2. Academic Validation
  3. SNRK modulates mTOR-autophagy pathway for liver lipid homeostasis in MAFLD

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

  • Mol Ther. 2025 Jan 8;33(1):279-296. doi: 10.1016/j.ymthe.2024.11.016.
Shan Lin 1,  Xiusheng Qiu 2,  Xiaoying Fu 1,  Shuting Zhang 1,  Changyong Tang 3,  Jian Kuang 4,  Haixia Guan 5,  Shuiqing Lai 6
Affiliations

Affiliations

  • 1 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.
  • 2 Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China.
  • 3 Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China.
  • 4 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. Electronic address: kuangjian@gdph.org.cn.
  • 5 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. Electronic address: guanhaixia@gdph.org.cn.
  • 6 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. Electronic address: laishuiqing@gdph.org.cn.
PMID: 39521960 DOI: 10.1016/j.ymthe.2024.11.016
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.

Keywords

AAV8.TBG-SNRK; autophagy; fatty acid oxidation; lipid homeostasis; metabolism-related fatty liver disease; sucrose non-fermenting-related kinase.

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