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The surface of plants is covered by the epidermis, which protects the plant’s body from the external environment and mediates inter-cell layer signaling to regulate plant development. Therefore, the manifestation of epidermal traits at a precise location is a prerequisite for their normal growth and development. In Arabidopsis thaliana, class IV homeodomain-leucine zipper transcription factors PROTODERMAL FACTOR2 (PDF2) and ARABIDOPSIS THALIANA MERISTEM LAYER1 (ATML1) play redundant roles in epidermal cell differentiation. Nevertheless, several pieces of evidence suggest that the activity and/or function of PDF2 and ATML1 are regulated differently. The role of the steroidogenic acute regulatory protein-related lipid transfer (START) domain of ATML1 in restricting this protein’s activity has been demonstrated; however, whether this lipid-dependent mechanism regulates PDF2 expression is unknown. In this study, we demonstrated that the START domains of PDF2 and ATML1, regulate protein turnover in a position-dependent manner and affect the dimeric proteins. Our results show that a conserved mechanism provides the basis for the functional redundancy of PDF2 and ATML1 in epidermal cell differentiation and that an unidentified regulatory layer specific to PDF2 or ATML1 is responsible for the difference in the activity and/or function of PDF2 and ATML1.

Background Women with PCOS have elevated levels of the harmful Advanced Glycation End Products (AGEs), which are highly reactive molecules formed after glycation of lipids and proteins. Additionally, AGEs accumulate in the ovaries of women with PCOS potentially contributing to the well-documented abnormal steroidogenesis and folliculogenesis. Main body A systematic review of articles and abstracts available in PubMed was conducted and presented in a systemic manner. This article reports changes in steroidogenic enzyme activity in granulosa and theca cells in PCOS and PCOS-models. It also described the changes in AGEs and their receptors in the ovaries of women with PCOS and presents the underlying mechanism(s) whereby AGEs could be responsible for the PCOS-related changes in granulosa and theca cell function thus adversely impacting steroidogenesis and follicular development. AGEs are associated with hyperandrogenism in PCOS possibly by altering the activity of various enzymes such as cholesterol side-chain cleavage enzyme cytochrome P450, steroidogenic acute regulatory protein, 17α-hydroxylase, and 3β-hydroxysteroid dehydrogenase. AGEs also affect luteinizing hormone receptor and anti-Mullerian hormone receptor expression as well as their signaling pathways in granulosa cells. Conclusions A better understanding of how AGEs alter granulosa and theca cell function is likely to contribute meaningfully to a conceptual framework whereby new interventions to prevent and/or treat ovarian dysfunction in PCOS can ultimately be developed.

Cancer is one of the major causes of death in developed countries and current therapies are based on surgery, chemotherapeutic agents, and radiation. To overcome side effects induced by chemo- and radiotherapy, in recent decades, targeted therapies have been proposed in second and even first lines. Targeted drugs act on the essential pathways involved in tumor induction, progression, and metastasis, basically all the hallmark of cancers. Among emerging pathways, the cholesterol metabolic pathway is a strong candidate for this purpose. Cancer cells have an accelerated metabolic rate and require a continuous supply of cholesterol for cell division and membrane renewal. Steroidogenic acute regulatory related lipid transfer (START) proteins are a family of proteins involved in the transfer of lipids and some of them are important in non-vesicular cholesterol transportation within the cell. The alteration of their expression levels is implicated in several diseases, including cancers. In this review, we report the latest discoveries on StAR-related lipid transfer protein domain 3 (STARD3), a member of the START family, which has a potential role in cancer, focusing on the structural and biochemical characteristics and mechanisms that regulate its activity. The role of the STARD3 protein as a molecular target for the development of cancer therapies is also discussed. As STARD3 is a key protein in the cholesterol movement in cancer cells, it is of interest to identify inhibitors able to block its activity.

Review the impact of StAR (STARD1) mutations on steroidogenesis and fertility in LCAH patients. Examine the endocrine mechanisms underlying the pathology of the disorder and the appropriate therapy for promoting fertility and pregnancies. Published data in the literature and a detailed 38-year follow-up of two sibling LCAH patients. Molecular structure and modeling of the STARD1 L275P mutation. University hospital. Patient A (46,XY female phenotype) and patient B (46,XX female) with LCAH bearing the L275P mutation in STARD1. Since early-age diagnosis, both patients underwent corticoid replacement therapy. Patient A received estrogen therapy at pubertal age. Clomiphene therapy was given to Patient B to induce ovulation. Pregnancies were protected with progesterone administration. Clinical and molecular assessment of adrenal and gonadal functions. Both patients have classic manifestations of corticosteroid deficiency observed in LCAH. Time of onset and severity were different. Patient A developed into a female phenotype due to early and severe damage of Leydig cells. Patient B started a progressive pubertal development, menarche and regular non-ovulatory cycle. She was able to have successful pregnancies. Understanding the molecular structure and function of STARD1 in all steroidogenic tissues is the key for comprehending the heterogeneous clinical manifestations of LCAH, and the development of an appropriate strategy for the induction of ovulation and protecting pregnancies in this disease.

Herein we summarize important discoveries made over many years about Leydig cell function and regulation. Fetal Leydig cells produce the high levels of androgen (testosterone or androstenedione, depending upon the species) required for differentiation of male genitalia and brain masculinization. Androgen production declines with loss of these cells, reaching a nadir at postpartum. Testosterone then gradually increases to high levels with adult Leydig cell development from stem cells. In the adult, luteinizing hormone (LH) binding to Leydig cell LH receptors stimulates cAMP production, increasing the rate of cholesterol translocation into the mitochondria. Cholesterol is metabolized to pregnenolone by the CYP11A1 enzyme at the inner mitochondrial membrane, and pregnenolone to testosterone by mitochondria and smooth endoplasmic reticulum enzymes. Cholesterol translocation to the inner mitochondrial membrane is mediated by a protein complex formed at mitochondrial contact sites that consists of the cholesterol binding translocator protein, voltage dependent anion channel, and other mitochondrial and cytosolic proteins. Steroidogenic acute regulatory protein acts at this complex to enhance cholesterol movement across the membranes and thus increase testosterone formation. The 14-3-3γ and ϵ adaptor proteins serve as negative regulators of steroidogenesis, controlling the maximal amount of steroid formed. Decline in testosterone production occurs in many aging and young men, resulting inmetabolic and quality-of-life changes. Testosterone replacement therapy is widely used to elevate serum testosterone levels in hypogonadal men. With knowledge gained of the mechanisms involved in testosterone formation, it is also conceivable to use pharmacological means to increase serum testosterone by Leydig cell stimulation. Summary Sentence A summary of important discoveriesmade over the course of many years about Leydig cell function and regulation, and discussion of important issues that remain to be understood.

Objective To investigate male reproductive parameters via changes of potential testicular protein markers in restraint-stress rats. Methods Male Sprague-Dawley rats were divided into two groups (non-immobilized control and restraint-immobilized/stress groups, n =8 each group). The stress animals were immobilized (12 h/d) by a restraint cage for 7 consecutive days. All reproductive parameters, morphology and histology were observed and compared between groups. In addition, the expression of steroidogenic acute regulatory (StAR) and phosphotyrosine proteins (previously localized in Sertoli and late spermatid cells) in testicular lysate was assayed by immuno-Western blotting. Results Testosterone level, sperm concentration and sperm head normality of stress rats were significantly decreased while the corticosterone level was increased as compared with the control ( P <0.05). Histologically, stress rats showed low sperm mass in epididymal lumen and some atrophy of seminiferous tubules. Although the expression of testicular StAR protein was not significantly different between groups, changed patterns of the 131, 95, and 75 kDa testicular phosphorylated proteins were observed in the stress group compared with the control group. The intensity of a testicular 95-kDa phosphorylated protein was significantly decreased in stress rats. Conclusions This study has demonstrated the alteration of testicular phosphorylated protein patterns, associated with adverse male reproductive parameters in stress rats. It could be an explanation of some infertility in stress males.

Transport of dietary cholesterol from endocytic organelles to the endoplasmic reticulum (ER) is essential for cholesterol homoeostasis, but the mechanism and regulation of this transport remains poorly defined. Membrane contact sites (MCS), microdomains of close membrane apposition, are gaining attention as important platforms for non-vesicular, inter-organellar communication. Here we investigate the impact of ER-endocytic organelle MCS on cholesterol transport. We report a role for Niemann-Pick type C protein 1 (NPC1) in tethering ER-endocytic organelle MCS where it interacts with the ER-localised sterol transport protein Gramd1b to regulate cholesterol egress. We show that artificially tethering MCS rescues the cholesterol accumulation that characterises NPC1-deficient cells, consistent with direct lysosome to ER cholesterol transport across MCS. Finally, we identify an expanded population of lysosome-mitochondria MCS in cells depleted of NPC1 or Gramd1b that is dependent on the late endosomal sterol-binding protein STARD3, likely underlying the mitochondrial cholesterol accumulation in NPC1-deficient cells. Though endocytosed dietary cholesterol is transferred to the endoplasmic reticulum (ER), how this is regulated is unclear. Here, the authors report a role for Niemann-Pick Type C Protein 1 (NPC1) in tethering endocytic organelles to the ER, which may contribute to interorganelle cholesterol transport.

Leydig cells play a critical role in male reproductive physiology, and their dysfunction is usually associated with male infertility. Melatonin has an important protective and regulatory role in these cells. However, the lack of suitable animal models impedes us from addressing the impact of endogenous melatonin on these cells. In the current study, by using arylalkylamine N-acetyltransferase (AANAT) overexpression transgenic sheep and AANAT knockout mice, we confirmed the regulatory effects of endogenously occurring melatonin on Leydig cells as well as its beneficial effects on male reproductive performance. The results showed that the endogenously elevated melatonin level was correlated with decreased Leydig cell apoptosis, increased testosterone production, and improved quality of sperm in melatonin-enriched transgenic mammals. Signal transduction analysis indicated that melatonin targeted the mitochondrial apoptotic Bax/Bcl2 pathway and thus suppressed Leydig cell apoptosis. In addition, melatonin upregulated the expression of testosterone synthesis-related genes of Steroidogenic Acute Regulatory Protein (StAR), Steroidogenic factor 1 (SF1), and Transcription factor GATA-4 (Gata4) in Leydig cells. This action was primarily mediated by the melatonin nuclear receptor RAR-related orphan receptor alpha (RORα) since blockade of this receptor suppressed the effect of melatonin on testosterone synthesis. All of these actions of melatonin cause Leydig cells to generate more testosterone, which is necessary for spermatogenesis in mammals. In contrast, AANAT knockout animals have dysfunctional Leydig cells and reduced reproductive performance. Graphical Abstract

Cholesterol is a lipid molecule essential for several key cellular processes including steroidogenesis. As such, the trafficking and distribution of cholesterol is tightly regulated by various pathways that include vesicular and non-vesicular mechanisms. One non-vesicular mechanism is the binding of cholesterol to cholesterol transport proteins, which facilitate the movement of cholesterol between cellular membranes. Classic examples of cholesterol transport proteins are the steroidogenic acute regulatory protein (STAR; STARD1), which facilitates cholesterol transport for acute steroidogenesis in mitochondria, and sterol carrier protein 2/sterol carrier protein-x (SCP2/SCPx), which are non-specific lipid transfer proteins involved in the transport and metabolism of many lipids including cholesterol between several cellular compartments. This review discusses the roles of STAR and SCP2/SCPx in cholesterol transport as model cholesterol transport proteins, as well as more recent findings that support the role of these proteins in the transport and/or metabolism of other lipids.

How rapid induction of steroid hormone biosynthesis occurs in response to trophic hormone stimulation of steroidogenic cells has been a subject of intensive investigation for approximately six decades. A key observation made very early was that acute regulation of steroid biosynthesis required swift and timely synthesis of a new protein whose role appeared to be involved in the delivery of the substrate for all steroid hormones, cholesterol, from the outer to the inner mitochondrial membrane where the process of steroidogenesis begins. It was quickly learned that this transfer of cholesterol to the inner mitochondrial membrane was the regulated and ratelimiting step in steroidogenesis. Following this observation, the quest for this putative regulator protein(s) began in earnest in the late 1950s. This review provides a history of this quest, the candidate proteins that arose over the years and facts surrounding their rise or decline. Only two have persisted—translocator protein (TSPO) and the steroidogenic acute regulatory protein (StAR). We present a detailed summary of the work that has been published for each of these two proteins, the specific data that has appeared in support of their role in cholesterol transport and steroidogenesis, and the ensuing observations that have arisen in recent years that have refuted the role of TSPO in this process. We believe that the only viable candidate that has been shown to be indispensable is the StAR protein. Lastly, we provide our view on what may be the most important questions concerning the acute regulation of steroidogenesis that need to be asked in future. Summary Sentence The acute regulation of steroidogenesis in the adrenal and gonads is controlled by cholesterol transfer into the mitochondria and this review covers two decades of research that has demonstrated StAR is indispensable for this process.