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Loss of autophagy impairs physiological steatosis by accumulation of NCoR1.

ABSTRACT: Lipid droplets (LDs) are dynamic organelles that store neutral lipids during times of energy excess, such as after a meal. LDs serve as an energy reservoir during fasting and have a buffering capacity that prevents lipotoxicity. Autophagy and the autophagic machinery have been proposed to play a role in LD biogenesis, but the underlying molecular mechanism remains unclear. Here, we show that when nuclear receptor co-repressor 1 (NCoR1), which inhibits the transactivation of nuclear receptors, accumulates because of autophagy suppression, LDs decrease in size and number. Ablation of ATG7, a gene essential for autophagy, suppressed the expression of gene targets of liver X receptor ?, a nuclear receptor responsible for fatty acid and triglyceride synthesis in an NCoR1-dependent manner. LD accumulation in response to fasting and after hepatectomy was hampered by the suppression of autophagy. These results suggest that autophagy controls physiological hepatosteatosis by fine-tuning NCoR1 protein levels.

SUBMITTER: Takahashi SS

PROVIDER: S-EPMC6932742 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Loss of autophagy impairs physiological steatosis by accumulation of NCoR1.

Takahashi Shun-Saku SS Sou Yu-Shin YS Saito Tetsuya T Kuma Akiko A Yabe Takayuki T Sugiura Yuki Y Lee Hyeon-Cheol HC Suematsu Makoto M Yokomizo Takehiko T Koike Masato M Terai Shuji S Mizushima Noboru N Waguri Satoshi S Komatsu Masaaki M

Life science alliance 20191226 1

Lipid droplets (LDs) are dynamic organelles that store neutral lipids during times of energy excess, such as after a meal. LDs serve as an energy reservoir during fasting and have a buffering capacity that prevents lipotoxicity. Autophagy and the autophagic machinery have been proposed to play a role in LD biogenesis, but the underlying molecular mechanism remains unclear. Here, we show that when nuclear receptor co-repressor 1 (NCoR1), which inhibits the transactivation of nuclear receptors, ac ...[more]

PMID: 31879337

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Project description:Macroautophagy (or autophagy) is a conserved cellular process in which cytoplasmic cargo is targeted for lysosomal degradation. Autophagy is crucial for the functional integrity of different subsets of T cells in various developmental stages. Since atherosclerosis is an inflammatory disease of the vessel wall which is partly characterized by T cell mediated autoimmunity, we investigated how advanced atherosclerotic lesions develop in mice with T cells that lack autophagy-related protein 7 (Atg7), a protein required for functional autophagy. Mice with a T cell-specific knock-out of Atg7 (Lck-Cre Atg7f/f) had a diminished naïve CD4+ and CD8+ T cell compartment in the spleen and mediastinal lymph node as compared to littermate controls (Atg7f/f). Lck-Cre Atg7f/f and Atg7f/f mice were injected intravenously with rAAV2/8-D377Y-mPCSK9 and fed a Western-type diet to induce atherosclerosis. While Lck-Cre Atg7f/f mice had equal serum Proprotein Convertase Subtilisin/Kexin type 9 levels as compared to Atg7f/f mice, serum cholesterol levels were significantly diminished in Lck-Cre Atg7f/f mice. Histological analysis of the liver revealed less steatosis, and liver gene expression profiling showed decreased expression of genes associated with hepatic steatosis in Lck-Cre Atg7f/f mice as compared to Atg7f/f mice. The level of hepatic CD4+ and CD8+ T cells was greatly diminished but both CD4+ and CD8+ T cells showed a relative increase in their IFN? and IL-17 production upon Atg7 deficiency. Atg7 deficiency furthermore reduced the hepatic NKT cell population which was decreased to < 0.1% of the lymphocyte population. Interestingly, T cell-specific knock-out of Atg7 decreased the mean atherosclerotic lesion size in the tri-valve area by over 50%. Taken together, T cell-specific deficiency of Atg7 resulted in a decrease in hepatic steatosis and limited inflammatory potency in the (naïve) T cell compartment in peripheral lymphoid tissues, which was associated with a strong reduction in experimental atherosclerosis.

Dataset Information

Loss of autophagy impairs physiological steatosis by accumulation of NCoR1.

Publications

Loss of autophagy impairs physiological steatosis by accumulation of NCoR1.

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