Autophagy regulates lipid metabolism through selective turnover of NCoR1

Tetsuya Saito, Akiko Kuma, Yuki Sugiura, Yoshinobu Ichimura, Miki Obata, Hiroshi Kitamura, Shujiro Okuda, Hyeon-Cheol Lee, Kazutaka Ikeda, Yumi Kanegae, Izumu Saito, Johan Auwerx, Hozumi Motohashi, Makoto Suematsu, Tomoyoshi Soga, Takehiko Yokomizo, Satoshi Waguri, Noboru Mizushima and Masaaki Komatsu ()
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Tetsuya Saito: Niigata University Graduate School of Medical and Dental Sciences
Akiko Kuma: The University of Tokyo
Yuki Sugiura: PRESTO
Yoshinobu Ichimura: Niigata University Graduate School of Medical and Dental Sciences
Miki Obata: Niigata University Graduate School of Medical and Dental Sciences
Hiroshi Kitamura: Tohoku University
Shujiro Okuda: Niigata University Graduate School of Medical and Dental Sciences
Hyeon-Cheol Lee: Juntendo University Graduate School of Medicine
Kazutaka Ikeda: RIKEN Center for Integrative Medical Sciences (IMS)
Yumi Kanegae: Jikei University School of Medicine
Izumu Saito: The University of Tokyo
Johan Auwerx: École Polytechnique Fédérale de Lausanne (EPFL)
Hozumi Motohashi: Tohoku University
Makoto Suematsu: Keio University School of Medicine
Tomoyoshi Soga: Keio University
Takehiko Yokomizo: Juntendo University Graduate School of Medicine
Satoshi Waguri: Fukushima Medical University School of Medicine
Noboru Mizushima: The University of Tokyo
Masaaki Komatsu: Niigata University Graduate School of Medical and Dental Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Selective autophagy ensures the removal of specific soluble proteins, protein aggregates, damaged mitochondria, and invasive bacteria from cells. Defective autophagy has been directly linked to metabolic disorders. However how selective autophagy regulates metabolism remains largely uncharacterized. Here we show that a deficiency in selective autophagy is associated with suppression of lipid oxidation. Hepatic loss of Atg7 or Atg5 significantly impairs the production of ketone bodies upon fasting, due to decreased expression of enzymes involved in β-oxidation following suppression of transactivation by PPARα. Mechanistically, nuclear receptor co-repressor 1 (NCoR1), which interacts with PPARα to suppress its transactivation, binds to the autophagosomal GABARAP family proteins and is degraded by autophagy. Consequently, loss of autophagy causes accumulation of NCoR1, suppressing PPARα activity and resulting in impaired lipid oxidation. These results suggest that autophagy contributes to PPARα activation upon fasting by promoting degradation of NCoR1 and thus regulates β-oxidation and ketone bodies production.

Date: 2019
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DOI: 10.1038/s41467-019-08829-3

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