LXRα (NR1H3) and LXRβ (NR1H2) are transcription factors belonging to the nuclear receptor superfamily, activated by specific oxysterols, oxidized derivatives of cholesterol. These receptors are involved in the regulation of testis physiology. Lxr-deficient mice pointed to the physiological roles of these nuclear receptors in steroid synthesis, lipid homeostasis and germ cell apoptosis and proliferation. Diethylstilbestrol (DES) is a synthetic estrogen considered as an endocrine disruptor that affects the functions of the testis. Various lines of evidences have made a clear link between estrogens, their nuclear receptors ERα (NR3A1) and ERβ (NR3A2), and Lxrα/β. As LXR activity could also be regulated by the nuclear receptor small heterodimer partner (SHP, NR0A2) and DES could act through SHP, we wondered whether LXR could be targeted by estrogen-like endocrine disruptors such as DES. For that purpose, wild-type and Lxr-deficient mice were daily treated with 0.75 μg DES from day 1 to 5 after birth. The effects of DES were investigated at 10 or 45 days of age. We demonstrated that DES induced a decrease of the body mass at 10 days only in the Lxr-deficient mice suggesting a protective effect of Lxr. We defined three categories of DES-target genes in testis: those whose accumulation is independent of Lxr; those whose accumulation is enhanced by the lack of both Lxrα/β; those whose accumulation is repressed by the absence of Lxrα/β. Lipid accumulation is also modified by neonatal DES injection. Lxr-deficient mice present different lipid profiles, demonstrating that DES could have its effects in part due to Lxrα/β. Altogether, our study shows that both nuclear receptors Lxrα and Lxrβ are not only basally important for testicular physiology but could also have a preventive effect against estrogen-like endocrine disruptors.
    Biochemical and Biophysical Research Communications 12/2013; · 2.41 Impact Factor
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    ABSTRACT: Introduction: Oxysterols are implicated in various cellular processes. Among their target proteins, liver X receptors (LXRs) α and β modulate the cell cycle in a large range of cancer cell lines. Besides their role as cholesterol sensors, LXRs are also involved in the proliferation/apoptosis balance regulation in various types of cancers. Areas covered: This review covers oxysterols and derivatives of cholesterol as well as synthetic or natural ligands (agonist/antagonist) of LXRs. Most tumor cell lines are sensitive to LXR activation. Indeed various cancers are concerned such as prostate, breast, glioblastoma, colorectal, and ovary tumors, and leukemia. Expert opinion: Developing the use of LXR ligands in human health, especially in the field of cancer, represents a novel and promising strategy. Despite a wide spectrum of applications, numerous adverse effects of LXR activation need to be solved before genuine clinical trials in humans. Future directions will be based on the engineering of selective LXRs modulators (SLiMs) as already done for nuclear steroid receptors.
    Expert Opinion on Therapeutic Targets 07/2013; · 4.90 Impact Factor
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    ABSTRACT: Bile acids are cholesterol metabolites that have been extensively studied in recent decades. In addition to having ancestral roles in digestion and fat solubilization, bile acids have recently been described as signaling molecules involved in many physiological functions, such as glucose and energy metabolisms. These signaling pathways involve the activation of the nuclear receptor farnesoid X receptor (FXRα) or of the G protein-coupled receptor TGR5. In this review, we will focus on the emerging role of FXRα, suggesting important functions for the receptor in steroid metabolism. It has been described that FXRα is expressed in the adrenal glands and testes, where it seems to control steroid production. FXRα also participates in steroid catabolism in the liver and interferes with the steroid signaling pathways in target tissues via crosstalk with steroid receptors. In this review, we discuss the potential impacts of bile acid (BA), through its interactions with steroid metabolism, on glucose metabolism, sexual function, and prostate and breast cancers. Although several of the published reports rely on in vitro studies, they highlight the need to understand the interactions that may affect health. This effect is important because BA levels are increased in several pathophysiological conditions related to liver injuries. Additionally, BA receptors are targeted clinically using therapeutics to treat liver diseases, diabetes, and cancers.
    Cellular and Molecular Life Sciences CMLS 06/2013; · 5.62 Impact Factor
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    ABSTRACT: LXR (Liver X Receptors) act as "sensor" proteins that regulate cholesterol uptake, storage, and efflux. LXR signaling is known to influence proliferation of different cell types including human prostatic carcinoma (PCa) cell lines. This study shows that deletion of LXR in mouse fed a high-cholesterol diet recapitulates initial steps of PCa development. Elevation of circulating cholesterol in Lxrαβ-/- double knockout mice results in aberrant cholesterol ester accumulation and prostatic intra-epithelial neoplasia. This phenotype is linked to increased expression of the histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2), which results in the down-regulation of the tumor suppressors Msmb and Nkx3.1 through increased methylation of lysine 27 of histone H3 (H3K27) on their promoter regions. Altogether, our data provide a novel link between LXR, cholesterol homeostasis, and epigenetic control of tumor suppressor gene expression.
    PLoS Genetics 05/2013; 9(5):e1003483. · 8.52 Impact Factor
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    ABSTRACT: Lipids play a complex role in prostate cancer (PCa). Increased de novo synthesis of fatty acids and/or cholesterol is associated with the development of prostate tumors. Liver X Receptors (LXRs) are members of the nuclear receptor family that regulates intracellular lipid homeostasis. Targeting the transcriptional activity of LXRs has, therefore, been proposed as a mechanism for attenuating the progression of PCa. Histone Deacetylases (HDACs), however, have a negative effect on LXR activity. Therefore, HDAC inhibition reduces intracellular cholesterol levels and thereby decreases tumor cell proliferation. LXRs and HDAC inhibitors can, therefore, inhibit tumor proliferation. This review discusses the interacting roles of lipids, LXRs and HDACs in the development of PCa, where increased lipid levels enhance HDAC activity thereby altering LXR-dependent regulation of cellular lipid homeostasis. It provides a new paradigm for the treatment of prostate cancer, where LXRs are activated and HDACs repressed.
    Biochemical pharmacology 04/2013; · 4.25 Impact Factor
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    ABSTRACT: BACKGROUND & AIMS: Nutrients influence non alcoholic fatty liver disease. Essential fatty acids deficiency promotes various syndromes including hepatic steatosis through increased de novo lipogenesis. The mechanisms underlying such increased lipogenic response remain unidentified. METHODS: We used wild-type mice and mice lacking Liver X Receptors to perform a nutrigenomic study that aimed at examining the role of these transcription factors. RESULTS: We showed that, in the absence of Liver X Receptors, essential fatty acids deficiency does not promote steatosis. Consistent with this, Liver X Receptors are required for the elevated expression of genes involved in lipogenesis in response to essential fatty acids deficiency. CONCLUSION: This work identifies for the first time the central role of Liver X Receptors in steatosis induced by essential fatty acids deficiency.
    Journal of Hepatology 01/2013; · 9.86 Impact Factor
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    ABSTRACT: Cholesterol is a fundamental molecule for life. Located in the cell membrane, this sterol participates to the cell signaling of growth factors. Inside the cell it can be converted in hormones such as androgens or modulate the immune response. Such important functions could not be solely dependent of external supply by diet hence de novo synthesis could occur from acetate in almost all mammalian cells. If a deficiency in cholesterol sourcing leads to development troubles, overstocking has been associated to various diseases such as atherosclerosis and can-cers. Cholesterol homeostasis should thus be tightly regulated at the uptake, de novo synthesis, storage and export processes. Various transcription factors have been described these last years as important to regulate cholesterol levels. Besides, synthetic molecules have been developed for many years to modulate cholesterol synthesis, such as statins. Many articles have associated prostate cancer, whose incidence is constantly increasing, to cholesterol disequilibrium. Targeting cholesterol could thus be a new pharmacological hit to counteract the initiation, develop-ment and/or progression of prostate cancer. Among the transcription factors regulating cholesterol homeostasis, the nuclear receptors Liver X Receptors (LXRs) control cholesterol uptake and export. Targeting the LXRs offers a new field of investigation to treat cancer. This review highlights the molecular relationships among LXRs, prostate cancer and cholesterol and why LXRs have good chance to be targeted one day in this tumor. LXRs, prostate cancer and cholesterol, more than a "Ménage à trois", The Good, the Bad and the Ugly.
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    ABSTRACT: Cholesterol is a fundamental molecule for life. Located in the cell membrane, this sterol participates to the cell signaling of growth factors. Inside the cell it can be converted in hormones such as androgens or modulate the immune response. Such important functions could not be solely dependent of external supply by diet hence de novo synthesis could occur from acetate in almost all mammalian cells. If a deficiency in cholesterol sourcing leads to development troubles, overstocking has been associated to various diseases such as atherosclerosis and cancers. Cholesterol homeostasis should thus be tightly regulated at the uptake, de novo synthesis, storage and export processes. Various transcription factors have been described these last years as important to regulate cholesterol levels. Besides, synthetic molecules have been developed for many years to modulate cholesterol synthesis, such as statins. Many articles have associated prostate cancer, whose incidence is constantly increasing, to cholesterol disequilibrium. Targeting cholesterol could thus be a new pharmacological hit to counteract the initiation, development and/or progression of prostate cancer. Among the transcription factors regulating cholesterol homeostasis, the nuclear receptors Liver X Receptors (LXRs) control cholesterol uptake and export. Targeting the LXRs offers a new field of investigation to treat cancer. This review highlights the molecular relationships among LXRs, prostate cancer and cholesterol and why LXRs have good chance to be targeted one day in this tumor. LXRs, prostate cancer and cholesterol, more than a "Ménage à trois", The Good, the Bad and the Ugly.
    American Journal of Cancer Research 01/2013; 3(1):58-69. · 2.65 Impact Factor
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    ABSTRACT: Recent studies underline the implication of Liver X Receptors (LXRs) in several prostate diseases such as benign prostatic hyperplasia (BPH) and prostate cancer. In order to understand the molecular mechanisms involved, we derived epithelial cells from dorsal prostate (MPECs) of wild type (WT) or Lxrαβ-/- mice. In the WT MPECs, our results show that LXR activation reduces proliferation and correlates with the modification of the AKT-survival pathway. Moreover, LXRs regulate lipid homeostasis with the regulation of Abca1, Abcg1 and Idol, and, in a lesser extent, Srebp1, Fas and Acc. Conversely cells derived from Lxrαβ-/- mice show a higher basal phosphorylation and consequently activation of the survival/proliferation transduction pathways AKT and MAPK. Altogether, our data point out that the cell model we developed allows deciphering the molecular mechanisms inducing the cell cycle arrest. Besides, we show that activated LXRs regulate AKT and MAPK transduction pathways and demonstrate that LXRs could be good pharmacological targets in prostate disease such as cancer.
    PLoS ONE 01/2013; 8(3):e58876. · 3.53 Impact Factor
  • Jean-Marc A Lobaccaro, Denis Gallot, Serge Lumbroso, Kevin Mouzat
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    ABSTRACT: The role of cholesterol in female reproductive physiology has been suspected for a long time, while the molecular bases were unknown. Cholesterol is the precursor of ovarian steroids biosynthesis and is also essential for fertility. In the uterus, cholesterol is essential to achieve correct contractions at term, but an excessive uterine cholesterol concentration has been associated with contractility defects. Liver X Receptor (LXR) alpha and LXR beta are nuclear receptors activated by oxysterols, oxidized derivatives of cholesterol. Since their discovery, the role of LXRs in the control of cholesterol homeostasis has been widely described. Beyond their cholesterol-lowering role, more recent data have linked these nuclear receptors to various physiological processes. In particular, they control ovarian endocrine and exocrine functions, as well as uterine contractility. Their contribution to female reproductive cancers will also be discussed. This review will try to enlighten on the LXRs as a molecular link between dietary cholesterol and reproductive diseases in women. In the future, a better comprehension of the various physiological processes regulated by the LXRs will help to develop new ligands to prevent or to cure these pathologies in women.
    Journal of endocrinological investigation 11/2012; · 1.65 Impact Factor
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    ABSTRACT: The Liver X Receptors (LXRs) α and β and the peroxisome proliferator-activated receptor α (PPARα) are transcription factors that belong to class II nuclear receptors. They drive the expression of genes involved in hepatic lipid homeostasis and therefore are important targets for the prevention and treatment of nonalcoholic fatty liver disease (NAFLD). LXRs and PPARα are regulated by endogenous ligands, oxysterols and fatty acid derived molecules respectively. In the liver, pharmacological activation of LXRs leads to the over-expression of genes involved in de novo lipogenesis, while PPARα is critical for fatty acid catabolism in nutrient deprivation. Even if these two nuclear receptors seemed to play opposite parts, recent studies have highlighted that PPARα also influence the expression of genes involved in fatty acids synthesis. In this study, we used pharmacological approaches and genetically engineered mice to investigate the cross-talk between LXRs and PPARα in the regulation of genes responsible for lipogenesis. We first investigated the effect of T0901317 and fenofibrate, two synthetic agonists of LXRs and PPARα, respectively. As expected, T0901317 and fenofibrate induce expression of genes involved LXR-dependent and PPARα-dependent lipogenic responses. Considering such overlapping effect, we then tested whether LXR agonist may influence PPARα driven response and vice versa. We show that the lack of PPARα does not influence the effects of T0901317 on lipogenic genes expression. However, PPARα deficiency prevents the up-regulation of genes involved in ω-hydroxylation that are induced by the LXR agonist. In addition, over-expression of lipogenic genes in response to fenofibrate is decreased in LXR knockout mice as well as the expression of PPARα target genes involved in fatty acid oxidation. Altogether, our work provides in vivo evidence for a central interconnection between nuclear receptors that drive hepatic lipid metabolism in response to oxysterol and fatty acids.
    Biochimie 10/2012; · 3.14 Impact Factor
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    ABSTRACT: Oxysterols derive from cholesterol oxidation. They display various biological activities such as regulating cholesterol, fatty acid and glucose homeostasis as well as cell survival/apoptosis balance. Oxysterols display these metabolic and transcriptional activities mainly through their nuclear receptors known as Liver X Receptors (LXRs) α and β. There is accumulating evidence that LXRs are key modulators of prostate cancer cell survival. Hence, LXR activation increases cholesterol efflux and induces a disruption of lipid rafts. The decrease of membrane cholesterol causes a down regulation of AKT survival pathway and consequently apoptosis. Moreover cholesterol is associated with an increased risk of developing aggressive forms of prostate cancer. These data highlight the interest of targeting the LXR-AKT axis in prostate carcinogenesis.
    Current Opinion in Pharmacology 07/2012; · 5.44 Impact Factor
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    ABSTRACT: The link between cholesterol homeostasis and male fertility has been clearly suggested in patients who suffer from hyperlipidemia and metabolic syndrome. This has been confirmed by the generation of several transgenic mouse models or in animals fed with high cholesterol diet. Next to the alteration of the endocrine signaling pathways through steroid receptors (androgen and estrogen receptors); "orphan" and "adopted" nuclear receptors, such as the Liver X Receptors (LXRs), the Proliferating Peroxisomal Activated Receptors (PPARs) or the Liver Receptor Homolog-1 (LRH-1), have been involved in this cross-talk. These transcription factors show distinct expression patterns in the male genital tract, explaining the large panel of phenotypes observed in transgenic male mice and highlighting the importance of lipid homesostasis and the complexity of the molecular pathways involved. Increasing our knowledge of the roles of these nuclear receptors in male germ cell differentiation could help in proposing new approaches to either treat infertile men or define new strategies for contraception.
    Molecular and Cellular Endocrinology 07/2012; · 4.04 Impact Factor
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    ABSTRACT: Bile acids (BAs) are cholesterol metabolites that have been extensively studied these last decades. BAs have been classified in two groups. Primary BAs are synthesized in liver, when secondary BAs are produced by intestinal bacteria. Recently, next to their ancestral roles in digestion and fat solubilization, BAs have been described as signaling molecules involved in many physiological functions, such as glucose and energy metabolisms. These signaling pathways involve the activation of the nuclear receptor FXRα or of the G-protein-coupled receptor TGR5. These two receptors have selective affinity to different types of BAs and show different expression patterns, leading to different described roles of BAs. It has been suggested for long that BAs could be molecules linked to tumor processes. Indeed, as many other molecules, regarding analyzed tissues, BAs could have either protective or pro-carcinogen activities. However, the molecular mechanisms responsible for these effects have not been characterized yet. It involves either chemical properties or their capacities to activate their specific receptors FXRα or TGR5. This review highlights and discusses the potential links between BAs and cancer diseases and the perspectives of using BAs as potential therapeutic targets in several pathologies.
    Biochimie 07/2012; · 3.14 Impact Factor
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    ABSTRACT: Nutritional status is known to control female reproductive physiology. Many reproductive pathologies such as anorexia nervosa, dystocia and preeclampsia, have been linked to body mass index and to metabolic syndrome. Lipid metabolism has also been associated with ovarian, uterine and placental functions. Among the regulators of lipid homeostasis, the Liver X Receptors (LXRs) and the Liver Receptor Homolog-1 (LRH-1), two members of the nuclear receptor superfamily, play a central role. LXRs are sensitive to intracellular cholesterol concentration and decrease plasma cholesterol, allowing to considering them as "cholesterol sensors". LRH-1 shares many target-genes with LXRs and has been considered for a long time as a real orphan nuclear receptor, but recent findings showed that phospholipids are ligands for this nuclear receptor. Acting in concert, LXRs and LRH-1 could thus be sensitive to slight modifications in cellular lipid balance, tightly maintaining their cellular concentrations. These last years, the use of transgenic mice clarified the roles of these nuclear receptors in many physiological functions. This review will be focused on the roles of LXRs and LRH-1 on female reproduction. Their contribution to ovarian endocrine and exocrine functions, as well as uterine and placental physiology will be discussed. The future challenge will thus be to target these nuclear receptors to prevent lipid-associated reproductive diseases in women.
    Molecular and Cellular Endocrinology 06/2012; · 4.04 Impact Factor
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    ABSTRACT: Benign prostatic hyperplasia is a nonmalignant enlargement of the prostate that commonly occurs in older men. We show that liver X receptor (Lxr)-α knockout mice (lxrα(-/-)) develop ventral prostate hypertrophy, correlating with an overaccumulation of secreted proteins in prostatic ducts and an alteration of vesicular trafficking in epithelial cells. In the fluid of the lxrα(-/-) prostates, spermine binding protein is highly accumulated and shows a 3000-fold increase of its mRNA. This overexpression is mediated by androgen hypersensitivity in lxrα(-/-) mice, restricted to the ventral prostate. Generation of chimeric recombinant prostates demonstrates that Lxrα is involved in the establishment of the epithelial-mesenchymal interactions in the mouse prostate. Altogether these results point out the crucial role of Lxrα in the homeostasis of the ventral prostate and suggest lxrα(-/-) mice may be a good model to investigate the molecular mechanisms of benign prostatic hyperplasia.
    Endocrinology 04/2012; 153(7):3211-23. · 4.72 Impact Factor
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    03/2012; , ISBN: 978-953-51-0194-9
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    ABSTRACT: Benign prostatic hyperplasia is a nonmalignant enlargement of the prostate that commonly occurs in older men. We show that liver X receptor (Lxr)-􏰀 knockout mice (lxr􏰀􏰃/􏰃) develop ventral pros- tate hypertrophy, correlating with an overaccumulation of secreted proteins in prostatic ducts and an alteration of vesicular trafficking in epithelial cells. In the fluid of the lxr􏰀􏰃/􏰃 prostates, spermine binding protein is highly accumulated and shows a 3000-fold increase of its mRNA. This overex- pression is mediated by androgen hypersensitivity in lxr􏰀􏰃/􏰃 mice, restricted to the ventral prostate. Generation of chimeric recombinant prostates demonstrates that Lxr􏰀 is involved in the estab- lishment of the epithelial-mesenchymal interactions in the mouse prostate. Altogether these re- sults point out the crucial role of Lxr􏰀 in the homeostasis of the ventral prostate and suggest lxr􏰀􏰃/􏰃 mice may be a good model to investigate the molecular mechanisms of benign prostatic hyperplasia.
    Endocrinology 01/2012; 153. · 4.72 Impact Factor

Publication Stats

3k Citations
299.95 Total Impact Points

Institutions

  • 2004–2014
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2005–2013
    • Université Blaise Pascal - Clermont-Ferrand II
      • Laboratoire Génétique, Reproduction et Développement
      Clermont, Auvergne, France
  • 2012
    • Centre Hospitalier Régional Universitaire de Nîmes
      Nismes, Languedoc-Roussillon, France
  • 2008
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2007
    • Institut de Radioprotection et de Sûreté Nucléaire (IRSN)
      • LRTOX - Laboratory of Experimental Radiotoxicology
      Fontenay, Île-de-France, France
  • 2006
    • University of Texas Southwestern Medical Center
      • Department of Pharmacology
      Dallas, TX, United States
  • 2003
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2000
    • Howard Hughes Medical Institute
      Maryland, United States