期刊
MOLECULAR METABOLISM
卷 30, 期 -, 页码 221-229出版社
ELSEVIER
DOI: 10.1016/j.molmet.2019.09.007
关键词
FXR; FGF21; Bile acids; Liver; Metabolism; Fasting; Gluconeogenesis; Diabetes; Steroidogenesis; Cyp17a1
资金
- Proteins at Work program of The Netherlands Organization for Scientific Research (NWO) [184.032.201]
- Wellcome Trust [P30874]
- NIHR
- Netherlands Organization for Scientific Research (NWO) Project VIDI [917.11.365]
- FP7 Marie Curie Actions IAPP (FXR-IBD) [611979]
- Sir Henry Dale Fellowship - Wellcome Trust [105545/Z/14/Z]
- Sir Henry Dale Fellowship - Royal Society [105545/Z/14/Z]
- NIHR at Imperial College Healthcare NHS Trust
- MRC
- BBSRC
- Integrative Mammalian Biology (IMB) Capacity Building Award
- EuroCHIP grant [FP7-HEALTH-2009-241592]
- NIHR Biomedical Research Centre Funding Scheme
- Rutherford Fund Fellowship
- MRC [MC_UP_1102/3, MC_UP_1102/18, MC_EX_MR/S300008/1] Funding Source: UKRI
- Wellcome Trust [105545/Z/14/Z] Funding Source: Wellcome Trust
Objective: Coupling metabolic and reproductive pathways is essential for the survival of species. However, the functions of steroidogenic enzymes expressed in metabolic tissues are largely unknown. Methods and results: Here, we show that in the liver, the classical steroidogenic enzyme Cyp17a1 forms an essential nexus for glucose and ketone metabolism during feed-fast cycles. Both gain- and loss-of-function approaches are used to show that hepatic Cyp17a1 is induced by fasting, catalyzes the production of at least one hormone-ligand (DHEA) for the nuclear receptor PPAR alpha, and is ultimately required for maintaining euglycemia and ketogenesis during nutrient deprivation. The feedback-loop that terminates Cyp17a1-PPAR alpha activity, and re-establishes anabolic liver metabolism during re-feeding is mapped to postprandial bile acid-signaling, involving the receptors FXR, SHP and LRH-1. Conclusions: Together, these findings represent a novel paradigm of homeostatic control in which nutritional cues feed-forward on to metabolic pathways by influencing extragonadal steroidogenesis. (C) 2019 The Authors. Published by Elsevier GmbH.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据