Journal of Endocrinology最新文献

GLP-1 receptor agonist-based therapies and cardiovascular risk: a review of mechanisms. GLP-1 受体激动剂与心血管风险：机制综述。

IF 3.4 3区医学

Journal of Endocrinology Pub Date : 2024-09-19 Print Date: 2024-10-01 DOI: 10.1530/JOE-24-0046

Neerav Mullur, Arianne Morissette, Nadya M Morrow, Erin E Mulvihill

{"title":"GLP-1 receptor agonist-based therapies and cardiovascular risk: a review of mechanisms.","authors":"Neerav Mullur, Arianne Morissette, Nadya M Morrow, Erin E Mulvihill","doi":"10.1530/JOE-24-0046","DOIUrl":"10.1530/JOE-24-0046","url":null,"abstract":"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.","PeriodicalId":15740,"journal":{"name":"Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Aldosterone, mitochondria and regulation of cardiovascular metabolic disease. 醛固酮、线粒体和心血管代谢疾病的调节。

IF 3.4 3区医学

Journal of Endocrinology Pub Date : 2024-09-13 Print Date: 2024-10-01 DOI: 10.1530/JOE-23-0350

Cheng-Hsuan Tsai, Zheng-Wei Chen, Bo-Ching Lee, Che-Wei Liao, Yi-Yao Chang, Yan-Rou Tsai, Chia-Hung Chou, Vin-Cent Wu, Chi-Sheng Hung, Yen-Hung Lin

{"title":"Aldosterone, mitochondria and regulation of cardiovascular metabolic disease.","authors":"Cheng-Hsuan Tsai, Zheng-Wei Chen, Bo-Ching Lee, Che-Wei Liao, Yi-Yao Chang, Yan-Rou Tsai, Chia-Hung Chou, Vin-Cent Wu, Chi-Sheng Hung, Yen-Hung Lin","doi":"10.1530/JOE-23-0350","DOIUrl":"10.1530/JOE-23-0350","url":null,"abstract":"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.","PeriodicalId":15740,"journal":{"name":"Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141909808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The GHSR1a antagonist LEAP2 regulates islet hormone release in a sex-specific manner GHSR1a 拮抗剂 LEAP2 以性别特异性方式调节胰岛激素的释放

IF 4 3区医学

Journal of Endocrinology Pub Date : 2024-09-01 DOI: 10.1530/joe-24-0135

Nirun Hewawasam, Debalina Sakar, Olivia Bolton, Blerinda Delishaj, Maha Almutairi, Aileen King, Ayse S Dereli, Chloe Despontin, Patrick Gilon, Sue Reeves, Michael Patterson, Astrid Christine Hauge-Evans

{"title":"The GHSR1a antagonist LEAP2 regulates islet hormone release in a sex-specific manner","authors":"Nirun Hewawasam, Debalina Sakar, Olivia Bolton, Blerinda Delishaj, Maha Almutairi, Aileen King, Ayse S Dereli, Chloe Despontin, Patrick Gilon, Sue Reeves, Michael Patterson, Astrid Christine Hauge-Evans","doi":"10.1530/joe-24-0135","DOIUrl":"https://doi.org/10.1530/joe-24-0135","url":null,"abstract":"LEAP2, a liver-derived antagonist for the ghrelin receptor, GHSR1a, counteracts effects of ghrelin on appetite and energy balance. Less is known about its impact on blood glucose-regulating hormones from pancreatic islets. Here we investigate whether acyl-ghrelin (AG) and LEAP2 regulate islet hormone release in a cell type- and sex-specific manner. Hormone content from secretion experiments with isolated islets from male and female mice was measured by radioimmunoassay and mRNA expression by qPCR. LEAP2 enhanced insulin secretion in islets from males (p<0.01) but not females (p<0.2), whilst AG-stimulated somatostatin release was significantly reversed by LEAP2 in males (p<0.001) but not females (p<0.2). Glucagon release was not significantly affected by AG and LEAP2. Ghsr1a, Ghrelin, Leap2, Mrap2, Mboat4 and Sstr3 islet mRNA expression did not differ between sexes. In control male islets maintained without 17-beta oestradiol (E2), AG exerted an insulinostatic effect (p<0.05), with a trend towards reversal by LEAP2 (p=0.06). Both were abolished by 72h E2 pre-treatment (10 nmol/l, p<0.2). AG-stimulated somatostatin release was inhibited by LEAP2 from control (p<0.001) but not E2-treated islets (p<0.2). LEAP2 and AG did not modulate insulin secretion from MIN6 beta cells and Mrap2 was downregulated (P<0.05) and Ghsr1a upregulated (P<0.0001) in islets from Sst-/-\u0000 mice. Our findings show that AG and LEAP2 regulate insulin and somatostatin release in an opposing and sex-dependent manner, which in males can be modulated by E2. We suggest that regulation of SST release is a key starting point for understanding the role of GHSR1a in islet function and glucose metabolism.","PeriodicalId":15740,"journal":{"name":"Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Glucocorticoid excess alters metabolic rate and substrate utilization via 11β-HSD1. 糖皮质激素过量会通过 11β-HSD1 改变代谢率和底物利用率。

IF 3.4 3区医学

Journal of Endocrinology Pub Date : 2024-09-01 DOI: 10.1530/JOE-24-0205

Samuel Richard Heaselgrave, Silke Heising, Stuart Andrew Morgan, David M Cartwright, Michael S Sagmeister, Rowan Hardy, Craig L Doig, Nicholas Morton, Kostas Tsintzas, Gareth G Lavery

{"title":"Glucocorticoid excess alters metabolic rate and substrate utilization via 11β-HSD1.","authors":"Samuel Richard Heaselgrave, Silke Heising, Stuart Andrew Morgan, David M Cartwright, Michael S Sagmeister, Rowan Hardy, Craig L Doig, Nicholas Morton, Kostas Tsintzas, Gareth G Lavery","doi":"10.1530/JOE-24-0205","DOIUrl":"https://doi.org/10.1530/JOE-24-0205","url":null,"abstract":"Systemic glucocorticoid excess causes several adverse metabolic conditions, most notably Cushing's syndrome. These effects are amplified by the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Here we determined the less well characterised effects of glucocorticoid excess, and the contribution of 11β-HSD1 amplification, on metabolic rate in mice. Male and female C57BL/6J (wild type, WT) and 11β-HSD1 knock out (11β-HSD1KO) mice were treated with high-dose corticosterone or a vehicle control for 3 weeks. Indirect calorimetry was conducted during the final week of treatment, with or without fasting, to determine the impact on metabolic rate. We found that corticosterone treatment elevated metabolic rate and promoted carbohydrate utilisation primarily in female WT mice, with effects more pronounced during the light phase. Corticosterone treatment also resulted in greater fat accumulation in female WT mice. Corticosterone induced hyperphagia was identified as a likely causal factor altering the respiratory exchange ratio (RER) but not energy expenditure (EE). Male and female 11β-HSD1KO mice were protected against these effects. We identify novel metabolic consequences of sustained glucocorticoid excess, identify a key mechanism of hyperphagia and demonstrate that 11β-HSD1 is required to manifest the full metabolic derangement.","PeriodicalId":15740,"journal":{"name":"Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142288974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Asprosin regulates male reproduction in teleosts: in vitro study in Channa punctata. 阿司匹林调节远洋鱼类的雄性繁殖：点鳢的体外研究。

IF 3.4 3区医学

Journal of Endocrinology Pub Date : 2024-09-01 DOI: 10.1530/JOE-24-0146

Priyanka Sathoria, Bhawna Chuphal, Umesh Rai, Brototi Roy

{"title":"Asprosin regulates male reproduction in teleosts: in vitro study in Channa punctata.","authors":"Priyanka Sathoria, Bhawna Chuphal, Umesh Rai, Brototi Roy","doi":"10.1530/JOE-24-0146","DOIUrl":"https://doi.org/10.1530/JOE-24-0146","url":null,"abstract":"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.","PeriodicalId":15740,"journal":{"name":"Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142288972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The mineralocorticoid system, cardiometabolic health and its interplay with adipose tissue 矿皮质激素系统、心脏代谢健康及其与脂肪组织的相互作用

IF 4 3区医学

Journal of Endocrinology Pub Date : 2024-09-01 DOI: 10.1530/joe-24-0119

Moe Thuzar, Muthanna Abdul Halim, Michael Stowasser

{"title":"The mineralocorticoid system, cardiometabolic health and its interplay with adipose tissue","authors":"Moe Thuzar, Muthanna Abdul Halim, Michael Stowasser","doi":"10.1530/joe-24-0119","DOIUrl":"https://doi.org/10.1530/joe-24-0119","url":null,"abstract":"The mineralocorticoid system, comprising the renin-angiotensin-aldosterone system (RAAS) and associated receptors, is traditionally viewed as a regulator of sodium and fluid balance and blood pressure (BP), with the main mineralocorticoid hormone aldosterone acting via the mineralocorticoid receptor (MR) in distal renal tubules. Over the past few decades, there has been a wider understanding of the role of the mineralocorticoid system in regulating both classical BP-dependent and non-BP-dependent systemic effects. Mounting evidence indicates the novel role of the mineralocorticoid system in cardiometabolic health with excess mineralocorticoid system activity being associated with adiposity, diabetes, insulin resistance and cardiovascular diseases independent of its effect on BP, and RAAS blockade and MR antagonists offering protection against cardiometabolic dysfunction. The metabolic manifestations of mineralocorticoid system overactivation are mainly mediated by their interactions with adipose tissue which orchestrates energy, lipids and glucose homeostasis via effects on the functions of brown and white adipocytes and immune cells. Adipose tissue can in turn influence mineralocorticoid system activity by harbouring its own RAAS system and by releasing mineralocorticoid-secretory factors/adipokines, with resultant further progression of cardiometabolic dysfunction. This article discusses the interplay between the mineralocorticoid system and adipose tissue in the pathophysiology of cardiometabolic diseases.","PeriodicalId":15740,"journal":{"name":"Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Glucagon-like peptide-1 analog, liraglutide, regulates Sertoli cell energy metabolism. 胰高血糖素样肽-1 类似物利拉鲁肽能调节 Sertoli 细胞的能量代谢。

IF 3.4 3区医学

Journal of Endocrinology Pub Date : 2024-09-01 DOI: 10.1530/JOE-24-0274

Marina Ercilia Dasso, Cecilia Lucia Centola, María Noel Galardo, Silvina Beatriz Meroni, Maria Fernanda Riera

{"title":"Glucagon-like peptide-1 analog, liraglutide, regulates Sertoli cell energy metabolism.","authors":"Marina Ercilia Dasso, Cecilia Lucia Centola, María Noel Galardo, Silvina Beatriz Meroni, Maria Fernanda Riera","doi":"10.1530/JOE-24-0274","DOIUrl":"https://doi.org/10.1530/JOE-24-0274","url":null,"abstract":"Liraglutide, an analog of the incretin hormone, glucagon-like peptide 1 (GLP-1), is widely used for obesity and type 2 diabetes treatment. However, there is scarce information about its effects on testicular function. Within the testis, Sertoli cells (SCs) provide nutritional support for germ cells: they metabolize glucose to lactate, which is delivered to germ cells to be used as a preferred energy substrate. Besides, SCs use fatty acids (FAs) as an energy source and store them as triacylglycerols (TAGs) within lipid droplets (LDs), which serve as an important energy reserve. In the present study, twenty-day-old rat SC cultures were used to assess whether liraglutide affects their metabolic functions related to nutritional support and lipid storage. The results show that liraglutide does not modify glucose consumption or lactate production. However, it increases TAG levels and LD content. These effects are accompanied by an increase in the mRNA levels of the fatty acid transporter FAT/CD36, glycerol-3-phosphate-acyltransferases 3, and perilipins 1 and 4. Then, the participation of the cAMP/PKA signaling pathway was explored. We observed that H89 (PKA inhibitor) decreases LD upregulation elicited by liraglutide, and that dibutyryl cAMP increases LD content and the expression of related genes. In summary, liraglutide promotes lipid storage in SCs through the regulation of key regulatory genes involved in FA transport, TAG synthesis, and LD formation. Considering the importance of lipid storage in SC energetic homeostasis maintenance, we postulate that liraglutide might improve the overall energetic status of the seminiferous tubule.","PeriodicalId":15740,"journal":{"name":"Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142288973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Incretin-mediated control of cardiac energy metabolism. 内泌素介导的心脏能量代谢控制。

IF 3.4 3区医学

Journal of Endocrinology Pub Date : 2024-08-08 Print Date: 2024-10-01 DOI: 10.1530/JOE-24-0011

Jordan S F Chan, Tanin Shafaati, John R Ussher

{"title":"Incretin-mediated control of cardiac energy metabolism.","authors":"Jordan S F Chan, Tanin Shafaati, John R Ussher","doi":"10.1530/JOE-24-0011","DOIUrl":"10.1530/JOE-24-0011","url":null,"abstract":"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.","PeriodicalId":15740,"journal":{"name":"Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The role of adipose tissue dysfunction in hepatic insulin resistance and T2D. 脂肪组织功能障碍在肝脏胰岛素抵抗和 T2D 中的作用。

IF 3.4 3区医学

Journal of Endocrinology Pub Date : 2024-08-02 Print Date: 2024-09-01 DOI: 10.1530/JOE-24-0115

Gencer Sancar, Andreas L Birkenfeld

引用次数: 0

NHE1 regulation in NAFLD in vitro contributes to hepatocyte injury and HSC crosstalk. 非酒精性脂肪肝的体外 NHE1 调节有助于肝细胞损伤和造血干细胞串联。

IF 3.4 3区医学

Journal of Endocrinology Pub Date : 2024-08-01 DOI: 10.1530/JOE-24-0099

Lise Margrethe Sjøgaard-Frich, Morten Sølling Henriksen, Shi Min Lam, Frida Jolande Birkbak, Dominika Czaplinska, Mette Flinck, Stine F Pedersen

{"title":"NHE1 regulation in NAFLD in vitro contributes to hepatocyte injury and HSC crosstalk.","authors":"Lise Margrethe Sjøgaard-Frich, Morten Sølling Henriksen, Shi Min Lam, Frida Jolande Birkbak, Dominika Czaplinska, Mette Flinck, Stine F Pedersen","doi":"10.1530/JOE-24-0099","DOIUrl":"https://doi.org/10.1530/JOE-24-0099","url":null,"abstract":"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-Cas knockout (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 (PARP cleavage). Conditioned medium from PA-treated hepatocytes increased expression of NHE1 and of the fibrosis regulator tissue inhibitor of matrix metalloproteases-2 (TIMP2) 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.","PeriodicalId":15740,"journal":{"name":"Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0