Estrogen and Apolipoproteins E and J in the Periphery

A considerable amount of data exists on estrogenic control of the blood-lipid profile and apoE levels. Estrogen replacement therapy (ERT) after natural or surgically induced menopause prevents elevations of total cholesterol and LDL-cholesterol, while maintaining high density lipoprotein (HDL)-cholesterol.6-10 Although ERT initially increases production of both HDL11 and LDL-cholesterol, ERT also increases the clearance of LDL6,12 and VLDL.13 One mechanism of faster clearance of postprandial lipids is an increase in hepatic LDL-receptor activity.14 However, HDL clearance does not appear to be affected by estrogen.6 Thus ERT shifts blood cholesterol and lipoproteins to a less atherogenic profile with a lower LDL/HDL ratio. The risk of cardiovascular disease is correlated with earlier age of menopause, with the greatest risk if menopause occurs before 39 years; the risk of cardiovascular disease is reduced by 2% for each year that menopause is delayed.15

The effects of estrogen on apoE in the periphery are less clear, and appear to be species/ genotype-specific. Both C57BL and C57L inbred strains of mice respond to estrogen with increased serum apoE, and a shift in apoE distribution from LDL and HDL fractions to LDL and IDL.16 However, CH3 and BALBc mice in the same study showed no serum apoE increase and a shift in apoE lipoprotein distribution from LDL to HDL particles. Estrogen

Clusterin in Normal Brain Functions and During Neurodegeneration, edited by Caleb E. Finch. ©1999 R.G. Landes Company.

treatment decreases plasma apoE, however, in humans9,17 and baboons10 and a shift in apoE distribution from HDL to VLDL.9

Estrogenic control of apoJ is evident during normal development and tissue reorganization. Apolopoprotein J is found in various areas of the developing rat brain as early as embryonic day 17.18 In addition to being widely expressed in the developing epithelia in skin, teeth, duodenum, lung, and kidney tissue19 apoJ is found in the uterus wall during pregnancy.20 During the estrous cycle, changes in apoJ levels are associated with uterine cell turnover and involution. In the mouse, apoJ increases in the lumenal epithelial cells during uterine involution through estrus and metestrus I. After ovariectomy (OVX), during the most intense periods of uterine atrophy, apoJ protein accumulates in the lumenal epithelial cells. Patterns are similar in humans with apoJ levels fluctuating throughout the menstrual cycle, reaching a peak in the mid-late secretory phase.21



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