High absorption of dietary cholesterol by the gut is known to have an inhibitory effect on cholesterol synthesis in the liver to maintain cholesterol homeostasis, but the factors that coordinate this process are poorly understood. A new study now identifies cholesin as a hormone that is secreted by the gut in response to cholesterol absorption and can inhibit cholesterol synthesis in the liver, which prevents an increase in circulating cholesterol levels. “Our study shifts the focus of cholesterol homeostasis research from individual-tissue regulation to the intricate interplay between various organs, providing a novel perspective that improves our comprehension of cholesterol homeostasis,” note lead investigators Huijie Zhang and Yiguo Wang. Moreover, this pathway might be a potential therapeutic target given that cholesin treatment mitigated atherosclerosis in mouse models.

To assess the factors that coordinate the balance between cholesterol absorption and synthesis, the researchers first analysed the plasma proteins from mice fed a normal diet or a high-cholesterol diet. They identified a protein, encoded by C7orf50 in humans and 3110082I17Rik in mice, that was upregulated after a high-cholesterol diet and had no previously known functions. The researchers named the protein cholesin in reference to its inhibitory role in cholesterol synthesis.