{"title":"下调肝脏中的 CerS4 而非 CerS2 能有效缓解高脂饮食雄性小鼠的肝脏胰岛素抵抗。","authors":"Kamila Roszczyc-Owsiejczuk, Piotr Zabielski, Monika Imierska, Karolina Pogodzińska, Patrycja Sadowska, Agnieszka Błachnio-Zabielska","doi":"10.1210/endocr/bqae118","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>Consumption of a high-fat diet (HFD) induces insulin resistance (IRes), significantly affecting the maintenance of normal glucose homeostasis. Nevertheless, despite decades of extensive research, the mechanisms and pathogenesis of IRes remain incomplete. Recent studies have primarily explored lipid intermediates such as diacylglycerol (DAG), given a limited knowledge about the role of ceramide (Cer) that is a potential mediator of the IRes in the liver.</p><p><strong>Methods: </strong>In order to investigate the role of ceramide produced by CerS2 and CerS4 for the purpose of inducing the hepatic IRes, we utilised a unique in vivo model employing shRNA-mediated hydrodynamic gene delivery (HGD) in the liver of HFD-fed C57BL/6J mice.</p><p><strong>Results: </strong>Downregulation of CerS4 instead of CerS2 reduced specific liver ceramides, notably C18:0-Cer and C24:0-Cer, as well as acylcarnitine levels. It concurrently promoted glycogen accumulation, leading to enhanced insulin sensitivity and glucose homeostasis.</p><p><strong>Conclusion: </strong>Those findings demonstrate that CerS4 downregulating lowers fasting blood glucose levels and mitigates the HFD-induced hepatic insulin resistance (IRes). It suggests that inhibiting the CerS4-mediated ceramide C18:0-Cer synthesis holds a promise to effectively address insulin resistance in obesity.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8000,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Downregulation of CerS4 Instead of CerS2 in Liver Effectively Alleviates Hepatic Insulin Resistance in HFD Male Mice.\",\"authors\":\"Kamila Roszczyc-Owsiejczuk, Piotr Zabielski, Monika Imierska, Karolina Pogodzińska, Patrycja Sadowska, Agnieszka Błachnio-Zabielska\",\"doi\":\"10.1210/endocr/bqae118\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>Consumption of a high-fat diet (HFD) induces insulin resistance (IRes), significantly affecting the maintenance of normal glucose homeostasis. Nevertheless, despite decades of extensive research, the mechanisms and pathogenesis of IRes remain incomplete. Recent studies have primarily explored lipid intermediates such as diacylglycerol (DAG), given a limited knowledge about the role of ceramide (Cer) that is a potential mediator of the IRes in the liver.</p><p><strong>Methods: </strong>In order to investigate the role of ceramide produced by CerS2 and CerS4 for the purpose of inducing the hepatic IRes, we utilised a unique in vivo model employing shRNA-mediated hydrodynamic gene delivery (HGD) in the liver of HFD-fed C57BL/6J mice.</p><p><strong>Results: </strong>Downregulation of CerS4 instead of CerS2 reduced specific liver ceramides, notably C18:0-Cer and C24:0-Cer, as well as acylcarnitine levels. It concurrently promoted glycogen accumulation, leading to enhanced insulin sensitivity and glucose homeostasis.</p><p><strong>Conclusion: </strong>Those findings demonstrate that CerS4 downregulating lowers fasting blood glucose levels and mitigates the HFD-induced hepatic insulin resistance (IRes). It suggests that inhibiting the CerS4-mediated ceramide C18:0-Cer synthesis holds a promise to effectively address insulin resistance in obesity.</p>\",\"PeriodicalId\":11819,\"journal\":{\"name\":\"Endocrinology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2024-09-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Endocrinology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1210/endocr/bqae118\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Endocrinology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1210/endocr/bqae118","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Downregulation of CerS4 Instead of CerS2 in Liver Effectively Alleviates Hepatic Insulin Resistance in HFD Male Mice.
Objective: Consumption of a high-fat diet (HFD) induces insulin resistance (IRes), significantly affecting the maintenance of normal glucose homeostasis. Nevertheless, despite decades of extensive research, the mechanisms and pathogenesis of IRes remain incomplete. Recent studies have primarily explored lipid intermediates such as diacylglycerol (DAG), given a limited knowledge about the role of ceramide (Cer) that is a potential mediator of the IRes in the liver.
Methods: In order to investigate the role of ceramide produced by CerS2 and CerS4 for the purpose of inducing the hepatic IRes, we utilised a unique in vivo model employing shRNA-mediated hydrodynamic gene delivery (HGD) in the liver of HFD-fed C57BL/6J mice.
Results: Downregulation of CerS4 instead of CerS2 reduced specific liver ceramides, notably C18:0-Cer and C24:0-Cer, as well as acylcarnitine levels. It concurrently promoted glycogen accumulation, leading to enhanced insulin sensitivity and glucose homeostasis.
Conclusion: Those findings demonstrate that CerS4 downregulating lowers fasting blood glucose levels and mitigates the HFD-induced hepatic insulin resistance (IRes). It suggests that inhibiting the CerS4-mediated ceramide C18:0-Cer synthesis holds a promise to effectively address insulin resistance in obesity.
期刊介绍:
The mission of Endocrinology is to be the authoritative source of emerging hormone science and to disseminate that new knowledge to scientists, clinicians, and the public in a way that will enable "hormone science to health." Endocrinology welcomes the submission of original research investigating endocrine systems and diseases at all levels of biological organization, incorporating molecular mechanistic studies, such as hormone-receptor interactions, in all areas of endocrinology, as well as cross-disciplinary and integrative studies. The editors of Endocrinology encourage the submission of research in emerging areas not traditionally recognized as endocrinology or metabolism in addition to the following traditionally recognized fields: Adrenal; Bone Health and Osteoporosis; Cardiovascular Endocrinology; Diabetes; Endocrine-Disrupting Chemicals; Endocrine Neoplasia and Cancer; Growth; Neuroendocrinology; Nuclear Receptors and Their Ligands; Obesity; Reproductive Endocrinology; Signaling Pathways; and Thyroid.