Sterol regulatory element-binding protein family as global regulators of lipid synthetic genes in energy metabolism

Abstract

Sterol regulatory element-binding proteins (SREBPs) have been established as lipid synthetic transcription factors for cholesterol and fatty acid synthesis. SREBPs are synthesized as membrane-bound precursors with their N-terminal active portions entering the nucleus to activate target genes after proteolytic cleavage in a sterol-regulated manner. This cleavage step is regulated by a putative sterol-sensing molecule, SREBP-activating protein (SCAP), that forms a complex with SREBPs and traffics between the rough endoplasmic reticulum and Golgi. DNA cis-elements that SREBPs bind, originally identified as sterol-regulatory elements (SREs), now expands to a variety of SRE-like sequences and some of E-boxes, which makes SREBPs eligible to regulate a wide range of lipid genes. Animal experiments including transgenic and knockout mice suggest that three isoforms, SREBP-1a, -1c, and -2, have different roles in lipid synthesis. In differentiated tissues and organs, SREBP-1c is involved in fatty acid, whereas SREBP-2 plays a major role in regulation of cholesterol synthesis. SREBP-1a is expressed in growing cells, providing both cholesterol and fatty acids that are required for membrane synthesis. SREBP-1c seems to be a mediator for insulin/glucose signaling to lipogenesis, and could be involved in insulin resistance, remnant lipoproteins, and fatty livers. Future studies in this field will certainly focus on understanding the molecular mechanisms sensing cellular sterol and energy states leading to the activation of SREBP-mediated gene transcription.