The three mammalian SREBPs differ in their tissue distribution and responses to regulatory cues. SREBP-1a and -1c are encoded from different promoters that drive expression of overlapping transcripts from the same gene, distinguished only by their unique 5’ terminal exons. The singular SREBP-2 isoform is encoded from a different gene (1
). The SREBP transcriptional activation domain is located at the extreme amino-terminus and the longer SREBP-1a isoform has a potent transcriptional activation domain whereas the shorter SREBP-1c isoform has a much weaker activation domain. SREBP-2 has a strong activation domain similar to that of SREBP-1a.
SREBP-1c is the predominant isoform in most adult non-dividing metabolic tissues such as liver and adipose. The SREBP-1c promoter is autoregulated by SREBPs (3
) and stimulated by both liver X receptor (LXR) and insulin signaling. Interestingly, LXR binding to a DR-4 binding site required for both responses (4
). Strong evidence in support of this model was revealed when endogenous LXR agonists were depleted by over-expressing the enzyme SULT2B1b sulfotransferase, which adds sulfate groups to sterol substrates making them unable to bind to and activate LXR (Glossary). As expected, in the presence of excess SULT2B1b, activation of the SREBP-1c promoter by endogenous LXR agonists was lost. However, SREBP-1c stimulation by insulin was also eliminated, suggesting that the nuclear receptor LXR plays a key role in the insulin dependent stimulation of SREBP-1c (6
SREBP-1a mRNA is expressed at very high levels in cells of the immune system and its promoter is activated by NFkB (Glossary) in macrophages, as part of the proinflammatory phase of the innate immune response (7
). The SREBP-2 gene promoter is both auto-regulated and stimulated by thyroid hormone (8
). Thyroid hormone receptor (TR) regulation of SREBP-2 provides a mechanism that may explain the low expression of LDL receptor and the hypercholesterolemia that is associated with low systemic thyroid hormone levels and hypothyroidism in humans (9
Interestingly, expression of SREBP-2 mRNA, but not SREBP-1, is regulated by insulin in the hypothalamus (10
) and following streptozotocin injection to induce diabetes, SREBP-2 levels in the hypothalamus are also reduced. Furthermore, direct addition of insulin increases SREBP-2 and its target genes in primary cultures of neurons and glial cells (10
). The reasons for the differential effects of insulin on SREBP-1c and SREBP-2 in the liver vs. hypothalamus, respectively, remain to be determined.
The microRNA miR-33a is encoded within an intron of the SREBP-2 gene (11
). Sequence prediction analysis and mechanistic studies together demonstrated that miR-33a targets the mRNAs encoding for ABCA1 and ABCG1 (Glossary), both of which are ATP dependent membrane cholesterol transporter proteins that control cellular cholesterol efflux. This observation indicates that miR-33a balances intracellular cholesterol by functioning together with the co-expressed SREBP-2. Because SREBP-2 mRNA is regulated by insulin in the brain where miR-33a is expressed at relatively high levels (12
), this may be another metabolic response where miR-33a regulation of cholesterol efflux may have significant physiological effects (10
A highly related mircroRNA, miR-33b, is encoded within an intron of the human SREBP-1 gene, but this is not conserved in rodents (13
). This suggests miR-33b expression is subject to regulation by mechanisms that influence both SREBP-1a and -1c in different human tissues. miR-33’s have also been shown to regulate fatty acid oxidation and glucose metabolism indicating that these micro RNAs may have a broader role in regulating metabolism(15