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Marta Santos-Hernández Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK

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Frank Reimann Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK

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Fiona M Gribble Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK

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Enteroendocrine cells located along the gastrointestinal epithelium sense different nutrients/luminal contents that trigger the secretion of a variety of gut hormones with different roles in glucose homeostasis and appetite regulation. The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are involved in the regulation of insulin secretion, appetite, food intake and body weight after their nutrient-induced secretion from the gut. GLP-1 mimetics have been developed and used in the treatment of type 2 diabetes mellitus and obesity. Modulating the release of endogenous intestinal hormones may be a promising approach for the treatment of obesity and type 2 diabetes without surgery. For that reason, current understanding of the cellular mechanisms underlying intestinal hormone secretion will be the focus of this review. The mechanisms controlling hormone secretion depend on the nature of the stimulus, involving a variety of signalling pathways including ion channels, nutrient transporters and G-protein-coupled receptors.

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Jenica H Kakadia Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
Children's Health Research Institute, London, Ontario, Canada

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Muhammad U Khalid Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada

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Ilka U Heinemann Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada

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Victor K Han Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
Children's Health Research Institute, London, Ontario, Canada
Department of Pediatrics, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada

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Mechanisms underlying limitations in glucose supply that restrict fetal growth are not well established. IGF-1 is an important regulator of fetal growth and IGF-1 bioavailability is markedly inhibited by IGFBP-1 especially when the binding protein is hyperphosphorylated. We hypothesized that the AMPK–mTORC1 pathway increases IGFBP-1 phosphorylation in response to glucose deprivation. Glucose deprivation in HepG2 cells activated AMPK and TSC2, inhibited mTORC1 and increased IGFBP-1 secretion and site-specific phosphorylation. Glucose deprivation also decreased IGF-1 bioavailability and IGF-dependent activation of IGF-1R. AICAR (an AMPK activator) activated TSC2, inhibited mTORC1, and increased IGFBP-1 secretion/phosphorylation. Further, siRNA silencing of either AMPK or TSC2 prevented mTORC1 inhibition and IGFBP-1 secretion and phosphorylation in glucose deprivation. Our data suggest that the increase in IGFBP-1 phosphorylation in response to glucose deprivation is mediated by the activation of AMPK/TSC2 and inhibition of mTORC1, providing a possible mechanistic link between glucose deprivation and restricted fetal growth.

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Isabelle Durrer Department of Nephrology and Hypertension University of Bern, Berne, Switzerland

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Daniel Ackermann Department of Nephrology and Hypertension University of Bern, Berne, Switzerland

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Rahel Klossner Department of Nephrology and Hypertension University of Bern, Berne, Switzerland
Department of Internal Medicine, Sonnenhof, Lindenhofgruppe, Berne, Switzerland

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Michael Grössl Department of Nephrology and Hypertension University of Bern, Berne, Switzerland

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Clarissa Vögel Department of Nephrology and Hypertension University of Bern, Berne, Switzerland

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Therina Du Toit Department for BioMedical Research University of Bern, Berne, Switzerland

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Bruno Vogt Department of Nephrology and Hypertension University of Bern, Berne, Switzerland

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Heidi Jamin Department of Nephrology and Hypertension University of Bern, Berne, Switzerland
Department for BioMedical Research University of Bern, Berne, Switzerland

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Markus G Mohaupt Department of Internal Medicine, Sonnenhof, Lindenhofgruppe, Berne, Switzerland
Department for BioMedical Research University of Bern, Berne, Switzerland

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Carine Gennari-Moser Department of Nephrology and Hypertension University of Bern, Berne, Switzerland
Department for BioMedical Research University of Bern, Berne, Switzerland

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Extra-adrenal de novo aldosterone (Aldo) production has been described inconsistently. Systematic data based upon state-of-the-art technology including validated controls are sparse. We hypothesized that aldosterone synthase (CYP11B2) expression and de novo Aldo production are absent in nonadrenal human cell lines, either immortalized cell lines or commercially available primary cell lines, including peripheral blood mononuclear cells (PBMCs) of individuals without and with primary hyperaldosteronism (PA). CYP11B2-transfected COS-7 and endogenous CYP11B2 expressing adrenal H295R cells served as positive controls. Various well-characterized, purchased, immortalized (BeWo, HEK293, HTR-8/SVneo, JEG-3) and primary (HAEC, HLEC, HRGEC, HRMC, HUAEC, HUVEC, PBMC) cell lines as well as self-isolated PBMCs from PA patients (n = 5) were incubated with the steroid hormone substrates progesterone, deoxycorticosterone, corticosterone or 18-OH-corticosterone with and without Ang II for 24 h to assess CYP11B2 enzymatic activity. CYP11B2 expression was analyzed by real-time PCR and liquid chromatography–mass spectrometry was used to quantify Aldo production. Pronounced CYP11B2 mRNA expression and Aldo production were observed in both positive controls, which followed an incremental time course. Neither substrates alone nor coincubation with Ang II significantly stimulated CYP11B2 expression or Aldo production in various immortalized and primary cell lines and PBMCs of PA patients. These results strongly support the absence of relevant de novo extra-adrenal Aldo production in nonadrenal cells, including blood mononuclear cells, irrespective of the absence or presence of autonomous adrenal Aldo production.

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Xiaojing Wei Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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Yutian Tan Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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Jiaqi Huang Institute of Basic Medicine, School of Medicine, Tsinghua University, Beijing, China

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Ximing Dong Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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Weijie Feng Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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Tanglin Liu Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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Zhao Yang Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China

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Guiying Yang Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China

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Xiao Luo Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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N1-methylnicotinamide (MNAM), a product of methylation of nicotinamide through nicotinamide N-methyltransferase, displays antidiabetic effects in male rodents. This study aimed to evaluate the ameliorative potential of MNAM on glucose metabolism in a gestational diabetes mellitus (GDM) model. C57BL/6N mice were fed with a high-fat diet (HFD) for 6 weeks before pregnancy and throughout gestation to establish the GDM model. Pregnant mice were treated with 0.3% or 1% MNAM during gestation. MNAM supplementation in CHOW diet and HFD both impaired glucose tolerance at gestational day 14.5 without changes in insulin tolerance. However, MNAM supplementation reduced hepatic lipid accumulation as well as mass and inflammation in visceral adipose tissue. MNAM treatment decreased GLUT4 mRNA and protein expression in skeletal muscle, where NAD+ salvage synthesis and antioxidant defenses were dampened. The NAD+/sirtuin system was enhanced in liver, which subsequently boosted hepatic gluconeogenesis. GLUT1 protein was diminished in placenta by MNAM. In addition, weight of placenta, fetus weight, and litter size were not affected by MNAM treatment. The decreased GLUT4 in skeletal muscle, boosted hepatic gluconeogenesis and dampened GLUT1 in placenta jointly contribute to the impairment of glucose tolerance tests by MNAM. Our data provide evidence for the careful usage of MNAM in treatment of GDM.

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Deyana Ivanova Department of Women and Children’s Health, Faculty of Life Science and Medicine, King’s College London, UK
Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

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Kevin T O’Byrne Department of Women and Children’s Health, Faculty of Life Science and Medicine, King’s College London, UK

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The exact neural construct underlying the dynamic secretion of gonadotrophin-releasing hormone (GnRH) has only recently been identified despite the detection of multiunit electrical activity volleys associated with pulsatile luteinising hormone (LH) secretion four decades ago. Since the discovery of kisspeptin/neurokinin B/dynorphin neurons in the mammalian hypothalamus, there has been much research into the role of this neuronal network in controlling the oscillatory secretion of gonadotrophin hormones. In this review, we provide an update of the progressive application of cutting-edge techniques combined with mathematical modelling by the neuroendocrine community, which are transforming the functional investigation of the GnRH pulse generator. Understanding the nature and function of the GnRH pulse generator can greatly inform a wide range of clinical studies investigating infertility treatments.

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Yan Meng Y Meng, School of LIfe Sciences, University of Nottingham Faculty of Medicine and Health Sciences, Nottingham, United Kingdom of Great Britain and Northern Ireland

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Maria Toledo-Rodriguez M Toledo-Rodriguez, School of Lfe Sciences, University of Nottingham Faculty of Medicine and Health Sciences, Nottingham, United Kingdom of Great Britain and Northern Ireland

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Olena Fedorenko O Fedorenko, Great Chesterford Research Park, Charles River Laboratories, Cambridge, United Kingdom of Great Britain and Northern Ireland

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Paul A. Smith P Smith, Life Sciences, University of Nottingham Faculty of Medicine and Health Sciences, Nottingham, United Kingdom of Great Britain and Northern Ireland

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White adipose tissue (WAT) requires extracellular Ca2+ influx for lipolysis, differentiation, and expansion. This partly occurs via plasma membrane Ca2+ voltage-dependent channels (CaVs). However, WFA exists in different depots whose function varies with age, sex, and location. To explore whether their CaV expression profiles also differ we used RNAseq and qPCR on gonadal, mesenteric, retroperitoneal, and inguinal subcutaneous fat depots from rats of different ages and sex. CaV expression was found dependent on age, sex, and WFA location. In the gonadal depots of both sexes a significantly lower expression of CaV1.2 and CaV1.3 was seen for adults compared to pre-pubescent juveniles. A lower level of expression was also seen for CaV3.1 in adult male but not female gonadal WFA; the latter of whose expression remained unchanged with age. Relatively little expression of CaV3.2 and 3.2 was observed. In post-pubescent inguinal subcutaneous fat, where mammary glands are sited, CaV3.1 was decreased in males but increased in females; data which suggests this channel is associated with mammogenesis, however no effect on intracellular Ca2+ levels or adipocyte size were noted. For all adult depots, CaV3.1 expression was larger in females than males; a difference not seen in pre-pubescent rats. These observations are consistent with the changes of CaV3.1 expression seen in 3T3-L1 cell differentiation and the ability of selective CaV3.1 antagonists to inhibit adipogensis. Our results show that changes in CaVs expression patterns occur in fat depots related to sexual dimorphism: reproductive tracts and mammogenesis.

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Megan Beetch Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

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Brian Akhaphong Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

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Alicia Wong Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

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Briana Clifton Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

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Seokwon Jo Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

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Ramkumar Mohan Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

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Juan E Abrahante Llorens University of Minnesota Informatics Institute (UMII), Minneapolis, Minnesota, USA

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Emilyn U Alejandro Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

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Suboptimal in utero environments such as poor maternal nutrition and gestational diabetes can impact fetal birth weight and the metabolic health trajectory of the adult offspring. Fetal growth is associated with alterations in placental mechanistic target of rapamycin (mTOR) signaling; it is reduced in fetal growth restriction and increased in fetal overgrowth. We previously reported that when metabolically challenged by a high-fat diet, placental mTORKO (mTORKOpl) adult female offspring develop obesity and insulin resistance, whereas placental TSC2KO (TSC2KOpl) female offspring are protected from diet-induced obesity and maintain proper glucose homeostasis. In the present study, we sought to investigate whether reducing or increasing placental mTOR signaling in utero alters the programming of adult offspring metabolic tissues preceding a metabolic challenge. Adult male and female mTORKOpl, TSC2KOpl, and respective controls on a normal chow diet were subjected to an acute intraperitoneal insulin injection. Upon insulin stimulation, insulin signaling via phosphorylation of Akt and nutrient sensing via phosphorylation of mTOR target ribosomal S6 were evaluated in the offspring liver, white adipose tissue, and skeletal muscle. Among tested tissues, we observed significant changes only in the liver signaling. In the male mTORKOpl adult offspring liver, insulin-stimulated phospho-Akt was enhanced compared to littermate controls. Basal phospho-S6 level was increased in the mTORKOpl female offspring liver compared to littermate controls and did not increase further in response to insulin. RNA sequencing of offspring liver identified placental mTORC1 programming-mediated differentially expressed genes. The expression of major urinary protein 1 (Mup1) was differentially altered in female mTORKOpl and TSC2KOpl offspring livers and we show that MUP1 level is dependent on overnutrition and fasting status. In summary, deletion of placental mTOR nutrient sensing in utero programs hepatic response to insulin action in a sexually dimorphic manner. Additionally, we highlight a possible role for hepatic and circulating MUP1 in glucose homeostasis that warrants further investigation.

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Guanghong Jia Department of Medicine-Endocrinology and Metabolism, University of Missouri School of Medicine, Columbia, Missouri, USA
Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA

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Michael A Hill Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA

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James R Sowers Department of Medicine-Endocrinology and Metabolism, University of Missouri School of Medicine, Columbia, Missouri, USA
Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA

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Metabolic syndrome is a group of risk factors that increase the risk of developing metabolic and cardiovascular disease (CVD) and include obesity, dyslipidemia, insulin resistance, atherosclerosis, hypertension, coronary artery disease, and heart failure. Recent research indicates that excessive production of aldosterone and associated activation of mineralocorticoid receptors (MR) impair insulin metabolic signaling, promote insulin resistance, and increase the risk of developing metabolic syndrome and CVD. Moreover, activation of specific epithelial sodium channels (ENaC) in endothelial cells (EnNaC), which are downstream targets of endothelial-specific MR (ECMR) signaling, are also believed to play a crucial role in the development of metabolic syndrome and CVD. These adverse effects of ECMR/EnNaC activation are mediated by increased oxidative stress, inflammation, and lipid metabolic disorders. It is worth noting that ECMR/EnNaC activation and the pathophysiology underlying metabolic syndrome and CVD appears to exhibit sexual dimorphism. Targeting ECMR/EnNaC signaling may have a beneficial effect in preventing insulin resistance, diabetes, metabolic syndrome, and related CVD. This review aims to examine our current understanding of the relationship between MR activation and increased metabolic syndrome and CVD, with particular emphasis placed on the role for endothelial-specific ECMR/EnNaC signaling in these pathological processes.

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Dorka Nagy Department of Metabolism, Digestion and Reproduction, Section of Genetics and Genomics, Imperial College London, London, UK
National Heart and Lung Institute, Imperial College London, London, UK

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Hannah Maude Department of Metabolism, Digestion and Reproduction, Section of Genetics and Genomics, Imperial College London, London, UK

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Graeme M Birdsey National Heart and Lung Institute, Imperial College London, London, UK

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Anna M Randi National Heart and Lung Institute, Imperial College London, London, UK

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Inês Cebola Department of Metabolism, Digestion and Reproduction, Section of Genetics and Genomics, Imperial College London, London, UK

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Liver sinusoidal endothelial cells (LSECs) are highly specialised endothelial cells that form the liver microvasculature. LSECs maintain liver homeostasis, scavenging bloodborne molecules, regulating immune response, and actively promoting hepatic stellate cell quiescence. These diverse functions are underpinned by a suite of unique phenotypical attributes distinct from other blood vessels. In recent years, studies have begun to reveal the specific contributions of LSECs to liver metabolic homeostasis and how LSEC dysfunction associates with disease aetiology. This has been particularly evident in the context of non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, which is associated with the loss of key LSEC phenotypical characteristics and molecular identity. Comparative transcriptome studies of LSECs and other endothelial cells, together with rodent knockout models, have revealed that loss of LSEC identity through disruption of core transcription factor activity leads to impaired metabolic homeostasis and to hallmarks of liver disease. This review explores the current knowledge of LSEC transcription factors, covering their roles in LSEC development and maintenance of key phenotypic features, which, when disturbed, lead to loss of liver metabolic homeostasis and promote features of chronic liver diseases, such as non-alcoholic liver disease.

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Tien-Chun Yang Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

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Mei-Hua Lu Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan

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Wei-Jie Wang Department of Entomology, University of California, Riverside, California, USA

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Jang-Yi Chen Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan

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The pathogenesis of hypertension is not fully understood; endothelin 1 (EDN1) is involved in developing essential hypertension. EDN1 can promote vascular smooth muscle cell (VSMC) proliferation or hypertrophy through autocrine and paracrine effects. Proliferating smooth muscle cells in the aorta are 'dedifferentiated' cells that cause increased arterial stiffness and remodeling. Male SHRs had higher aortic stiffness than normal control male WKY rats. Male SHR VSMCs expressed high levels of the EDN1 gene, but endothelial cells did not. Therefore, it is necessary to understand the molecular mechanism of enhanced EDN1 expression in SHR VSMCs. We identified POU2F2 and CEBPB as the main molecules that enhance EDN1 expression in male SHR VSMCs. A promoter activity analysis confirmed that the enhancer region of the Edn1 promoter in male SHR VSMCs was from −1309 to −1279 bp. POU2F2 and CEBPB exhibited an additive role in the enhancer region of the EdnET1 promoter. POU2F2 or CEBPB overexpression sufficiently increased EDN1 expression, and co-transfection with the CEBPB and POU2F2 expression plasmids had additive effects on the activity of the Edn1 promoter and EDN1 secretion level of male WKY VSMCs. In addition, the knockdown of POU2F2 also revealed that POU2F2 is necessary to enhance EDN1 expression in SHR VSMCs. The enhancer region of the Edn1 promoter is highly conserved in rats, mice, and humans. POU2F2 and CEBPB mRNA levels were significantly increased in remodeled human VMSCs. In conclusion, the novel regulation of POU2F2 and CEBPB in VSMCs will help us understand the pathogenesis of hypertension and support the development of future treatments for hypertension.

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