Abstract:Little is known about lipid transport and metabolism in the brain. As a further step toward understanding the origin and function of CNS lipoproteins, we have characterized by size and density fractionation lipoprotein particles from human CSF and primary cultures of rat astrocytes. The fractions were analyzed for esterified and free cholesterol, triglyceride, phospholipid, albumin, and apolipoproteins (apo) E, Al, All, and J. As determined by lipid and apolipoprotein profiles, gel electrophoresis, and electron microscopy, nascent astrocyte particles contain little core lipid, are primarily discoidal in shape, and contain apoE and apoJ. In contrast, CSF lipoproteins are the size and density of plasma high-density lipoprotein, contain the core lipid, esterified cholesterol, and are spherical. CSF lipoproteins were heterogeneous in apolipoprotein content with apoE, the most abundant apolipoprotein, localized to the largest particles, apoAl and apoAll localized to progressively smaller particles, and apoJ distributed relatively evenly across particle size. There was substantial loss of protein from both CSF and astrocyte particles after density centrifugation compared with gel-filtration chromatography. The differences between lipoproteins secreted by astrocytes and present in CSF suggest that in addition to delivery of their constituents to cells, lipoprotein particles secreted within the brain by astrocytes may have the potential to participate in cholesterol clearance, developing a core of esterified cholesterol before reaching the CSF. Study of the functional properties of both astrocyte-secreted and CSF lipoproteins isolated by techniques that preserve native particle structure may also provide insight into the function of apoE in the pathophysiology of specific neurological diseases such as Alzheimer's disease. Key Words: Apolipoprotein E-Apolipoprotein J -Apolipoprotein Al -Alzheimer's disease-Cholesterol. J. Neurochem. 70, 2070Neurochem. 70, -2081Neurochem. 70, (1998.The intercellular transport of lipids through the aqueous circulatory system requires the packaging of these hydrophobic molecules into water-soluble carriers known as lipoproteins (high-density lipoprotein HDL; low-density lipoprotein LDL; and very-low-density lipoprotein, VLDL). Lipoproteins are macromolecular complexes composed of a phospholipid (PL) and free cholesterol (FC) shell surrounding a triglyceride (TG) and cholesteryl ester (CE) core (see Fig. 6A). Lipoproteins also contain apolipoproteins (apo), proteins that stabilize the surface of lipoproteins as they have both hydrophobic and hydrophilic domains. Apolipoproteins can also serve as cofactors for enzymatic reactions (Fielding et al., 1972) and ligands for cell surface receptors (Brown and Goldstein, 1986). In addition, alterations in apolipoproteins are associated with pathological conditions (Mahley, 1988). Whereas the regulation of lipoprotein metabolism and its effects on systemic lipid regulation have been studied extensively, much less is known about lipid tran...
Abstract-To determine whether T cells and B cells influence lipid metabolism and atherosclerosis, we crossed apolipoprotein E-deficient (apoE°) mice with recombination activating gene 2-deficient (RAG2°) mice. Total plasma cholesterol levels were Ϸ20% higher in male apoE°mice compared with the apoE°RAG2°mice at 8 weeks of age, and plasma triglyceride levels were 2.5-fold higher in the apoE°mice even when plasma cholesterol levels were similar. Male mice with plasma cholesterol levels between 400 and 600 mg/dL at 8 weeks of age were euthanized at 27 and 40 weeks of age. The aortic root lesion area in the apoE°RAG2°mice, compared with that in the immune-competent apoE°m ice, was 81% and 57% smaller at 27 and 40 weeks of age, respectively. In contrast, there was no difference in the size of the brachiocephalic trunk lesions. Similar results were obtained with mice euthanized at 40 weeks of age that had 8-week cholesterol levels between 300 and 399 mg/dL. In apoE°RAG2°mice, aortic root atherosclerosis was more profoundly suppressed at lower cholesterol levels. Thus, T and B cells and their products differentially influence the development of atherosclerosis at different sites. We also demonstrate a profound effect of the immune system on plasma lipid homeostasis. Key Words: atherosclerosis Ⅲ apolipoprotein E Ⅲ immune deficiency Ⅲ T cells Ⅲ lipoproteins T here is strong circumstantial evidence indicating that the immune response participates in the evolution of atherosclerosis in humans and experimental animals. Many components involved in this response have been detected in atherosclerotic vessels (see review 1 ). T cells are present in human 2 and murine 3 atherosclerotic lesions. Atherosclerotic plaques of apoE-deficient (apoE°) mice contain T cells reactive with oxidized lipoproteins and heat shock proteins. 4 ApoE°mice on a chow diet develop complex lesions throughout the vascular tree, and this occurrence is accelerated by a Western diet. 5,6 These mice have been crossed with recombination activating gene (RAG)1-deficient (RAG1°) and RAG2-deficient (RAG2°) mice. Both of these RAG proteins are necessary for recombination of the T-cell receptor and immunoglobulin genes; thus, RAG°mice lack mature T and B cells. ApoE°RAG1°mice fed a chow diet for 16 weeks showed a 2-fold reduction in aortic root atherosclerosis. 7 The male apoE°RAG1°mice also exhibited modest reductions in plasma cholesterol levels. On the other hand, the extent of atherosclerosis in apoE°mice with either RAG1 or RAG2 deficiency fed a Western diet was similar to that found in immune-competent apoE°mice. 7,8 The role of B cells in the development of atherosclerosis is less clear. Antibodies to oxidized lipoproteins 9 and to heat shock protein 65 10 have been detected in the plasma of subjects with atherosclerotic cardiovascular disease. High titers of circulating autoantibodies to oxidized lipoproteins have also been detected in apoE°mice. 11 Recently, Zhou and Hansson 12 demonstrated the presence of CD22ϩ B cells and IgM in the aortic root lesions...
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