Insulin-induced gene 1 (INSIG1)

Insulin-induced gene 1 (INSIG1) is a critical endoplasmic reticulum (ER) membrane protein that serves as a central regulator of lipid and cholesterol homeostasis. It acts by sensing sterol levels and mediating the feedback inhibition of cholesterol synthesis through two primary mechanisms: retaining the SCAP-SREBP complex in the ER to prevent transcriptional activation of lipogenic genes, and promoting the ubiquitin-mediated degradation of HMG-CoA reductase. INSIG1 is highly expressed in the liver and adipose tissue, where it functions as a biological 'brake' on lipogenesis and adipocyte differentiation. Dysregulation or genetic variation in INSIG1 is closely linked to metabolic disorders such as obesity, hyperlipidemia, and non-alcoholic fatty liver disease (NAFLD). Emerging therapeutic strategies, including small-molecule binders like 25-hydroxylanosterol, aim to leverage INSIG1 to inhibit SREBP-mediated lipotoxicity and the progression of non-alcoholic steatohapatitis (NASH).

Other names

INSIG1CL-6CL6MGC1405Insulin-induced gene 1 proteinINSIG-1 membrane protein

Insulin-induced gene 1 (INSIG1) functions as an ER-resident anchor that mediates sterol-dependent feedback inhibition of lipid synthesis. When sterol levels are high, INSIG1 binds to the sterol-sensing domain of SCAP (SREBP cleavage-activating protein), retaining the SCAP-SREBP complex in the ER and preventing its translocation to the Golgi for proteolytic activation, which downregulates lipogenic gene transcription. Additionally, INSIG1 binds to HMG-CoA reductase (HMGCR) to recruit E3 ubiquitin ligases, such as AMFR (gp78) and RNF139, triggering HMGCR degradation via the ER-associated degradation (ERAD) pathway.