Inhibition of Retinoic Acid Biosynthesis by the Bisdichloroacetyldiamine WIN 18,446 Markedly Suppresses Spermatogenesis and Alters Retinoid Metabolism in Mice

Paik, Ji-Sun; Haenisch, Michael; Müller, Charles; Goldstein, Alex S.; Arnold, Samuel; Isoherranen, Nina; Brabb, Thea; Treuting, Piper M.; Amory, John K.

doi:10.1074/jbc.m113.540211

Cited by 66 publications

(82 citation statements)

References 36 publications

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“…Similarly, in normal mice atRA enhances fatty acid oxidation and ketogenesis via RAR activation and FGF21 induction (Amengual et al, 2012;Li et al, 2013). In agreement with a role of atRA in maintaining lipid homeostasis in the liver, decrease of hepatic atRA concentrations via inhibition of atRA synthesis in mice led to microvesicular vacuolation but without a change in liver triglycerides (Paik et al, 2014). However, in diet-induced obese mice atRA treatment decreased hepatic triglyceride content (Berry and Noy, 2009) and hepatic lipid accumulation (Kim et al, 2014).…”

Section: Introductionmentioning

confidence: 57%

All-Trans-Retinoic Acid Enhances Mitochondrial Function in Models of Human Liver

et al. 2016

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All-trans-retinoic acid (atRA) is the active metabolite of vitamin A. The liver is the main storage organ of vitamin A, but activation of the retinoic acid receptors (RARs) in mouse liver and in human liver cell lines has also been shown. Although atRA treatment improves mitochondrial function in skeletal muscle in rodents, its role in modulating mitochondrial function in the liver is controversial, and little data are available regarding the human liver. The aim of this study was to determine whether atRA regulates hepatic mitochondrial activity. atRA treatment increased the mRNA and protein expression of multiple components of mitochondrial b-oxidation, tricarboxylic acid (TCA) cycle, and respiratory chain. Additionally, atRA increased mitochondrial biogenesis in human hepatocytes and in HepG2 cells with and without lipid loading based on peroxisome proliferator activated receptor gamma coactivator 1a and 1b and nuclear respiratory factor 1 mRNA and mitochondrial DNA quantification. atRA also increased b-oxidation and ATP production in HepG2 cells and in human hepatocytes. Knockdown studies of RARa, RARb, and PPARd revealed that the enhancement of mitochondrial biogenesis and b-oxidation by atRA requires peroxisome proliferator activated receptor delta. In vivo in mice, atRA treatment increased mitochondrial biogenesis markers after an overnight fast. Inhibition of atRA metabolism by talarozole, a cytochrome P450 (CYP) 26 specific inhibitor, increased the effects of atRA on mitochondrial biogenesis markers in HepG2 cells and in vivo in mice. These studies show that atRA regulates mitochondrial function and lipid metabolism and that increasing atRA concentrations in human liver via CYP26 inhibition may increase mitochondrial biogenesis and fatty acid b-oxidation and provide therapeutic benefit in diseases associated with mitochondrial dysfunction.

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Section: Introductionmentioning

confidence: 57%

All-Trans-Retinoic Acid Enhances Mitochondrial Function in Models of Human Liver

et al. 2016

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“…Because of this, further development of WIN 18,446 was abandoned without an understanding of its mechanism of action. Our group demonstrated that WIN 18,446 suppresses spermatogenesis by inhibiting testicular retinoic acid biosynthesis, via inhibition of the testes-specific aldehyde dehydrogenase ALDH1A2 (77, 78). Using a rabbit model, we observed that oral administration of WIN 18,446 induced reversible azoospermia, and reductions in spermatogenesis were preceded by a reduction in intra-testicular retinoic acid.…”

Section: Experimental Male Contraceptivesmentioning

confidence: 99%

Male contraception

Amory

2016

Fertility and Sterility

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NARRATIVE ABSTRACT Although female contraceptives are very effective at preventing unintended pregnancy, some women cannot use them due to health conditions or side effects, leaving some couples without effective contraceptive options. In addition, many men wish to take active responsibility for family planning. Thus, there is a great need for male contraceptives to prevent unintended pregnancy, of which 80–90 million occur annually. At present, effective male contraceptive options are condoms and vasectomy, which are not ideal for all men. Therefore, efforts are under way to develop novel male contraceptives. This paper will briefly review the advantages and disadvantages of condoms and vasectomies, and then discuss the research directed towards the development of novel methods of male contraception.

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“…We recently developed a method using WIN 18,446 and RA to synchronize spermatogenesis in both juvenile and adult testes [22] as a means of overcoming this complexity. WIN 18,446 is a potent inhibitor of the retinaldehyde dehydrogenases (RALDH) [23], the enzymes responsible for oxidizing retinaldehyde to RA, and treatment of male mice with this compound results in a decrease in intratesticular RA levels, blocking male germ cell differentiation and generating testes full of undifferentiated type A spermatogonia [22,23]. Following WIN 18,446 treatment with an injection of RA, spermatogonia begin to differentiate simultaneously, driving synchronous spermatogenesis.…”

Section: Introductionmentioning

confidence: 99%

Processive Pulses of Retinoic Acid Propel Asynchronous and Continuous Murine Sperm Production1

Hogarth

Arnold

Kent

et al. 2015

Biology of Reproduction

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The asynchronous cyclic nature of spermatogenesis is essential for continual sperm production and is one of the hallmarks of mammalian male fertility. While various mRNA and protein localization studies have indirectly implicated changing retinoid levels along testis tubules, no quantitative evidence for these changes across the cycle of the seminiferous epithelium currently exists. This study utilized a unique mouse model of induced synchronous spermatogenesis, localization of the retinoid-signaling marker STRA8, and sensitive quantification of retinoic acid concentrations to determine whether there are fluctuations in retinoid levels at each of the individual stages of germ cell differentiation and maturation to sperm. These data show that processive pulses of retinoic acid are generated during spermatogonial differentiation and are the likely trigger for cyclic spermatogenesis and allow us, for the first time, to understand how the cycle of the seminiferous epithelium is generated and maintained. In addition, this study represents the first direct quantification of a retinoid gradient controlling cellular differentiation in a postnatal tissue.

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Inhibition of Retinoic Acid Biosynthesis by the Bisdichloroacetyldiamine WIN 18,446 Markedly Suppresses Spermatogenesis and Alters Retinoid Metabolism in Mice

Cited by 66 publications

References 36 publications

All-Trans-Retinoic Acid Enhances Mitochondrial Function in Models of Human Liver

All-Trans-Retinoic Acid Enhances Mitochondrial Function in Models of Human Liver

Male contraception

Processive Pulses of Retinoic Acid Propel Asynchronous and Continuous Murine Sperm Production1

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