Insig1-flox Mouse

Insig1, or insulin-induced gene 1, is an endoplasmic reticulum-resident protein that plays a crucial role in regulating intracellular cholesterol and fatty acid synthesis. It is part of a complex with SREBP cleavage-activating protein (SCAP) and sterols, which inhibits sterol regulatory element-binding proteins (SREBPs) [1,3,4,5,6,7]. This regulation of SREBPs is essential for lipid metabolism, and dysregulation can lead to various metabolic disorders.

In cancer, studies have shown significant roles of Insig1. In human hepatocellular carcinoma (HCC), phosphorylated PCK1 translocates to the endoplasmic reticulum and phosphorylates Insig1, disrupting the Insig-SCAP interaction, activating SREBPs, and promoting lipogenesis, tumor cell proliferation, and tumorigenesis. Phosphorylation of Insig1 at Ser207 is associated with poor HCC prognosis [1]. In colorectal cancer, a hypoxia-responsive circRNA named circINSIG1 encodes a protein that promotes ubiquitin-dependent degradation of Insig1, reprogramming cholesterol metabolism to enhance CRC proliferation and metastasis [2]. In esophageal squamous cell carcinoma, LPCAT1 activates EGFR, leading to down-regulation of Insig-1 expression, facilitating SREBP-1 entry into the nucleus to promote cholesterol synthesis and cancer progression [7]. In non-alcoholic fatty liver disease (NAFLD), miR-363-3p targets Insig1, promoting SREBP cleavage and nuclear translocation, leading to lipid accumulation, and apigenin alleviates NAFLD by regulating the miR-363-3p/Insig1/SREBP1 pathway [4].

In conclusion, Insig1 is a key regulator in lipid metabolism-related pathways. Its dysregulation is associated with multiple diseases, especially cancers and metabolic disorders. Studies using gene-related models, though not specifically KO/CKO mouse models in the provided references, have revealed its significance in disease-related biological processes. Understanding Insig1's functions can potentially provide new therapeutic targets for treating these diseases.