Transcription of the mitochondrial citrate carrier gene: Role of SREBP-1, upregulation by insulin and downregulation by PUFA

Microarray analyses of SREBP-1a and SREBP-1c target genes identify new regulatory pathways in muscle

“…More recently, it was demonstrated that SREBP-1 regulates the transcription of the mitochondrial citrate carrier (CIC), which exports citrate from the mitochondria to the cytosol (22). Interestingly, 30 genes among the 55 genes encoding mitochondrial proteins regulated in this study have SRE motifs in their promoter sequences.…”

Citrate – new functions for an old metabolite

“…Interestingly, SREBP, a key regulator of CIC gene expression (Infantino et al, 2007) that mediates lipogenesis, is a critical component of mTORC1-driven cell proliferation (Kim et al, 2006;Duvel et al, 2010). Another major target of mTORC1 is the hypoxia inducible factor 1 (HIF1), which is not crucial in mTORC1-driven cell proliferation.…”

“…Thus, the availability of citrate depends on the amount of citrate transported from the mitochondria, which, in turn, depends on the regulation of CIC gene expression in different cellular and metabolic conditions. Different regulatory transcription factors of the CIC gene have been identified so far: Sp1 is involved in basal and epigenetic regulation (Iacobazzi et al, 2008;Infantino et al, 2011b); FOXA1 is a gene activator in liver and pancreatic cells (Iacobazzi et al, 2009a;Menga et al, 2013); insulin activates and fatty acids repress gene expression through SREBP-1 (Infantino et al, 2007); ZNF224 acts as a strong repressor (Iacobazzi et al, 2009b); NF-κB mediates CIC overexpression in inflammation (Infantino et al, 2011a); PPARs are gene activators (Damiano et al, 2012;Bonofiglio et al, 2013). These findings support the view of a complex regulation of the CIC gene expression related to different biological processes in which citrate is involved.…”

Sterol Regulatory Element Binding Protein Regulates the Expression and Metabolic Functions of Wild-Type and Oncogenic IDH1

“…Overexpression of mature, active SREBP in the liver of mice increases the transcription of genes encoding glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and malic enzyme 1, which are all major sources of NADPH production (9,10). Similarly, mature SREBP increases the expression of acetyl coenzyme A (acetyl-CoA) synthetase (ACSS2) and ATP-citrate lyase (ACLY), as well as the mitochondrial citrate transporter (SLC25A1), which facilitate the flux of carbons into lipids from acetate and citrate, respectively (11)(12)(13)(14). Isocitrate dehydrogenase 1 (IDH1) is another enzyme that can support lipogenesis either through NADPH production or, through reductive carboxylation, facilitating the flux of carbon to lipids (15)(16)(17).…”