CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Key Laboratory of Biotechnology of Antibiotics, The National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Int J Mol Sci. 2024 May 7;25(10):5086. doi: 10.3390/ijms25105086.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades of target exploration and hundreds of clinical trials have failed, highlighting the urgent need to find new druggable targets for the discovery of innovative drug candidates against MASLD. Here, we found that glutathione S-transferase alpha 1 (GSTA1) expression was negatively associated with lipid droplet accumulation and . Overexpression of GSTA1 significantly attenuated oleic acid-induced steatosis in hepatocytes or high-fat diet-induced steatosis in the mouse liver. The hepatoprotective and anti-inflammatory drug bicyclol also attenuated steatosis by upregulating GSTA1 expression. A detailed mechanism showed that GSTA1 directly interacts with fatty acid binding protein 1 (FABP1) and facilitates the degradation of FABP1, thereby inhibiting intracellular triglyceride synthesis by impeding the uptake and transportation of free fatty acids. Conclusion: GSTA1 may be a good target for the discovery of innovative drug candidates as GSTA1 stabilizers or enhancers against MASLD.
代谢相关脂肪性肝病（MASLD）是最常见的肝脏代谢疾病，其特征是 5%以上的肝细胞发生脂肪变性。然而，尽管最近批准了第一种用于治疗代谢相关脂肪性肝炎的药物雷西莫特，几十年来的靶点探索和数百项临床试验都以失败告终，这突显了迫切需要寻找新的可成药靶点，以发现针对 MASLD 的创新药物候选物。在这里，我们发现谷胱甘肽 S-转移酶 alpha 1（GSTA1）的表达与脂滴积累呈负相关。GSTA1 的过表达显著减轻了油酸诱导的肝细胞脂肪变性或高脂肪饮食诱导的小鼠肝脏脂肪变性。保肝抗炎药双环醇也通过上调 GSTA1 的表达来减轻脂肪变性。详细的机制表明，GSTA1 与脂肪酸结合蛋白 1（FABP1）直接相互作用，并促进 FABP1 的降解，从而通过阻碍游离脂肪酸的摄取和转运来抑制细胞内甘油三酯的合成。结论：GSTA1 可能是发现针对 MASLD 的创新药物候选物的一个很好的靶点，可作为 GSTA1 稳定剂或增强剂。
