CREating a SCAP-less liver keeps SREBPs pinned in the ER membrane and prevents increased lipid synthesis in response to low cholesterol and high insulin.

Abstract

Cellular cholesterol homeostasis in mammals is governed by a small subfamily of bHLHLZ transcription factors called the sterol regulatory element binding proteins (SREBPs). When they were first identified in 1993 (Hua et al. 1993; Tontonoz et al. 1993; Yokoyama et al. 1993), the significance of the amino-terminal bHLHLZ domain as a transcriptional regulatory protein was obvious because of its similarity with other proteins such as Myc and Max. However, because the remaining 50% of the predicted protein sequence was not similar to any other known proteins, its significance was not appreciated. Elegant studies over the ensuing years have shown that the SREBPs are synthesized as precursor proteins that are threaded into the endoplasmic reticulum (ER) membrane and anchored there through a two-pass membrane-spanning domain (Brown and Goldstein 1999). The twomembrane domains pin the inactive precursor in a rigid hairpin orienting both the aminoand carboxy-terminal domains to the cytosolic face of the membrane. SREBPs are maintained in this inactive form until a low sterol level is sensed and they are needed to increase lipid accumulation. The low sterol level sets a proteolytic cascade in motion that results in nuclear accumulation of an amino-terminal fragment that corresponds to the mature SREBP transcriptional regulatory protein. Key steps in the mechanism for the sterol-regulated cleavage process have been revealed through a classic combination of somatic cell-molecular genetics and biochemistry (Brown and Goldstein 1999). Three additional membrane-bound proteins are involved in the multistep regulation in addition to the SREBPs themselves. These include two proteases (Rawson et al. 1997; Sakai et al. 1998) and a polytopic ER membrane protein with a putative sterol-sensing domain (Hua et al. 1996a), which is involved in modulating access of the substrate SREBPs with the first protease. Although the need for proteolysis was obvious, the role of the regulatory protein, called SREBP cleavage activation protein or SCAP, was not apparent. It is now clear that SCAP is the key to sterol regulation because the identical proteases, but not SCAP, are involved in releasing the ATF 6 protein from ER membranes in response to cellular stress (Ye et al. 2000). In addition, a complex between SCAP and SREBPs moves from the ER to the golgi in a sterol-regulated manner (Nohturfft et al. 1999, 2000). This places the substrate SREBPs into the same cellular compartment as the proteases (Fig. 1). Thus, the role of SCAP is to escort the SREBPs from one cellular compartment to another in a sterol-regulated fashion Sheng et al. (1995) showed that processing of SREBP-1 and SREBP-2 is regulated differently in animals, whereas their processing is coordinately regulated in cultured cells in response to sterol depletion (Wang et al. 1994; Hua et al. 1996b). SCAP is required for maturation of both SREBP-1 and SREBP-2 isoforms in cultured cells, but because of the results of Sheng et al. (1995) there was a question as to whether SCAP was really involved in processing both SREBP-1 and SREBP-2 in animals. Recently, Matsuda et al. (2001) used Cre–loxP gene knockout technology combined with animal feeding studies to evaluate SCAP’s role in processing precursor SREBPs in livers of adult mammals. Loss of liver SCAP resulted in severely reduced levels of mRNAs and precursor proteins for both SREBP-1 and SREBP-2 in livers of animals fed a standard rodent balanced chow diet. Thus, SCAP is definitely involved in maturation of both SREBPs, but there is surely more to be uncovered in this system because of the differential regulation noted by Sheng et al. (1995). In the first part of this article, I provide a brief overview to the SREBP pathway and refer the reader to other recent reviews of this more general topic (Brown and Goldstein 1999; Edwards and Ericsson 1999; Edwards et al. 2000; Osborne 2000). The second part of the 1E-MAIL tfosborn@uci.edu; FAX (949) 824-8551. Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/ gad.916601.