Glycerol-3-phosphate acyltransferase, mitochondrial (GPAM) is a rate-limiting enzyme catalyzing triglyceride synthesis. Recently, we demonstrated that the anti-viral drug ribavirin (RBV) reduces GPAM expression by downregulating CCAAT/enhancer-binding protein α (C/EBPα). However, the precise mechanisms of GPAM suppression have remained unclear. Here, we found that RBV suppressed GPAM expression by downregulating not only C/EBPα, but also sterol regulatory element-binding protein-1c (SREBP-1c). We also found that cis-elements regulated by C/EBPα and SREBP-1c functioned as distal and proximal enhancers, respectively, to express hepatocyte- and adipocytes-specific GPAM variants. These results imply that RBV disrupts formation of the enhancer machineries on the GPAM genome by downregulating both transcription factors. Our findings may contribute to the development of treatments for fatty liver diseases caused by aberrant triglyceride synthesis.

甘油3-磷酸酰基转移酶线粒体（GPAM）是催化甘油三酸酯合成的限速酶。最近，我们证明了抗病毒药物利巴韦林（RBV）通过下调CCAAT /增强子结合蛋白α（C /EBPα）降低GPAM表达。但是，GPAM抑制的确切机制仍不清楚。在这里，我们发现RBV不仅通过下调C /EBPα，还通过下调固醇调节元件结合蛋白1c（SREBP-1c）来抑制GPAM表达。我们还发现，受C /EBPα和SREBP-1c调节的顺式元件分别充当远端和近端增强子，以表达肝细胞和脂肪细胞特异性GPAM变体。这些结果暗示RBV通过下调两个转录因子来破坏GPAM基因组上增强子机制的形成。我们的发现可能有助于开发由甘油三酸酯合成异常引起的脂肪肝疾病的治疗方法。