Scap, short for SREBP cleavage-activating protein, is a polytopic membrane protein. It serves as a crucial 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 part of the cholesterol homeostasis pathway, which is vital for maintaining normal cellular lipid levels [1].

In murine models, deleting Scap in the liver (a form of KO or CKO) exacerbated liver injury, fibrosis, and carcinogenesis in non-alcoholic steatohepatitis (NASH), despite reducing hepatic steatosis. This was due to alterations in fatty acid composition of phosphatidylcholines, leading to ER stress and hepatocyte injury [2]. Also, macrophage-specific knockout of Scap in mice attenuated Paigen diet-induced meta-inflammation and ectopic lipid deposition by reducing the activation of the STING-NF-κB pathway, suggesting Scap's role in lean NAFLD pathogenesis [3].

In conclusion, Scap is essential for regulating cholesterol homeostasis and lipid metabolism. The study of Scap using KO/CKO mouse models has provided insights into its role in diseases such as NASH and lean NAFLD, highlighting its potential as a therapeutic target for these metabolic disorders.