Sterol regulatory element-binding transcription factor (SREBF) (SREBF)

Sterol regulatory element-binding transcription factors (SREBFs), also known as SREBPs, are essential membrane-bound transcription factors that maintain cellular lipid and cholesterol homeostasis (UniProt P36956, Q12772). They are synthesized as inactive precursors in the endoplasmic reticulum (ER) and require transport to the Golgi for proteolytic activation by Site-1 and Site-2 proteases when sterol levels are low (PubMed: 10503334). SREBF1 primarily regulates genes for fatty acid and triglyceride synthesis, while SREBF2 is the master regulator of cholesterol biosynthesis and the LDL receptor (PubMed: 11013310). Dysregulation of SREBF activity is a hallmark of metabolic diseases, including nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes, and is increasingly recognized as a driver of lipid metabolism reprogramming in cancer (PubMed: 22020111). Therapeutic strategies include small molecules like Fatostatin and Betulin that inhibit the SCAP-SREBP translocation complex, as well as inhibitors of the processing proteases (PubMed: 19706470, 21278737). While promising, targeting SREBFs poses challenges regarding systemic lipid balance and potential hepatotoxicity due to the central role of these factors in essential physiological processes.

Other names

Sterol regulatory element-binding proteinSREBPAdipocyte determination- and differentiation-dependent factor 1ADD1BHLHE31BHLHE32

Inhibition of the proteolytic processing and activation of SREBP precursors, preventing their translocation to the nucleus and subsequent binding to sterol regulatory elements (SREs) in the promoters of target genes (PubMed: 19706470).