Balancing cholesterol metabolism in the liver and gut: perspectives in health and disease.

Increasingly, cholesterol is implicated in diseases beyond the cardiovascular system. Major diseases of the gastrointestinal tract and liver are a case in point and are a focus of this Review. Particularly active in whole-body cholesterol metabolism, the gut and liver are the major organs that produce and secrete plasma lipoproteins, specifically chylomicrons, very-low-density lipoprotein and high-density lipoprotein. In addition, the liver is the only organ in which cholesterol is converted into bile acids. In this Review, we summarize how the liver and gut handle cholesterol to achieve homeostasis. A multitude of diverse and elaborate mechanisms strictly regulate whole-body cholesterol homeostasis by maintaining crucial liver and gut functions, notably cholesterol biosynthesis, absorption, metabolism, transport and excretion. Perturbation of cholesterol homeostasis is associated with liver and gut diseases, including metabolic dysfunction-associated steatotic liver disease, hepatocellular carcinoma and colorectal cancer. Therefore, the molecular machinery involved in cholesterol regulation is of great therapeutic interest. We provide an overview of how cholesterol balance is normally maintained, how its dysregulation can contribute to liver and gut diseases, and how cholesterol homeostasis is targetable to combat these diseases.