High-Fat Diet–Induced Lysosomal Dysfunction and Impaired Autophagic Flux Contribute to Lipotoxicity in the Kidney
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- Takeshi Yamamoto
- Departments of *Nephrology and
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- Yoshitsugu Takabatake
- Departments of *Nephrology and
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- Atsushi Takahashi
- Departments of *Nephrology and
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- Tomonori Kimura
- Departments of *Nephrology and
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- Tomoko Namba
- Departments of *Nephrology and
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- Jun Matsuda
- Departments of *Nephrology and
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- Satoshi Minami
- Departments of *Nephrology and
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- Jun-ya Kaimori
- Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan;
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- Isao Matsui
- Departments of *Nephrology and
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- Taiji Matsusaka
- Institute of Medical Sciences and Department of Molecular Life Sciences and
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- Fumio Niimura
- Department of Pediatrics, Tokai University School of Medicine, Isehara, Kanagawa, Japan; and
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- Motoko Yanagita
- Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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- Yoshitaka Isaka
- Departments of *Nephrology and
書誌事項
- 公開日
- 2016-12-08
- 資源種別
- journal article
- DOI
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- 10.1681/asn.2016070731
- 公開者
- Ovid Technologies (Wolters Kluwer Health)
この論文をさがす
説明
<jats:p>Excessive fat intake contributes to the progression of metabolic diseases <jats:italic toggle="yes">via</jats:italic> cellular injury and inflammation, a process termed lipotoxicity. Here, we investigated the role of lysosomal dysfunction and impaired autophagic flux in the pathogenesis of lipotoxicity in the kidney. In mice, a high-fat diet (HFD) resulted in an accumulation of phospholipids in enlarged lysosomes within kidney proximal tubular cells (PTCs). In isolated PTCs treated with palmitic acid, autophagic degradation activity progressively stagnated in association with impaired lysosomal acidification and excessive lipid accumulation. Pulse-chase experiments revealed that the accumulated lipids originated from cellular membranes. In mice with induced PTC-specific ablation of autophagy, PTCs of HFD-mice exhibited greater accumulation of ubiquitin-positive protein aggregates normally removed by autophagy than did PTCs of mice fed a normal diet. Furthermore, HFD-mice had no capacity to augment autophagic activity upon another pathologic stress. Autophagy ablation also exaggerated HFD-induced mitochondrial dysfunction and inflammasome activation. Moreover, renal ischemia-reperfusion induced greater injury in HFD-mice than in mice fed a normal diet, and ablation of autophagy further exacerbated this effect. Finally, we detected similarly enhanced phospholipid accumulation in enlarged lysosomes and impaired autophagic flux in the kidneys of obese patients compared with nonobese patients. These findings provide key insights regarding the pathophysiology of lipotoxicity in the kidney and clues to a novel treatment for obesity-related kidney diseases.</jats:p>
収録刊行物
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- Journal of the American Society of Nephrology
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Journal of the American Society of Nephrology 28 (5), 1534-1551, 2016-12-08
Ovid Technologies (Wolters Kluwer Health)
