SNRK modulates mTOR-autophagy pathway for liver lipid homeostasis in MAFLD.

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Shan Lin, Xiusheng Qiu, Xiaoying Fu, Shuting Zhang, Changyong Tang, Jian Kuang, Haixia Guan, Shuiqing Lai
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引用次数: 0

Abstract

Metabolism-related fatty liver disease (MAFLD) is associated with abnormal fat accumulation in the liver. The exact mechanism underlying the occurrence and development of MAFLD remains to be elucidated. Here, we discovered that the expression of sucrose non-fermenting-related kinase (SNRK) is elevated in the liver of the MAFLD population. Mice deficient in SNRK exhibited damage to fatty acid oxidation and persistent accumulation of lipids in the liver. Pharmacological inhibition of the mTOR pathway in SNRK-deficient mice restored autophagy and improved lipid accumulation. In terms of mechanism, we observed that SNRK binds to the raptor component of mTOR complex 1, promoting fatty acid oxidation in the liver by activating autophagy. Overexpression of SNRK in high-fat diet-induced obese mice restored autophagy and ameliorated lipid accumulation. Notably, we also demonstrated that overexpression of SNRK significantly enhanced fatty acid oxidation in the mouse liver. We further confirmed that SNRK is essential for the liver to regulate autophagy and fatty acid oxidation. These findings underscore the importance of the potential of SNRK in the treatment of MAFLD.

SNRK调节mTOR-自噬通路,促进MAFLD患者的肝脂稳态。
代谢相关性脂肪肝(MAFLD)与肝脏中异常的脂肪堆积有关。MAFLD发生和发展的确切机制仍有待阐明。在这里,我们发现蔗糖不发酵相关激酶(SNRK)在 MAFLD 患者的肝脏中表达升高。缺乏 SNRK 的小鼠表现出脂肪酸氧化损伤和肝脏中脂质的持续积累。在 SNRK 缺乏的小鼠中,对 mTOR 通路的药理抑制可恢复自噬并改善脂质积累。在机制方面,我们观察到 SNRK 与 mTOR 复合物 1 的猛禽成分结合,通过激活自噬促进肝脏中的脂肪酸氧化。在高脂饮食诱导的肥胖小鼠体内过量表达 SNRK 可恢复自噬,改善脂质积累。值得注意的是,我们还证明过表达 SNRK 能显著增强小鼠肝脏中的脂肪酸氧化。我们进一步证实,SNRK 对肝脏调节自噬和脂肪酸氧化至关重要。这些发现凸显了 SNRK 在治疗 MAFLD 方面潜力的重要性。
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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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