Journal Article

Autophagy regulates lipid metabolism through selective turnover of NCoR1

Soga, Tomoyoshi, Kitamura, Hiroshi, Okuda, Shujiro, Kuma, Akiko, Saito, Tetsuya, Obata, Miki, Kanegae, Yumi, Auwerx, Johan, Waguri, Satoshi, Saito, Izumu, Yokomizo, Takehiko, Ikeda, Kazutaka, Sugiura, Yuki, Mizushima, Noboru, Motohashi, Hozumi, Komatsu, Masaaki, Suematsu, Makoto, Ichimura, Yoshinobu, Lee, Hyeon-Cheol

2019

Overview

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. Defective autophagy has been associated with metabolic disorders. Here Saito et al. show that autophagy promotes the selective degradation of NCoR1, a repressor of lipid metabolism regulator PPARα, in response to starvation, and thus induces the expression of enzymes involved in lipid oxidation and the production of ketone bodies.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/51 / 13/95 / 14/19 / 14/28 / 38/15 / 38/89 / 631/45 / 631/80 / 64/60 / 82/58 / Animals / Autophagy / Autophagy-Related Protein 5 - genetics / Autophagy-Related Protein 5 - metabolism / Autophagy-Related Protein 5 - physiology / Autophagy-Related Protein 7 - genetics / Autophagy-Related Protein 7 - metabolism / Autophagy-Related Protein 7 - physiology / Biodegradation / Fasting / GABARAP protein / Humanities and Social Sciences / Ketone Bodies - metabolism / Ketones / Lipid Metabolism / Lipid peroxidation / Lipids / Liver - metabolism / Metabolic disorders / Metabolism / Mice / Mitochondria / multidisciplinary / Nuclear Receptor Co-Repressor 1 - metabolism / Nuclear Receptor Co-Repressor 1 - physiology / Oxidation / Oxidation-Reduction / Phagocytosis / PPAR alpha / Proteins / Science / Science (multidisciplinary)