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

The Sterol Regulatory Element-Binding Protein (SREBP) maturation pathway is a central regulatory mechanism for cellular lipid homeostasis. SREBPs (SREBP-1a, SREBP-1c, and SREBP-2) are transcription factors synthesized as inactive precursors anchored in the endoplasmic reticulum (ER) membrane. When cellular sterol levels are low, the SREBP-SCAP complex translocates to the Golgi apparatus, where it is sequentially cleaved by Site-1 and Site-2 proteases to release the active N-terminal transcription factor domain (Zimmer et al., 2017, Hepatology Communications). This mature form enters the nucleus to upregulate genes involved in cholesterol and fatty acid synthesis, such as HMG-CoA reductase and PCSK9. CAT-2003 is a clinical-stage small molecule conjugate of eicosapentaenoic acid (EPA) and niacin that specifically inhibits the maturation of SREBP-1 and SREBP-2 (Catabasis Pharmaceuticals, SEC Filings). In the presence of statins, which normally trigger a compensatory increase in SREBP maturation and PCSK9 expression as a feedback mechanism, CAT-2003 acts to suppress this loop, leading to synergistic reductions in LDL cholesterol and triglycerides. This pathway is a key therapeutic target for treating severe hypertriglyceridemia, hypercholesterolemia, and nonalcoholic steatohepatitis (NASH).

Other names

SREBP processing pathwaySREBP activation pathwaySREBP-1/2 maturationSterol regulatory element-binding protein pathway

Inhibition of the proteolytic cleavage of SREBP-1 and SREBP-2 precursors in the Golgi apparatus, preventing the release and nuclear translocation of the active transcription factor domain.