Abstract
SREBPs (Sterol Regulatory Element-binding Proteins) regulate the transcription of genes encoding proteins and enzymes involved in cholesterol or fatty acid metabolism. There exist two isoforms, SREBP-1 and-2, with 47% amino acid homology. Unlike other members of the basic helix-loop-helix leucine zipper (bHLH-Zip) family, SREBPs are synthesized as precursors bound to the ER membrane and nuclear envelope. The transcriptionally active NH2-terminal portion including the bHLH-Zip domain is released from the membrane by two-step proteolysis. Among the SREBP family members, SREBP 1 mainly regulates fatty acid metabolism. The alternative splicing generates SREBP la and lc, the latter lacks 24 amino acids in the NH2-terminal transactivation domain, thereby being a weaker transcription factor than la. Their responsive genes include fatty acid synthase, acetyl CoA carboxylase, ATP citrate-lyase, stearoyl CoA desaturase, glycerol-3-phosphate acyltransferase gene. Recent studies demonstrate that unsaturated fatty acids downregulate the SREBP 1 activities, but that the precise regulatory mechanism remains unclear. It is noted that both cholesterol and fatty acid metabolism are coordinately regulated through the actions of the SREBPs.
