Ribavirin-induced down-regulation of CCAAT/enhancer-binding protein α leads to suppression of lipogenesis

Abstract

Recently, we demonstrated that the anti-viral drug ribavirin (RBV) had the ability to suppress lipogenesis through down-regulation of retinoid X receptor α (RXRα) under the control of the intracellular GTP-level and AMP-activated protein kinase-related kinases, especially microtubule affinity regulating kinase 4 (MARK4). RXRα-overexpression attenuated but did not abolish lipogenesis suppression by RBV, implying that additional factor(s) were involved in this suppressive effect. In the present study, we found that the protein level, but not the mRNA level, of CCAAT/enhancer-binding protein α (C/EBPα) was down-regulated by RBV in hepatic cells. Treatment with proteasome inhibitor attenuated RBV-induced down-regulation of C/EBPα, suggesting that RBV promoted degradation of C/EBPα protein via the ubiquitin–proteasome pathway. Depletion of intracellular GTP through inosine monophosphate dehydrogenase inhibition by RBV led to down-regulation of C/EBPα. In contrast, down-regulation of C/EBPα by RBV was independent of RXRα and MARK4. Knockdown of C/EBPα reduced the intracellular neutral lipid levels and the expression of genes related to the triglyceride (TG) synthesis pathway, especially glycerol-3-phosphate acyltransferase, mitochondrial (GPAM), which encodes the first rate-limiting TG enzyme. Overexpression of C/EBPα yielded the opposite results. We also observed that RBV decreased GPAM expression. Moreover, overexpression of GPAM attenuated RBV-induced reduction in the intracellular neutral lipid levels. These data suggest that down-regulation of C/EBPα by RBV leads to the reduction in GPAM expression, which contributes to the suppression of lipogenesis. Our findings about the mechanism of RBV action in lipogenesis suppression will provide new insights for therapy against the active lipogenesis involved in hepatic steatosis and hepatocellular carcinomas.

LINC00673 is activated by YY1 and promotes the proliferation of breast cancer cells via the miR-515-5p/MARK4/Hippo signaling pathway

“…Here, we used RNA-seq to identify the regulatory networks of mRNAs and noncoding RNAs in breast cancer. Among the results from the analysis of potential mRNA interactions, MARK4 sparked our interest since it is associated with tumorigenesis [49,50]. Previous studies showed that MARK4 attenuates the proliferation and migration of MDA-MB-231 cells via the Hippo signaling pathway [39].…”

Inhibition of Estrogen-Related Receptor α Blocks Liver Steatosis and Steatohepatitis and Attenuates Triglyceride Biosynthesis

“…To address the mechanisms by which ERRa regulates the expression of these genes involved in glycerolipid synthesis, the role of C/EBPb was explored, as GPAT1, DGAT1, and DGAT2 are transcriptional targets of C/EBPb. 38,39 Consistent with a positive regulatory role of C/EBPb on the transcription of GPAT1 and DGAT2, expression of exogenous C/EBPb in Huh7 cells led to their induction compared with the untreated vector controls (Figure 6A). Although inhibiting ERRa with ERR-PA reduces the expression of GPAT1 and DGAT2, introduction of C/EBPb blocks this effect.…”

Hijacking the Supplies: Metabolism as a Novel Facet of Virus-Host Interaction

“…Similarly, inhibition of FASN with C75 reduced HCV replication in vitro (88). Other evidence suggests that currently used anti-HCV agents like ribavirin inhibit lipogenesis as a side effect, which may contribute to their antiviral properties (95, 96). Mechanistically, ribavirin suppresses the expression of lipogenic genes such as SREBP-1c, FASN, and SCD-1 in a retinoid X receptor α- and CCAAT/enhancer-binding protein α-dependent manner (95, 96).…”

“…Other evidence suggests that currently used anti-HCV agents like ribavirin inhibit lipogenesis as a side effect, which may contribute to their antiviral properties (95, 96). Mechanistically, ribavirin suppresses the expression of lipogenic genes such as SREBP-1c, FASN, and SCD-1 in a retinoid X receptor α- and CCAAT/enhancer-binding protein α-dependent manner (95, 96). Statins, another class of drugs used in a wide number of patients due to their cholesterol- and lipid-lowering properties, exhibited an inhibitory effect on HCV replication probably due to the inhibition of the rate-limiting step of the mevalonate pathway, 3-hydroxy3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase) (97, 98).…”