Lin Shan, Qiu Xiusheng, Fu Xiaoying, Zhang Shuting, Tang Changyong, Kuang Jian, Guan Haixia, Lai Shuiqing
Department of Endocrinology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan Er Road, Guangzhou 510080, Guangdong Province, China.
Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China.
Mol Ther. 2025 Jan 8;33(1):279-296. doi: 10.1016/j.ymthe.2024.11.016. Epub 2024 Nov 9.
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.
代谢相关脂肪性肝病（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。在此，我们发现蔗糖非发酵相关激酶（SNRK）在MAFLD人群的肝脏中表达升高。缺乏SNRK的小鼠表现出脂肪酸氧化受损以及肝脏中脂质的持续积累。对SNRK缺陷小鼠的mTOR通路进行药理学抑制可恢复自噬并改善脂质堆积。在机制方面，我们观察到SNRK与mTOR复合物1的raptor组分结合，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中过表达SNRK可恢复自噬并改善脂质堆积。值得注意的是，我们还证明了SNRK的过表达显著增强了小鼠肝脏中的脂肪酸氧化。我们进一步证实SNRK对于肝脏调节自噬和脂肪酸氧化至关重要。这些发现强调了SNRK在治疗MAFLD方面潜力的重要性。
