Sterol regulatory element-binding protein transcriptional pathway (SREBP pathway)

The Sterol Regulatory Element-Binding Protein (SREBP) transcriptional pathway is a master regulator of cellular lipid homeostasis, controlling the expression of genes required for the synthesis and uptake of cholesterol, fatty acids, and triglycerides (Brown & Goldstein, 1997). The pathway involves three primary isoforms: SREBP-1a and SREBP-1c, which primarily regulate fatty acid metabolism, and SREBP-2, which is specific for cholesterol homeostasis (Horton et al., 2002). These proteins are synthesized as inactive precursors localized to the endoplasmic reticulum (ER) and are activated through a unique regulated intramembrane proteolysis mechanism triggered by low sterol levels. When activated, the N-terminal transcription factor domain translocates to the nucleus to bind sterol regulatory elements (SREs) in the promoters of target genes like HMG-CoA reductase and fatty acid synthase. Dysregulation of SREBP signaling is a hallmark of metabolic diseases, including non-alcoholic fatty liver disease (NAFLD) and hyperlipidemia, and is increasingly recognized as a driver of metabolic reprogramming in cancer cells (Guo et al., 2014). Therapeutic interventions targeting this pathway, such as SCAP inhibitors like Fatostatin or protease inhibitors like PF-429242, aim to reduce pathological lipid accumulation and inhibit the growth of lipid-dependent tumors (Kamisuki et al., 2009; Hawkins et al., 2008).

Other names

SREBP signaling pathwaySterol regulatory element-binding transcription factor pathwaySREBF pathway

Inhibition of SREBP activation by blocking the SCAP-mediated transport from the endoplasmic reticulum to the Golgi apparatus or by inhibiting the Site-1 (S1P) and Site-2 (S2P) proteases responsible for proteolytic cleavage.