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
- Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697, USA
This extract was created in the absence of an 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 two membrane domains pin the inactive precursor in a rigid hairpin orienting both the amino- and 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 …
