2. Academic Validation
  3. Peroxisomal β-oxidation acts as a sensor for intracellular fatty acids and regulates lipolysis

Peroxisomal β-oxidation acts as a sensor for intracellular fatty acids and regulates lipolysis

  • Nat Metab. 2021 Dec;3(12):1648-1661. doi: 10.1038/s42255-021-00489-2.
Lianggong Ding 1,  Wenfei Sun 1,  Miroslav Balaz 1 2 3,  Anyuan He 4 5,  Manuel Klug 1,  Stefan Wieland 6,  Robert Caiazzo 7,  Violeta Raverdy 7,  Francois Pattou 7,  Philippe Lefebvre 8,  Irfan J Lodhi 4,  Bart Staels 8,  Markus Heim 6 9,  Christian Wolfrum 10
Affiliations

Affiliations

  • 1 Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland.
  • 2 Institute of Experimental Endocrinology, Biomedical Research Center at the Slovak Academy of Sciences, Bratislava, Slovakia.
  • 3 Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia.
  • 4 Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • 5 School of Life Sciences, Anhui Medical University, Hefei, China.
  • 6 Hepatology, Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland.
  • 7 University Lille, CHU Lille, Institut Pasteur Lille, Inserm, UMR1190 Translational Research in Diabetes, Lille, France.
  • 8 University Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.
  • 9 Division of Gastroenterology and Hepatology, Clarunis, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland.
  • 10 Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland. christian-wolfrum@ethz.ch.
PMID: 34903883 DOI: 10.1038/s42255-021-00489-2
Abstract

To liberate fatty acids (FAs) from intracellular stores, lipolysis is regulated by the activity of the lipases adipose triglyceride Lipase (ATGL), hormone-sensitive Lipase and monoacylglycerol Lipase. Excessive FA release as a result of uncontrolled lipolysis results in lipotoxicity, which can in turn promote the progression of metabolic disorders. However, whether cells can directly sense FAs to maintain cellular lipid homeostasis is unknown. Here we report a sensing mechanism for cellular FAs based on peroxisomal degradation of FAs and coupled with Reactive Oxygen Species (ROS) production, which in turn regulates FA release by modulating lipolysis. Changes in ROS levels are sensed by PEX2, which modulates ATGL levels through post-translational ubiquitination. We demonstrate the importance of this pathway for non-alcoholic fatty liver disease progression using genetic and pharmacological approaches to alter ROS levels in vivo, which can be utilized to increase hepatic ATGL levels and ameliorate hepatic steatosis. The discovery of this peroxisomal β-oxidation-mediated feedback mechanism, which is conserved in multiple organs, couples the functions of peroxisomes and lipid droplets and might serve as a new way to manipulate lipolysis to treat metabolic disorders.

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