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Glucose controls lipolysis through Golgi PtdIns4P-mediated regulation of ATGL.
Ding, Lianggong; Huwyler, Florian; Long, Fen; Yang, Wu; Binz, Jonas; Wernlé, Kendra; Pfister, Matthias; Klug, Manuel; Balaz, Miroslav; Ukropcova, Barbara; Ukropec, Jozef; Wu, Chunyan; Wang, Tongtong; Gao, Min; Clavien, Pierre-Alain; Dutkowski, Philipp; Tibbitt, Mark W; Wolfrum, Christian.
Afiliación
  • Ding L; Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland.
  • Huwyler F; Macromolecular Engineering Laboratory, Institute of Energy and Process Engineering, ETH Zürich, Zurich, Switzerland.
  • Long F; Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland.
  • Yang W; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • Binz J; Macromolecular Engineering Laboratory, Institute of Energy and Process Engineering, ETH Zürich, Zurich, Switzerland.
  • Wernlé K; Department of Surgery and Transplantation, University of Zurich, Zurich, Switzerland.
  • Pfister M; Wyss Zurich Translational Center, ETH Zurich and University of Zurich, Zurich, Switzerland.
  • Klug M; Department of Surgery and Transplantation, University of Zurich, Zurich, Switzerland.
  • Balaz M; Wyss Zurich Translational Center, ETH Zurich and University of Zurich, Zurich, Switzerland.
  • Ukropcova B; Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland.
  • Ukropec J; Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
  • Wu C; Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
  • Wang T; Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
  • Gao M; Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland.
  • Clavien PA; Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland.
  • Dutkowski P; Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland.
  • Tibbitt MW; Department of Pharmacy, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • Wolfrum C; Department of Surgery and Transplantation, University of Zurich, Zurich, Switzerland.
Nat Cell Biol ; 26(4): 552-566, 2024 Apr.
Article en En | MEDLINE | ID: mdl-38561547
ABSTRACT
Metabolic crosstalk of the major nutrients glucose, amino acids and fatty acids (FAs) ensures systemic metabolic homeostasis. The coordination between the supply of glucose and FAs to meet various physiological demands is especially important as improper nutrient levels lead to metabolic disorders, such as diabetes and metabolic dysfunction-associated steatohepatitis (MASH). In response to the oscillations in blood glucose levels, lipolysis is thought to be mainly regulated hormonally to control FA liberation from lipid droplets by insulin, catecholamine and glucagon. However, whether general cell-intrinsic mechanisms exist to directly modulate lipolysis via glucose sensing remains largely unknown. Here we report the identification of such an intrinsic mechanism, which involves Golgi PtdIns4P-mediated regulation of adipose triglyceride lipase (ATGL)-driven lipolysis via intracellular glucose sensing. Mechanistically, depletion of intracellular glucose results in lower Golgi PtdIns4P levels, and thus reduced assembly of the E3 ligase complex CUL7FBXW8 in the Golgi apparatus. Decreased levels of the E3 ligase complex lead to reduced polyubiquitylation of ATGL in the Golgi and enhancement of ATGL-driven lipolysis. This cell-intrinsic mechanism regulates both the pool of intracellular FAs and their extracellular release to meet physiological demands during fasting and glucose deprivation. Moreover, genetic and pharmacological manipulation of the Golgi PtdIns4P-CUL7FBXW8-ATGL axis in mouse models of simple hepatic steatosis and MASH, as well as during ex vivo perfusion of a human steatotic liver graft leads to the amelioration of steatosis, suggesting that this pathway might be a promising target for metabolic dysfunction-associated steatotic liver disease and possibly MASH.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Glucemia / Fosfatos de Fosfatidilinositol / Lipólisis Límite: Animals / Humans Idioma: En Revista: Nat Cell Biol Año: 2024 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Glucemia / Fosfatos de Fosfatidilinositol / Lipólisis Límite: Animals / Humans Idioma: En Revista: Nat Cell Biol Año: 2024 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Reino Unido