SREBP

Supporting information

SREBPs (sterol regulatory element-binding proteins) are membrane bound transcription factors that are essential in the regulation of cholesterol, fatty acid and triglyceride biosynthesis. There are two SREBP genes in mammals, SREBP-1, which is most abundant in the liver and adrenal glands, and SREBP-2, which is ubiquitously expressed. In addition, SREBP-1 encodes two different isoforms of the protein, SREBP-1a and SREBP-1c, expression of which is dependent on the promoter. The proteins form a subgroup of the larger class of bHLHZ (basic-helix loop-helix leucine zipper domain) transcription factors. SREBP-1c primarily regulates fatty acid metabolism, including the fatty acid synthase (FASN) gene, SREBP-2 is primarily responsible for cholesterol metabolism-related genes, including HMG-CoA reductase, while SREBP-1a targets both.

SREBPs are synthesized as inactive precursors bound to the endoplasmic reticulum (ER). When intracellular cholesterol levels are low, SREBP cleavage activating protein (SCAP), which acts as a cholesterol sensor, transports SREBP from the ER to the Golgi apparatus, where it is cleaved by site-1 protease (S1P). The amino-terminal bHLHZ domain is then further cleaved by site-2 protease (S2P) giving rise to nSREBP (or nuclear SREBP), which translocates to the nucleus where it activates transcription. SREBP-1a appears to be constitutively expressed at low levels, whereas expression of SREBP-1c and SREBP-2 is regulated by a feed-forward loop whereby nSREBPs activate transcription of their own genes. SREBP-1c is also regulated by liver X receptors, insulin and glucagon.

Insulin stimulates the production of fatty acids in the liver at times of carbohydrate excess. Evidence suggests that this effect of insulin is mediated by SREBP-1c via the PI 3-kinase/Akt signaling pathway, and that the fatty liver associated with insulin resistance is due to elevated SREBP-1c levels. Drugs targeting SREBP may therefore have potential to treat metabolic disorders, such as type II diabetes and insulin resistance, as well as atherosclerosis. SREBP could also be a potential target in cancer therapy, since cancer cells require increased lipogenesis for growth and proliferation.

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Gene Species Gene Symbol Gene Accession No. Protein Accession No.
SREBF1 Human SREBF1 NM_004176 P36956
Mouse Srebf1 NM_011480 Q9WTN3
Rat Srebf1 NM_001276707 P56720
SREBF2 Human SREBF2 NM_004599 Q12772
Mouse Srebf2 NM_033218 Q3U1N2
Rat Srebf2 NM_001033694 Q3T1I5

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