Zhang Xiaojuan, Liu Yao, Liu Weiwei, Shen Yuhu, Cao Fangqi, Deng Yunxia, Cao Zhangjun, Huang Zhiwei
College of Biological Science and Medical Engineering, Donghua University, Shanghai, China.
Key Laboratory of Adaptation and Evolution of Plateau Biota, Qinghai Provincial Key Laboratory of Crop Molecular Breeding, Northwest Institute of Plateau Biology, Innovation Academy for Seed Design, Chinese Academy of Sciences, Xining, China.
J Basic Microbiol. 2025 May;65(5):e70005. doi: 10.1002/jobm.70005. Epub 2025 Feb 18.
Gemfibrozil (GEM) is a phenoxy aromatic acid-based lipid-lowering drug. It activates peroxisome proliferator-activated receptor alpha (PPAR-α), which leads to altered lipid metabolism and lowers serum triglyceride levels by modulating lipoprotein lipase. However, the action of the mode of GEM is still unclear. Herein, the model organism Saccharomyces cerevisiae was applied to explore the molecular mechanism of GEM regulating lipid metabolism. The results showed that the triacylglycerol (TAG) content and the number of lipid droplets of yeast increased significantly after GEM treatment in the wild-type BY4741. Screening of mutations related to lipid metabolism pathways (PAH1, DGK1, TGL3, TGL4, LRO1, ARE1, ARE2, and DGA1) showed that dgk1Δ had no change in lipid accumulation under GEM. In the wild type, GEM inhibited the expression of DGK1, resulting in a significant decrease in the contents of phospholipids (phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS)) and neutral lipids (TAG and diacylglycerol (DAG)). However, their abundances could not be changed in dgk1Δ after the treatment with GEM Luciferase assay further showed that DGK1 may be a target of GEM to induce lipid accumulation via TUP1/CYC8, which could act on the DGK1 promoter-TATA highly conserved element (-400 bp - 200 bp). Altogether, the effect of GEM on lipid metabolism was associated with the upregulation of TUP1/CYC8, leading to a decrease in the expression of DGK1, thereby increasing the TAG content in yeast cells. It is expected that the data will help to clarify the molecular mechanism of GEM regulating lipid metabolism in humans.
吉非贝齐（GEM）是一种基于苯氧芳酸的降脂药物。它激活过氧化物酶体增殖物激活受体α（PPAR-α），这会导致脂质代谢改变，并通过调节脂蛋白脂肪酶降低血清甘油三酯水平。然而，GEM的作用模式仍不清楚。在此，应用模式生物酿酒酵母来探索GEM调节脂质代谢的分子机制。结果表明，在野生型BY4741中，GEM处理后酵母的三酰甘油（TAG）含量和脂滴数量显著增加。对与脂质代谢途径相关的突变（PAH1、DGK1、TGL3、TGL4、LRO1、ARE1、ARE2和DGA1）进行筛选，结果显示在GEM处理下，dgk1Δ的脂质积累没有变化。在野生型中，GEM抑制DGK1的表达，导致磷脂（磷脂酰胆碱（PC）、磷脂酰乙醇胺（PE）和磷脂酰丝氨酸（PS））和中性脂质（TAG和二酰甘油（DAG））的含量显著降低。然而，用GEM处理后，dgk1Δ中的这些物质丰度没有变化。荧光素酶测定进一步表明，DGK1可能是GEM通过TUP1/CYC8诱导脂质积累的靶点，TUP1/CYC8可作用于DGK1启动子-TATA高度保守元件（-400 bp - 200 bp）。总之，GEM对脂质代谢的影响与TUP1/CYC8的上调有关，导致DGK1表达降低，从而增加酵母细胞中的TAG含量。预计这些数据将有助于阐明GEM在人体内调节脂质代谢的分子机制。
