Studies on the transcriptional regulation of genes involved in fatty acid and cholesterol metabolism by SREBP

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SREBP is a transcription factor which plays a critical role in regulation of genes encoding enzymes and proteins involved in fatty acid and cholesterol metabolism.The promoters of both HMG CoA synthase and squalene synthase genes contain multiple SREBP-binding and NF-Y-binding sites.A number of reporter luciferase assays revealed that SREBP and NF-Y, a ubiquitous transcription factor, coordinately regulate transcription of these genes.Reporter gene assays using constructs containing various nucleotide spacing lengths between the SREBP-binding and NF-Y-binding sites demonstrate that the 16 to 20-bp spacing range is required for maximal transcriptional regulation, suggesting that the interaction between them might be critical for the coordinate regulation.To investigate the difference between two members of SREBP family, SREBP-l and -2, in the individual physiological roles, a HeLa cell line transiently expressing SREBP-2 was established using a lac-switch system.When the cell was cultured with sterols, endogenous SREBPs were inactivated and exogenous SREBP-2 was transiently active.SREBP-2 preferentially stimulate the transcription of genes related to cholesterol metabolism, not to fatty acid metabolism.These results indicate that SREBP-2 mainly regulates cholesterol metabolism while SREBP-l regulates fatty acid metabolism.