دورية أكاديمية
Autophagy mediates hepatic GRK2 degradation to facilitate glucagon-induced metabolic adaptation to fasting
| العنوان: | Autophagy mediates hepatic GRK2 degradation to facilitate glucagon-induced metabolic adaptation to fasting |
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| المؤلفون: | Cruces-Sande, Marta, Arcones, Alba C., Vila-Bedmar, Rocío, Val-Blasco, Almudena, Sharabi, Kfir, Díaz-Rodríguez, Daniel, Puigserver, Pere, Mayor Méndez, Federico Jr., Murga, Cristina |
| المساهمون: | Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Cardiovaculares (España), Instituto de Salud Carlos III, European Foundation for the Study of Diabetes, Novo Nordisk, Comunidad de Madrid, Fundación Ramón Areces, Banco Santander |
| بيانات النشر: | Federation of American Societies for Experimental Biology |
| سنة النشر: | 2019 |
| المجموعة: | Digital.CSIC (Consejo Superior de Investigaciones Científicas / Spanish National Research Council) |
| مصطلحات موضوعية: | Autophagy, Calorie restriction, Fasting, Glucagon signaling, Gluconeogenesis, GPCR, GRK2, Intermittent fasting |
| الوصف: | The liver plays a key role during fasting to maintain energy homeostasis and euglycemia via metabolic processes mainly orchestrated by the insulin/glucagon ratio. We report here that fasting or calorie restriction protocols in C57BL6 mice promote a marked decrease in the hepatic protein levels of G protein-coupled receptor kinase 2 (GRK2), an important negative modulator of both G protein-coupled receptors (GPCRs) and insulin signaling. Such downregulation of GRK2 levels is liver-specific and can be rapidly reversed by refeeding. We find that autophagy, and not the proteasome, represents the main mechanism implicated in fasting-induced GRK2 degradation in the liver in vivo. Reducing GRK2 levels in murine primary hepatocytes facilitates glucagon-induced glucose production and enhances the expression of the key gluconeogenic enzyme Pck1. Conversely, preventing full downregulation of hepatic GRK2 during fasting using adenovirus-driven overexpression of this kinase in the liver leads to glycogen accumulation, decreased glycemia, and hampered glucagon-induced gluconeogenesis, thus preventing a proper and complete adaptation to nutrient deprivation. Overall, our data indicate that physiological fasting-induced downregulation of GRK2 in the liver is key for allowing complete glucagon-mediated responses and efficient metabolic adaptation to fasting in vivo. ; Ministerio de Economia y Competitividad (MINECO/FEDER), Spain (grant SAF2017-84125-R to F.M. and C. M.); CIBER de Enfermedades Cardiovasculares (CIBERCV). Instituto de Salud Carlos III, Spain (grant CB16/11/00278 to FM, co-funded with European FEDER contribution); European Foundation for the Study of Diabetes (EFSD) Novo Nordisk Partnership for Diabetes Research in Europe Grant (to FM); NIH R01 DK089883 grant to P.P. and Programa de Actividades en Biomedicina de la Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE to F.M and CBMSO from Fundacion Ramon Areces and Fundacion Banco de Santander |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| تدمد: | 1530-6860 |
| العلاقة: | Publisher's version; http://dx.doi.org/10.1096/fj.201901444RTest; Sí; FASEB Journal 34: 399- 409 (2020); http://hdl.handle.net/10261/241169Test; http://dx.doi.org/10.13039/501100001648Test; http://dx.doi.org/10.13039/100008054Test; http://dx.doi.org/10.13039/501100004587Test; http://dx.doi.org/10.13039/501100003329Test; http://dx.doi.org/10.13039/100010784Test; http://dx.doi.org/10.13039/100012818Test |
| DOI: | 10.1096/fj.201901444R |
| DOI: | 10.13039/501100001648 |
| DOI: | 10.13039/100008054 |
| DOI: | 10.13039/501100004587 |
| DOI: | 10.13039/501100003329 |
| DOI: | 10.13039/100010784 |
| DOI: | 10.13039/100012818 |
| الإتاحة: | https://doi.org/10.1096/fj.201901444RTest https://doi.org/10.13039/501100001648Test https://doi.org/10.13039/100008054Test https://doi.org/10.13039/501100004587Test https://doi.org/10.13039/501100003329Test https://doi.org/10.13039/100010784Test https://doi.org/10.13039/100012818Test http://hdl.handle.net/10261/241169Test |
| حقوق: | open |
| رقم الانضمام: | edsbas.FDC8A965 |
| قاعدة البيانات: | BASE |
| تدمد: | 15306860 |
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| DOI: | 10.1096/fj.201901444R |