Abstract
The major net flux of cholesterol in the intact animal or human is from the peripheral organs to the liver. This flux is made up of cholesterol that is either synthesized in these peripheral tissues or taken up as lipoprotein cholesterol. This study investigates whether it is the concentration of apolipoprotein (apo) A-I or high density lipoprotein in the plasma that determines the magnitude of this flux or, alternatively, whether events within the peripheral cells themselves regulate this important process. In mice that lack apoA-I and have very low concentrations of circulating high density lipoprotein, it was found that there was no accumulation of cholesterol in any peripheral organ so that the mean sterol concentration in these tissues was the same (2208 ± 29 mg/kg body weight) as in control mice (2176 ± 50 mg/kg). Furthermore, by measuring the rates of net cholesterol acquisition in the peripheral organs from de novo synthesis and uptake of low density lipoprotein, it was demonstrated that the magnitude of centripetal sterol movement from the peripheral organs to the liver was virtually identical in control animals (78 ± 5 mg/day per kg) and in those lacking apoA-I (72 ± 4 mg/day per kg). These studies indicate that the magnitude of net sterol flux through the body is not related to the concentration of high density lipoprotein or apolipoprotein A-I in the plasma, but is probably determined by intracellular processes in the peripheral organs that dictate the rate of movement of cholesterol from the endoplasmic reticulum to the plasma membrane. —Jolley, C. D., L. A. Woollett, S. D. Turley, and J. M. Dietschy. Centripetal cholesterol flux to the liver is dictated by events in the peripheral organs and not by the plasma high density lipoprotein or apolipoprotein A-I concentration. J. Lipid. Res. 1998. 39: 2143–2149.
Highlights
The major net flux of cholesterol in the intact animal or human is from the peripheral organs to the liver
0.05) from those in the control mice. These studies provide direct evidence that in the mouse, the concentrations of high density lipoprotein (HDL)-C and apolipoprotein A-I (apoA-I) in the plasma play no role in maintenance of cholesterol homeostasis in any peripheral organ and do not regulate the rate of net centripetal flux of sterol from these tissues to the liver
These findings are consistent with several previous reports and support the view that changes in resistance to cholesterol flow through the plasma space brought about by alterations in the levels of cholesteryl ester transfer protein (CETP), lecithin:cholesterol acyltransferase (LCAT), or apoA-I (Fig. 1) profoundly affect the steady-state concentration of HDL-C but have virtually no effect on the magnitude of net sterol movement through this pathway
Summary
The major net flux of cholesterol in the intact animal or human is from the peripheral organs to the liver. The first of these relates to those poorly understood mechanisms that maintain sterol balance within the cells of all of the extrahepatic organs The second involves those processes that maintain sterol balance across the Abbreviations: peripheral organs, all tissues except liver and endocrine glands; LDL-C, low density lipoprotein cholesterol; ER, endoplasmic reticulum; HDL, high density lipoprotein; apoA-I, apolipoprotein A-I; apoE, apolipoprotein E; LCAT, lecithin:cholesterol acyltransferase; CETP, cholesteryl ester transfer protein; LDLR, LDL receptor. This cholesterol is apparently continuously transferred outward through the Golgi stack and becomes incorporated into structures like caveolae and the plasma membrane [8,9,10]. The relative importance of each of these pathways varies in different species [18, 21]
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