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      MDR1 Gene Expression in Normal and Atherosclerotic Human Arteries<footref rid="foot01"> 1</footref>


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          Recent studies have shown that a membrane p-glycoprotein, encoded by MDR1 gene, is involved in the transport of free cholesterol from the plasma membrane to endoplasmic reticulum, the site of cholesterol esterification by acyl-CoA:cholesterol acyltransferase (ACAT). Moreover, results deriving from our previous studies have shown that the rate of cell proliferation was positively correlated with cholesteryl ester levels as well as with ACAT and MDR1 gene expression. In this study, lipid content and the expression of the genes involved in cholesterol metabolism such as hydroxy-methylglutaryl coenzyme A reductase (HMGCoA-R), low-density lipoprotein receptor (LDL-R), ACAT and MDR1 have been investigated in control and atherosclerotic arteries. The results have shown that the levels of cholesteryl ester increase with the age of cadaveric donors in arteries prone to atherosclerosis (abdominal aorta, superficial femoral artery) and become predominant in advanced atherosclerotic lesions. The mRNA levels of ACAT and MDR1 showed the same age correlation, reaching the highest values in atherosclerotic specimens. These results suggest that MDR1 may be involved in the accumulation of intracellular cholesterol ester levels found in atherosclerotic lesions. Moreover, the levels of HMGCoA-R, LDL-R and ACAT gene expressions progressively increased with the age of cadaveric donors; conversely, in atherosclerotic specimens, the mRNA levels of HMGCoA-R and LDL-R drastically decreased while ACAT gene expression reached its maximum. These findings suggest a reactivation of normal homeostatic regulation of cholesterol in advanced and complicated lesions.

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          Role of multidrug resistance P-glycoproteins in cholesterol esterification.

          Cholesterol esterification, catalyzed by acyl-CoA:cholesterol acyltransferase (ACAT), plays a central role in cellular cholesterol homeostasis and in physiologic processes that lead to coronary heart disease. Although ACAT resides in the endoplasmic reticulum (ER), the cholesterol substrate for esterification originates in the plasma membrane and must be transported to the ER for esterification. Progesterone inhibits esterification, possibly by blocking the transport of cholesterol to the ER. Recent studies suggest that progesterone acts by inhibiting the activity of one or more of the multidrug-resistant (MDR) P-glycoproteins. In the current manuscript, we demonstrate that progesterone's ability to inhibit esterification is not mediated through the progesterone receptor. We evaluate a series of steroid hormones and find a strong correlation between a steroid hormone's hydrophobicity and its ability to inhibit both cholesterol esterification and MDR-catalyzed drug efflux. We also find that cholesterol esterification is inhibited by nonsteroidal MDR inhibitors, and that this inhibition specifically affects the esterification of cholesterol derived from the plasma membrane. MDR inhibitors also inhibit cholesterol esterification in a wide range of cultured human cell lines. These observations suggest that MDR activity normally functions in a general process of intracellular cholesterol transport.
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            The fate of cholesterol exiting lysosomes.

            Cholesterol released from ingested low density lipoproteins in lysosomes moves both to the plasma membrane and to the endoplasmic reticulum (ER) where it is re-esterified. Whether cholesterol can move directly from lysosomes to ER or first must traverse the plasma membrane has not been established. To examine this question, the endocytic pathway of rat hepatoma cells was loaded at 18 degrees C with low density lipoproteins (LDL) labeled with [3H]cholesteryl linoleate, and the label then was chased at 37 degrees C. The hydrolysis of the accumulated ester proceeded linearly for several hours. Almost all of the released [3H]cholesterol moved to the plasma membrane rapidly and without a discernable lag. In contrast, the re-esterification in the ER of the released [3H]cholesterol showed a characteristic lag of 0.5-1 h. These data are inconsistent with direct cholesterol transfer from lysosomes to ER; rather, they suggest movement through the plasma membrane. Furthermore, we found that progesterone, imipramine and 3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one (U18666A) strongly inhibited the re-esterification of lysosomal cholesterol in the ER. However, contrary to previous reports, they did not block transfer of [3H]cholesterol from lysosomes to the cell surface. Therefore, the site of action of these agents was not at the lysosomes. We suggest instead that their known ability to block cholesterol movement from the plasma membrane to the ER accounts for the inhibition of lysosomal cholesterol esterification. These findings are consistent with the hypothesis that cholesterol released from lysosomes passes through the plasma membrane on its way to the ER rather than proceeding there directly. As a result, ingested cholesterol is subject to the same homeostatic regulation as the bulk of cell cholesterol, which is located in the plasma membrane.
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              Role of multidrug resistance P-glycoproteins in cholesterol biosynthesis.

              Multidrug resistance (MDR) P-glycoproteins were first recognized for their ability to catalyze ATP-dependent efflux of cytotoxic agents from tumor cells when overexpressed. Despite extensive study, little is known about the normal substrate(s) and normal cellular function of these proteins. In the accompanying manuscript (Metherall, J. E., Waugh, K., and Li, H. (1996) J. Biol. Chem. 271, 2627-2633), we demonstrate that progesterone inhibits cholesterol biosynthesis, causing the accumulation of a number of cholesterol precursors. In the current manuscript, we use several criteria to show that the progesterone receptor is not involved in this inhibition. Rather, we demonstrate that progesterone inhibits cholesterol biosynthesis by interfering with MDR activity. We show that a steroid hormone's ability to inhibit cholesterol biosynthesis is correlated with: 1) its general hydrophobicity and 2) its ability to inhibit MDR activity. The only exception to this finding is beta-estradiol, which is a more potent inhibitor of cholesterol biosynthesis than expected based solely on hydrophobicity and MDR inhibition. We further demonstrate that nonsteroidal inhibitors of MDR also inhibit cholesterol biosynthesis. Since MDR activity is required for esterification of LDL-derived cholesterol (P. DeBry and J. E. Metherall, submitted for publication), we investigated the relationship between these phenomena and show that inhibition of cholesterol esterification does not cause inhibition of cholesterol biosynthesis and that inhibition of cholesterol biosynthesis does not cause inhibition of cholesterol esterification. We propose a model in which MDR is required for transport of sterols from the plasma membrane to the endoplasmic reticulum (ER). Inhibiting this transport prevents cholesterol esterification and cholesterol biosynthesis by preventing sterol substrates from reaching ER-resident enzymes.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                August 1999
                27 August 1999
                : 36
                : 4
                : 261-271
                aExperimental Pathology Institute and bDepartment of Surgical Sciences and Organ Transplantation of Cagliari University, Cagliari, Italy
                25654 J Vasc Res 1999;36:261–271
                © 1999 S. Karger AG, Basel

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                Page count
                Figures: 7, Tables: 4, References: 27, Pages: 11
                Research Paper


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