Scap, short for SREBP cleavage-activating protein, is a polytopic membrane protein. It functions as a key regulator in controlling the cholesterol content of membranes in mammalian cells. Scap binds to sterol regulatory element-binding proteins (SREBPs) and transports them from the endoplasmic reticulum (ER) to the Golgi for proteolytic processing. This process is integral to cholesterol synthesis and uptake regulation, and thus crucial for maintaining cholesterol homeostasis [1].

In murine models, deletion of Scap in the liver, a form of loss-of-function experiment, exacerbated liver injury, fibrosis, and carcinogenesis in non-alcoholic steatohepatitis (NASH), despite reducing hepatic steatosis. This was due to altered fatty acid composition of phosphatidylcholines, endoplasmic reticulum stress, and hepatocyte injury [2]. In macrophages, Scap-SREBP2 complex translocation is required for optimal NLRP3 inflammasome activation, showing its role in integrating cholesterol metabolism with inflammation [3].

In conclusion, Scap is essential for regulating cholesterol homeostasis, lipid metabolism, and inflammation. Studies using Scap KO/CKO mouse models have provided insights into its role in diseases like NASH and in immune-metabolic crosstalk, highlighting its potential as a therapeutic target for related metabolic and inflammatory diseases.

References:

1. Brown, Michael S, Radhakrishnan, Arun, Goldstein, Joseph L. 2017. Retrospective on Cholesterol Homeostasis: The Central Role of Scap. In Annual review of biochemistry, 87, 783-807. doi:10.1146/annurev-biochem-062917-011852. https://pubmed.ncbi.nlm.nih.gov/28841344/

2. Kawamura, Satoshi, Matsushita, Yuki, Kurosaki, Shigeyuki, Koike, Kazuhiko, Nakagawa, Hayato. . Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis. In The Journal of clinical investigation, 132, . doi:10.1172/JCI151895. https://pubmed.ncbi.nlm.nih.gov/35380992/

3. Guo, Chuansheng, Chi, Zhexu, Jiang, Danlu, Song, Bao-Liang, Wang, Di. 2018. Cholesterol Homeostatic Regulator SCAP-SREBP2 Integrates NLRP3 Inflammasome Activation and Cholesterol Biosynthetic Signaling in Macrophages. In Immunity, 49, 842-856.e7. doi:10.1016/j.immuni.2018.08.021. https://pubmed.ncbi.nlm.nih.gov/30366764/