Insig1, short for insulin-induced gene 1, is an endoplasmic reticulum-resident protein. It plays a crucial role in regulating intracellular cholesterol metabolism. Insig1 is part of a complex with SREBP cleavage-activating protein (SCAP) and sterols, which inhibits sterol regulatory element-binding proteins (SREBPs) [1,2,4,5]. This regulation of SREBPs is essential for lipid homeostasis, as SREBPs control the transcription of genes involved in lipogenesis and cholesterol synthesis. Genetic models, such as knockout (KO) or conditional knockout (CKO) mouse models, can provide insights into Insig1's function in vivo.

In Asgr1-knockout mice, increased Insig1 expression led to fewer nuclear SREBPs, resulting in lower non-HDL-cholesterol and triglyceride levels. This shows that Insig1 can modulate lipid homeostasis through SREBP signaling suppression [2]. In buffalo mammary epithelial cells, overexpression of Insig1 decreased the expression of genes related to milk fat synthesis and triglyceride content, while knockdown had the opposite effect, indicating its role in regulating milk fat synthesis [3]. In non-alcoholic fatty liver disease (NAFLD), liver-specific deletion of Insig1 promoted SREBP1 nuclear translocation, leading to lipid accumulation. Also, miR-363-3p, which is overexpressed in NAFLD, directly targets Insig1 to facilitate SREBP cleavage and nuclear translocation [4].

In conclusion, Insig1 is a key regulator of lipid-related biological processes, including cholesterol metabolism, milk fat synthesis, and lipid homeostasis in the liver. Studies using KO or CKO mouse models have revealed its importance in diseases like NAFLD and in modulating lipid profiles. Understanding Insig1's function provides potential targets for treating lipid-related disorders and metabolic diseases.