Ketogenic diet alleviates renal fibrosis in mice by enhancing fatty acid oxidation through the free fatty acid receptor 3 pathway

被引:8
作者
Qiu, Yang [1 ]
Hu, Xiaofan [1 ]
Xu, Cong [1 ]
Lu, Chenqi [1 ]
Cao, Rui [1 ]
Xie, Yanan [1 ]
Yang, Jun [1 ]
机构
[1] Chinese Acad Med Sci, Inst Organ Transplantat, Tongji Hosp, Tongji Med Coll,Huazhong Univ Sci & Technol,Key La, Wuhan, Peoples R China
基金
中国国家自然科学基金;
关键词
ketogenic diet; renal fibrosis; beta-hydroxybutyrate; fatty acid oxidation; free fatty acid receptor 3; BETA-HYDROXYBUTYRATE; KIDNEY-DISEASE; MECHANISMS; AMPK; INFLAMMATION; METABOLITE; INJURY; CELLS;
D O I
10.3389/fnut.2023.1127845
中图分类号
R15 [营养卫生、食品卫生]; TS201 [基础科学];
学科分类号
100403 ;
摘要
Introduction: The ketogenic diet (KD), as a dietary intervention, has gained importance in the treatment of solid organ structural remodeling, but its role in renal fibrosis has not been explored. Methods: Male C57BL/6 mice were fed a normal diet or a KD for 6 weeks prior to unilateral ureteral obstruction (UUO), a well-established in vivo model of renal fibrosis in rodents. Seven days after UUO, serum and kidney samples were collected. Serum beta-hydroxybutyrate (beta-OHB) concentrations and renal fibrosis were assessed. NRK52E cells were treated with TGF beta 1, a fibrosis-inducing cytokine, and with or without beta-OHB, a ketone body metabolized by KD, to investigate the mechanism underlying renal fibrosis. Results: KD significantly enhanced serum beta-OHB levels in mice. Histological analysis revealed that KD alleviated structural destruction and fibrosis in obstructed kidneys and reduced the expression of the fibrosis protein markers alpha-SMA, Col1a1, and Col3a1. Expression of the rate-limiting enzymes involved in fatty acid oxidation (FAO), Cpt1a and Acox1, significantly decreased after UUO and were upregulated by KD. However, the protective e ect of KD was abolished by etomoxir (a Cpt1a inhibitor). Besides, our study observed that KD significantly suppressedUUO-inducedmacrophage infiltration and the expression of IL-6 in the obstructive kidneys. In NRK52E cells, fibrosis-related signaling was increased by TGFb1 and reduced by beta-OHB. beta-OHB treatment restored the impaired expression of Cpt1a. The e ect of beta-OHB was blocked by siRNA targeting free fatty acid receptor 3 (FFAR3), suggesting that beta-OHB might function through the FFAR3-dependent pathway. Discussion: Our results highlight that KD attenuates UUO-induced renal fibrosis by enhancing FAO via the FFAR3-dependent pathway, which provides a promising dietary therapy for renal fibrosis.
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页数:13
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