Kwon Yong Seong, Cho Ye Eun, Kim Yeonsoo, Koh Minseob, Hwang Seonghwan
College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea.
Department of Chemistry, Pusan National University, Busan 46241, Republic of Korea.
Curr Issues Mol Biol. 2024 Mar 13;46(3):2386-2397. doi: 10.3390/cimb46030151.
Dimethyloxalylglycine (DMOG) is a representative inhibitor of the prolyl hydroxylase domain (PHD), which mediates the degradation of hypoxia-inducible factor-1-alpha (HIF1A). DMOG exerts its pharmacological effects via the canonical pathway that involves PHD inhibition; however, it remains unclear whether DMOG affects lipogenic gene expression in hepatocytes. We aimed to elucidate the effects of DMOG on sterol regulatory element-binding protein-1c (SREBP1c), a master regulator of fatty acid synthesis in hepatocytes. DMOG treatment inhibited SREBP1c mRNA and protein expression in HepG2 and AML12 hepatocytes and reduced the transcript levels of SREBP1c-regulated lipogenic genes. A luciferase reporter assay revealed that DMOG inhibited the transcriptional activity of SREBP1c. Moreover, DMOG suppressed SREBP1c expression in mice liver. Mechanistically, treatment with DMOG enhanced the expression of HIF1A and insulin-induced gene 2 (INSIG2), which inhibits the activation of SREBP1c. However, or knockdown failed to reverse the inhibitory effect of DMOG on SREBP1c expression, suggesting a redundant role of HIF1A and INSIG2 in terms of repressing SREBP1c. DMOG did not function through the canonical pathway involving inhibition of SREBP1c by PHD, highlighting the presence of non-canonical pathways that mediate its anti-lipogenic effect.
二甲基草酰甘氨酸（DMOG）是脯氨酰羟化酶结构域（PHD）的代表性抑制剂，该酶介导缺氧诱导因子-1α（HIF1A）的降解。DMOG通过涉及PHD抑制的经典途径发挥其药理作用；然而，DMOG是否影响肝细胞中脂肪生成基因的表达仍不清楚。我们旨在阐明DMOG对固醇调节元件结合蛋白-1c（SREBP1c）的影响，SREBP1c是肝细胞中脂肪酸合成的主要调节因子。DMOG处理抑制了HepG2和AML12肝细胞中SREBP1c的mRNA和蛋白表达，并降低了SREBP1c调节的脂肪生成基因的转录水平。荧光素酶报告基因检测显示，DMOG抑制了SREBP1c的转录活性。此外，DMOG抑制了小鼠肝脏中SREBP1c的表达。从机制上讲，DMOG处理增强了HIF1A和胰岛素诱导基因2（INSIG2）的表达，而INSIG2抑制SREBP1c的激活。然而，HIF1A或INSIG2基因敲低未能逆转DMOG对SREBP1c表达的抑制作用，这表明HIF1A和INSIG2在抑制SREBP1c方面具有冗余作用。DMOG并非通过涉及PHD抑制SREBP1c的经典途径发挥作用，这突出了存在介导其抗脂肪生成作用的非经典途径。
