Cholesterol Transport Revisited: A New Turbo Mechanism to Drive Cholesterol Excretion

A fine-tuned balance between cholesterol uptake and excretion by the body is pivotal to maintain health and to remain free from the deleterious consequences of cholesterol accumulation such as cardiovascular disease. The pathways involved in intracellular and extracellular cholesterol transport are a subject of intense investigation and are being unraveled in increasing detail. In addition, insight into the complex interactions between cholesterol and bile acid metabolism has increased considerably in the last couple of years. This review provides an overview of the mechanisms involved in cholesterol uptake and excretion, with a particular emphasis on the most recent progress in this field. Special attention is given to the transintestinal cholesterol excretion (TICE) pathway, which was recently demonstrated to have a remarkably high transport capacity and to be sensitive to pharmacological modulation. Membrane fluidity appears important for the uptake of lipids, including cholesterol, in the intestine. Enzymes such as LPCAT3 may therefore represent therapeutic targets. Emerging information on the mechanism of LDL internalization as well as intracellular cholesterol transport will lead to identification of novel genes involved in familial hyperlipidemia. TICE is active in humans. Recent data indicate that this process can be induced in humans, which opens opportunities for therapeutic stimulation of this pathway to lower plasma cholesterol levels. Bile acid synthesis not only represents an important catabolic pathway for cholesterol removal, but also the composition of the bile acid pool impacts cholesterol uptake and active excretion by the intestine. The farnesoid X receptor (FXR) mediates cholesterol metabolism, not only by regulating bile acid synthesis but also by impacting intestinal cholesterol secretion.