Sterol Regulatory Element-binding Proteins (SREBPs): Key Regulators of Nutritional Homeostasis and Insulin Action

Abstract

sterol regulatory element-binding protein sterol regulatory element sterol regulatory element-binding protein-1c or adipocyte differentiation and determination factor-1 basic helix-loop-helix bHLH leucine zipper low density lipoprotein cAMP-response element-binding protein vitamin D receptor-interacting protein activator-recruited cofactor fatty acid synthase polyunsaturated fatty acid(s) The sterol regulatory element-binding proteins (SREBPs)1 were first identified by two groups working independently on cholesterol metabolism (1Yokoyama C. Wang X. Briggs M.R. Admon A. Wu J. Hua X. Goldstein J.L. Brown M.S. Cell. 1993; 75: 185-197Crossref Google Scholar, 2Hua X. Yokoyama C. Wu J. Briggs M.R. Brown M.S. Goldstein J.L. Wang X. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 11603-11607Crossref PubMed Scopus (522) Google Scholar) and fat cell differentiation (3Tontonoz P. Kim J.B. Graves R.A. Spiegelman B.M. Mol. Cell. Biol. 1993; 13: 4753-4759Crossref PubMed Scopus (545) Google Scholar). Subsequent studies have demonstrated there are three major SREBP isoforms encoded by two different genes (4Brown M.S. Goldstein J.L. Cell. 1997; 89: 331-340Abstract Full Text Full Text PDF PubMed Scopus (3097) Google Scholar). These unique members of the basic helix-loop-helix leucine zipper (bHLHLZ) family of transcriptional regulatory proteins can be distinguished from other family members by two characteristics. The first is they are synthesized as precursors that are threaded into membranes of the endoplasmic reticulum and nuclear envelope in a hairpin orientation such that the amino and carboxyl tails both face the cytoplasm. The amino-terminal half of the precursor is clipped out of the membrane in two steps responding to regulatory cues that signal the need for increased cellular cholesterol (5Sakai J. Duncan E.A. Rawson R.B. Hua X. Brown M.S. Goldstein J.L. Cell. 1996; 85: 1037-1046Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar). The released amino-terminal fragment, which contains the transcriptional activation and DNA binding domains, is targeted to the nucleus where it activates expression of SREBP target genes. The second distinguishing feature of the SREBPs is that they have a unique dual DNA binding specificity, which is discussed below. Two of the three major isoforms are produced from the SREBP-1 gene, which contains two promoters (6Miserez A.R. Cao G. Probst L. Hobbs H.H. Genomics. 1997; 40: 31-40Crossref PubMed Scopus (91) Google Scholar). Transcription from each promoter produces an mRNA with a unique first exon that encodes one of the alternative amino termini referred to as 1a and 1c, respectively (Fig.1). These alternate exons are attached during mRNA splicing to a common second exon in the same reading frame, and therefore, the remaining protein coding information of both isoforms is identical. There is alternative mRNA splicing at the 3′-end as well (7Hua X. Wu J. Goldstein J.L. Brown M.S. Hobbs H.H. Genomics. 1995; 25: 667-673Crossref PubMed Scopus (253) Google Scholar), but this does not appear to be conserved in all mammalian species and its functional significance remains unclear (8Shimomura L. Shimano H. Horton J.D. Goldstein J.L. Brown M.S. J. Clin. Invest. 1997; 99: 838-845Crossref PubMed Scopus (650) Google Scholar). In contrast, mRNAs produced through alternative promoter usage at the 5′-end yield proteins with significant differences in their capacity to activate gene expression (9Shimano H. Horton J.D. Shimomura L. Hammer R.E. Brown M.S. Goldstein J.L. J. Clin. Invest. 1997; 99: 846-854Crossref PubMed Scopus (704) Google Scholar). The longer amino-terminal region in SREBP-1a contains a high percentage of acidic amino acids that make it a potent transcriptional activation domain. The SREBP-1c isoform is a much weaker activator of gene expression because it lacks 29 acidic amino acids present in 1a. Using a nuclease mapping technique to evaluate the relative levels of SREBP-1a and SREBP-1c mRNA, the ratio was shown to vary over an ∼50–100-fold range in different tissues of the body. In liver and adipocytes, 1c mRNA is 9- and 3-fold, respectively, more abundant than SREBP-1a, whereas in spleen SREBP-1a is 10 times more abundant than 1c (8Shimomura L. Shimano H. Horton J.D. Goldstein J.L. Brown M.S. J. Clin. Invest. 1997; 99: 838-845Crossref PubMed Scopus (650) Google Scholar). Whether these ratios reflect similar differences in the levels of each protein remains to be firmly established. In all cultured cell lines examined, SREBP-1a was expressed at higher levels (8Shimomura L. Shimano H. Horton J.D. Goldstein J.L. Brown M.S. J. Clin. Invest. 1997; 99: 838-845Crossref PubMed Scopus (650) Google Scholar). 1c mRNA is the predominant isoform in adult liver and adipocytes, so it is likely to be the key protein involved in SREBP-1-dependent processes in these tissues. Why different tissues express different ratios of SREBP-1a and -1c is not clear. It is possible that the more active 1