Control of Cholesterol Turnover in the Mouse*

General Pathways for Net Cholesterol Flux through the Mouse The mouse is now commonly used to explore the physiological changes that take place in sterol metabolism when a specific protein function involved in cholesterol turnover is either deleted or overexpressed. The major pathways for the net flow of cholesterol through the tissue compartments of this species are outlined in Fig. 1. This diagram separates the overall process of cholesterol turnover into those events that occur within the cells of the extrahepatic tissues (90% of body mass), that promote movement through the plasma space (4.6% of body mass), and that are involved in secretion from the liver (5% of body mass) into the intestine. As implied by the thickness of the arrows, most cholesterol is synthesized in the extrahepatic organs and moves from the ER to the bulk phase and specialized microdomains of the plasma membrane (1–3). Because cholesterol does not accumulate in these tissues, it must be continuously removed from the plasma membrane and bound to circulating apoA-I, a process recently postulated to be under the control of ABCA1 (4, 5). Within the plasma space, cholesterol is esterified to CE in the mature HDL particle utilizing the enzyme lecithin:cholesterol acyltransferase. This CE is then selectively removed from the lipoprotein particle by SR-BI primarily in the liver (and endocrine tissues) and hydrolyzed (6–8). The resultant cholesterol mixes with other sterols newly synthesized in the liver or absorbed from the diet. A portion of this pool is utilized as substrate for bile acid synthesis or for secretion into the bile and, ultimately, into the intestine. Alternatively, part of this sterol may be esterified by acyl-CoA:cholesterol acyltransferase, incorporated into the nascent VLDL particle, and secreted into the plasma space (9). During metabolism of this VLDL particle, a portion of the cholesterol reaches the LDL particle, and a small fraction ( 20%) of this lipoprotein is cleared by the cells of the extrahepatic tissues utilizing the LDLR clustered in clathrin-coated pits (10). After processing through the lysosomal pathway, this small amount of cholesterol joins the much larger pool of newly synthesized cholesterol destined for transport to the plasma membrane (Fig. 1). This scheme emphasizes that most cholesterol is synthesized in the extrahepatic tissues and that the excretion of this sterol from the body largely takes place by secreting cholesterol itself from the liver into the feces or after first metabolizing the cholesterol molecule to bile acid and then secreting this acidic sterol into the feces (11). Significant amounts of cholesterol are also excreted from the body through the sloughing of skin cells and secretions and after conversion to steroid hormones, but these pathways are not shown in Fig. 1. Nevertheless, in the mouse, measuring the output of fecal neutral and acidic sterols always underestimates cholesterol turnover when compared with quantifying sterol input into the animal from dietary cholesterol intake and de novo synthesis.