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Non-alcoholic fatty liver disease (NAFLD) is the fastest-growing cause of liver-associated death globally. Whole-body knockout (KO) of Na+/H+ exchanger 1 (NHE1, SLC9A1) was previously proposed to protect against high-fat diet-induced liver damage; however, mechanistic insight was lacking. The aim of the present work was to address this question in vitro to determine how NHE1, specifically in hepatocytes, impacts lipid overload-induced inflammation, fibrosis, and hepatocyte–hepatic stellate cell (HSC) crosstalk. We induced palmitate (PA)-based steatosis in AML12 and HepG2 hepatocytes; manipulated NHE1 activity pharmacologically and by CRISPR/Cas9-mediated KO and overexpression; and measured intracellular pH (pHi), steatosis-associated inflammatory and fibrotic mediators, and cell death. PA treatment increased NHE1 mRNA levels but modestly reduced NHE1 protein expression and hepatocyte pHi. NHE1 KO in hepatocytes did not alter lipid droplet accumulation but reduced inflammatory signaling (p38 MAPK activity), lipotoxicity (4-HNE accumulation), and apoptosis (poly-ADP-ribose-polymerase-1 (PARP) cleavage). Conditioned medium from PA-treated hepatocytes increased the expression of NHE1 and of the fibrosis regulator tissue inhibitor of matrix metalloproteinases-2 in LX-2 HSCs, in a manner abolished by NHE1 KO in hepatocytes. We conclude that NHE1 is regulated in NAFLD in vitro and contributes to the ensuing damage by aggravating hepatocyte injury and stimulating hepatocyte–HSC crosstalk.
Centre de recherche en reproduction, développement et santé intergénérationnelle, Department of Obstetrics, Gynecology, and Reproduction, Université Laval, Québec, Quebec, Canada
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Centre de recherche en reproduction, développement et santé intergénérationnelle, Department of Obstetrics, Gynecology, and Reproduction, Université Laval, Québec, Quebec, Canada
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The steroidogenic acute regulatory (STAR) protein is an essential cholesterol transporter that shuttles cholesterol from the outer to the inner mitochondrial membrane in the major steroidogenic endocrine organs. It is a key player in the acute regulation of steroid hormone biosynthesis in response to tropic hormone stimulation. Its discovery 30 years ago sparked immediate interest in understanding how STAR action is controlled. Since increased STAR gene expression is a classic feature of the acute regulation of steroidogenesis, a special emphasis was placed on defining the transcriptional regulatory mechanisms that underlie its rapid induction in response to tropic hormone stimulation. These mechanisms include the effects of enhancers, the regulation of chromatin accessibility, the impact of epigenetic factors, and the role of transcription factors. Over the past three decades, understanding the transcription factors that regulate STAR gene expression has been the subject of more than 170 independent scientific publications, making it one of, and if not the best, studied genes in the steroidogenic pathway. This intense research effort has led to the identification of dozens of transcription factors and their related binding sites in STAR 5' flanking (promoter) sequences across multiple species. STAR gene transcription appears to be complex in that a large number of transcription factors have been proposed to interact with either isolated or overlapping regulatory sequences that are tightly clustered over a relatively short promoter region upstream of the STAR transcription start site. Many of these transcription factors appear to work in unique combinatorial codes and are impacted by diverse hormonal and intracellular signaling pathways. This review provides a retrospective overview of the transcription factors proposed to regulate both basal and acute (hormonal) STAR gene expression, and how insights in this area have evolved over the past 30 years.
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Diabetes mellitus disturbs kisspeptin–neurokinin B–dynorphin A (KNDy) neurons in the arcuate nucleus (ARC), which regulate pulsatile luteinizing hormone (LH) secretion in both sexes. However, it remains unclear whether a sex-specific association with the negative effects of diabetes on KNDy neurons exists. Therefore, we examined mRNA expression in KNDy neurons of diabetic male and female rats 7 weeks after streptozotocin (STZ) injection using histochemistry. In gonad-intact rats, the numbers of Kiss1 and Pdyn mRNA-expressing cells in the ARC decreased in an STZ-dose-dependent manner; moreover, no sex-dependent association with STZ treatment was observed. In males, plasma LH and sex steroid levels decreased in diabetic rats. Conversely, those of females did not vary significantly between the control and diabetic rats. Kiss1 expression in the anteroventral periventricular nucleus was slightly affected in diabetic animals, but did not exhibit sex-dependent differences. In gonadectomized rats, the numbers of KNDy mRNA-expressing cells in the ARC and plasma LH levels decreased in diabetic male and female rats; however, sex-dependent differences did not exist. These results demonstrated that a sex-specific association with the negative effects of diabetes on KNDy neurons did not exist. Therefore, the stage of diabetes that induces the suppression of the hypothalamus may not vary according to sex.
National Taiwan University Hospital Primary Aldosteronism Center, Taipei, Taiwan
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Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
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National Taiwan University Hospital Primary Aldosteronism Center, Taipei, Taiwan
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National Taiwan University Hospital Primary Aldosteronism Center, Taipei, Taiwan
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Aldosterone is a mineralocorticoid hormone involved in controlling electrolyte balance, blood pressure, and cellular signaling. It plays a pivotal role in cardiovascular and metabolic physiology. Excess aldosterone activates mineralocorticoid receptors, leading to subsequent inflammatory responses, increased oxidative stress, and tissue remodeling. Various mechanisms have been reported to link aldosterone with cardiovascular and metabolic diseases. However, mitochondria, responsible for energy generation through oxidative phosphorylation, have received less attention regarding their potential role in aldosterone-related pathogenesis. Excess aldosterone leads to mitochondrial dysfunction, and this may play a role in the development of cardiovascular and metabolic diseases. Aldosterone has the potential to affect mitochondrial structure, function, and dynamic processes, such as mitochondrial fusion and fission. In addition, aldosterone has been associated with the suppression of mitochondrial DNA, mitochondria-specific proteins, and ATP production in the myocardium through mineralocorticoid receptor, nicotinamide adenine dinucleotide phosphate oxidase, and reactive oxygen species pathways. In this review, we explore the mechanisms underlying aldosterone-induced cardiovascular and metabolic mitochondrial dysfunction, including mineralocorticoid receptor activation and subsequent inflammatory responses, as well as increased oxidative stress. Furthermore, we review potential therapeutic targets aimed at restoring mitochondrial function in the context of aldosterone-associated pathologies. Understanding these mechanisms is vital, as it offers insights into novel therapeutic strategies to mitigate the impact of aldosterone-induced mitochondrial dysfunction, thereby potentially improving the outcomes of individuals affected by cardiovascular and metabolic disorders.
Obesity and Comorbidities Research Center, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, Coimbra, Portugal
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University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal
Clinical and Academic Centre of Coimbra (CACC), Coimbra, Portugal
Polytechnic University of Coimbra, Coimbra Health School, H&T Research Center, Coimbra, Portugal
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Obesity and Comorbidities Research Center, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
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Ghrelin has effects that range from the maturation of the central nervous system to the regulation of energy balance. The production of ghrelin increases significantly during the first weeks of life. Studies have addressed the metabolic effects of liver-expressed antimicrobial peptide 2 (LEAP2) in inhibiting the effects evoked by ghrelin, mainly in glucose homeostasis, insulin resistance, and lipid metabolism. Despite the known roles of ghrelin in the postnatal development, little is known about the long-term metabolic influences of modulation with the endogenous expressed growth hormone secretagogue receptor (GHSR) inverse agonist LEAP2. This study aimed to evaluate the contribution of GHSR signalling during perinatal phases, to neurodevelopment and energy metabolism in young animals, under inverse antagonism by LEAP2[1–14]. For this, two experimental models were used: (i) LEAP2[1–14] injections in female rats during the pregnancy. (ii) Postnatal modulation of GHSR with LEAP2[1–14] or MK677. Perinatal GHSR modulation by LEAP2[1–14] impacts glucose homeostasis in a sex and phase-dependent manner, despite no effects on body weight gain or food intake. Interestingly, liver PEPCK expression was remarkably impacted by LEAP2 injections. The observed results suggests that perinatal LEAP2 exposure can modulate liver metabolism and systemic glucose homeostasis. In addition, these results, although not expressive, may just be the beginning of the metabolic imbalance that will occur in adulthood.
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Department of Biochemistry, Microbiology and Immunology, The University of Ottawa, Faculty of Medicine, Ottawa, Ontario, Canada
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Department of Biochemistry, Microbiology and Immunology, The University of Ottawa, Faculty of Medicine, Ottawa, Ontario, Canada
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Cardiovascular outcome trials (CVOTs) in people living with type 2 diabetes mellitus and obesity have confirmed the cardiovascular benefits of glucagon-like peptide 1 receptor agonists (GLP-1RAs), including reduced cardiovascular mortality, lower rates of myocardial infarction, and lower rates of stroke. The cardiovascular benefits observed following GLP-1RA treatment could be secondary to improvements in glycemia, blood pressure, postprandial lipidemia, and inflammation. Yet, the GLP-1R is also expressed in the heart and vasculature, suggesting that GLP-1R agonism may impact the cardiovascular system. The emergence of GLP-1RAs combined with glucose-dependent insulinotropic polypeptide and glucagon receptor agonists has shown promising results as new weight loss medications. Dual-agonist and tri-agonist therapies have demonstrated superior outcomes in weight loss, lowered blood sugar and lipid levels, restoration of tissue function, and enhancement of overall substrate metabolism compared to using GLP-1R agonists alone. However, the precise mechanisms underlying their cardiovascular benefits remain to be fully elucidated. This review aims to summarize the findings from CVOTs of GLP-1RAs, explore the latest data on dual and tri-agonist therapies, and delve into potential mechanisms contributing to their cardioprotective effects. It also addresses current gaps in understanding and areas for further research.
Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) are incretin hormones that stimulate insulin secretion and improve glycemic control in individuals with type 2 diabetes (T2D). Data from several cardiovascular outcome trials for GLP-1 receptor (GLP-1R) agonists have demonstrated significant reductions in the occurrence of major adverse cardiovascular events in individuals with T2D. Although the cardiovascular actions attributed to GLP-1R agonism have been extensively studied, little is known regarding the cardiovascular consequences attributed to GIP receptor (GIPR) agonism. As there is now an increasing focus on the development of incretin-based co-agonist therapies that activate both the GLP-1R and GIPR, it is imperative that we understand the mechanism(s) through which these incretins impact cardiovascular function. This is especially important considering that cardiovascular disease represents the leading cause of death in individuals with T2D. With increasing evidence that perturbations in cardiac energy metabolism are a major contributor to the pathology of diabetes-related cardiovascular disease, this may represent a key component through which GLP-1R and GIPR agonism influence cardiovascular outcomes. Not only do GIP and GLP-1 increase the secretion of insulin, they may also modify glucagon secretion, both of which have potent actions on cardiac substrate utilization. Herein we will discuss the potential direct and indirect actions through which GLP-1R and GIPR agonism impact cardiac energy metabolism while interrogating the evidence to support whether such actions may account for incretin-mediated cardioprotection in T2D.
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Polycystic ovary syndrome (PCOS) is a primary endocrinological disorder in women of reproductive age that is characterized by androgen excess and ovulatory irregularities. This syndrome is associated with adipose tissue dysfunction, an elevated risk of insulin resistance, hyperinsulinemia, obesity, and type 2 diabetes. Adipocyte dysfunction affects the secretion of adipokines and pro-inflammatory cytokines. Nevertheless, adipose tissue is not an exclusive source of adipokines as it can also be produced locally by reproductive tissues. Although adipokines have been recognized in the development of PCOS, the role of oncostatin M (OSM), a multifaceted adipokine, remains unclear. Current evidence suggests that this cytokine is associated with key aspects of the syndrome, including obesity, insulin resistance, hyperandrogenism, and inflammation. However, the data are often contradictory, likely due to variations in study designs, methodologies, and species differences. By investigating the link between OSM and PCOS-associated issues, this review identified the potential role of this adipokine in PCOS pathogenesis. This underscores the need for further research to clarify its predominant effects and assess its relevance as a therapeutic target.
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The novel adipokine asprosin produced by the furin enzymatic cleavage of profibrillin 1 protein (encoded by the Fbn1 gene) is implicated in regulating many physiological functions including reproduction in mammals. In males, asprosin is reported to increase sperm density, sperm motility, and steroid production by interacting with Olfr734 belonging to the G-protein coupled receptor family (GPCR). In 2023, our group predicted and characterized asprosin in silico for the first time and demonstrated the robust expression of fbn1, and furin in the gonads of teleost spotted snakehead (ss) Channa punctata. Taking it forward, in the current study, we have investigated the effect of asprosin on the testicular functions of the spotted snakehead. As C. punctata is a seasonal breeder, reproductive-phase dependent expression of fbn1 in the testis was analysed, which showed significant upregulation during the preparatory and post-spawning phases. In addition, bacterially overexpressed recombinant asprosin of C. punctata was purified to study the effect of ss asprosin on gametogenesis and steroidogenesis. Ex vivo treatment with recombinant asprosin resulted in significant upregulation of spermatogenic marker genes pcna, aldh1a2, cyp26a1, and sycp3. Asprosin also enhanced the gene expression of gonadotropin receptors as well as sex steroid receptors in addition to steroidogenic genes, star and cyp17a1. Further to explore the downstream signalling cascade, the second messenger of GPCRs, cAMP level following asprosin treatment was analysed. Asprosin treatment prominently enhanced the cAMP levels, thereby indicating the involvement of GPCR in transduction of asprosin action. Hence, the study elucidates the regulation of male reproductive function by asprosin in spotted snakehead.
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Osteosarcopenia, which refers to the concomitant presence of osteoporosis and sarcopenia, is expected to increase in the rapidly progressive aging world, with serious clinical implications. However, the pathophysiology of osteosarcopenia has not been fully elucidated, and no optimal treatment specific to osteosarcopenia is available. The RANKL–RANK pathway is widely used as a therapeutic target for osteoporosis. Growing evidence supports the importance of the RANKL–RANK pathway, not only in bone, but also in muscle, and the therapeutic potential of targeting this pathway in muscle diseases has been noted. The muscles and bones closely communicate with each other through various secretory factors called myokines and osteokines. This review covers the roles of the RANKL–RANK pathway in the bone and muscle and their reciprocal interactions. Moreover, we will suggest future directions to move forward for the treatment of osteosarcopenia to prepare for an upcoming aging society.