Fractional esterification rate of cholesterol in high density lipoprotein (HDL) (FER[HDL]) can predict the size distribution and physicochemical characteristics of HDL in plasma. In the present study, we investigated the correlation of FER(HDL) with the particle size of low density lipoprotein (LDL) (LDL-size) in 111 patients (81 males and 30 females) with coronary heart disease (CHD). The correlations of FER(HDL) and LDL-size with conventional lipid and lipoprotein parameters were also studied. FER(HDL) was closely associated with LDL-size (males: r = -0.618, females: r = -0.629, P < 0.001). Plasma levels of TG, HDL-cholesterol (HDL-C), HDL2-cholesterol (HDL2-C) and apo B were also associated with LDL-size in male CHD patients (r = -0.534, 0.314, 0.358, and -0.482, P < 0.01 or 0.001), while plasma levels of TG and apo B were associated with LDL-size in female patients (r = -0.350 and -0.348, P < 0.05). In a stepwise multiple regression analysis, FER(HDL) alone accounted for 38 and 40% of the variability in LDL-size in male and female CHD patients, respectively. Other parameters accounted for an additional 6-10%. With respect to the relation between FER(HDL) and HDL subfractions, FER(HDL) related only to HDL2-C (males: r = -0.640, females: r = -0.652, P < 0.001). This result suggests that FER(HDL) is better able to predict the presence (or absence) of large HDL, rather than that of small HDL. All these data taken together, suggest that FER(HDL) is a useful tool to predict the particle size of both LDL and HDL, even in CHD patients.
The qualitative and quantitative changes in LDL and HDL in diabetic children are similar to those associated with a reduced risk for CAD. Intensive insulin therapy in children may help preventing coronary heart disease in adulthood.
Cholesteryl ester transfer protein (CETP) is thought to regulate plasma HDL. Patients with CETP deficiency caused by mutation of the CETP gene [D442G; a missense mutation (Asp4423 Gly)] have been reported to show high plasma HDL levels. However, there are no data available on children with D442G. To determine the effects of plasma CETP and CETP gene mutation (D442G) on lipids and lipoproteins in children, we screened children by PCR and restriction fragment length polymorphism analysis of the CETP gene. Plasma lipids, apolipoproteins, and CETP mass levels were also determined. In the current study, 22 children with D442G were found (21 heterozygotes and a homozygote). A homozygous child showed high plasma HDL level and very low plasma CETP mass. In heterozygous children, plasma concentrations of HDL cholesterol, apo A-I and apo A-II were not increased, whereas plasma CETP mass was significantly decreased. Plasma CETP mass in heterozygous children was correlated with plasma concentrations of total cholesterol, LDL cholesterol, and apo B. Plasma CETP mass in children without D442G was not correlated with the plasma concentration of any lipid or apolipoprotein. All of these data suggest that the D442G mutation, by itself, might not affect HDL metabolism in children. The CETP mass required for efficient HDL-cholesteryl ester clearance in children may be less than that in older subjects. Esterification of cholesterol from peripheral tissues and subsequent transfer of CE from HDL to other lipoproteins are key steps in reverse cholesterol transport, i.e. transport from peripheral cells to the liver for excretion (1, 2). In humans, extracellular cholesterol is esterified by the action of LCAT, and the CE generated is transferred to the liver by two known pathways: 1) uptake of HDL particles by the liver (3, 4), and 2) uptake of HDL CE by LDL receptor in the liver via transfer of HDL-CE to VLDL and LDL, in a process mediated by CETP (1, 2, 5). Most LCAT and CETP are associated with HDL particles in human plasma (6, 7). Cholesterol esterification in HDL by LCAT increases the size of HDL particles, and the transfer of CE from HDL particles reduces the size of HDL. Thus, the size of HDL particles reflects the net rate of CE generation on and CE transfer from HDL particles. Furthermore, we have shown in previous studies that the function of HDL, as well as the particle size, is strongly affected in the presence of LCAT or CETP deficiency (8, 9). These findings, taken together, suggest that LCAT and CETP play a central role in maintaining the antiatherogenic nature of HDL.To date, several common polymorphisms have been reported in the CETP gene (10 -12). Most are located within intronic regions and do not appear to affect either the secretion or the function of CETP. Two mutations, an intron 14 splice donor site mutation (Int14A) and a missense mutation within exon 15 (D442G), have been reported in Japanese subjects with high HDL-C levels (Ͼ100 mg/dL) (13-15). These mutations affect the structure and function of CETP and are ...
We have previously shown that acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) protein content increases significantly during the human monocyte-macrophage differentiation process. To gain further insight, we used undifferentiated human monocytic THP-1 cells as a model system with which to examine whether ACAT-1 mRNA and protein content can be increased by treating cells with 1,25-dihydroxyvitamin D 3 [1,25-(OH) 2 D 3 ] or with 9-cis -retinoic acid (9-cis -RA), two agents known to upregulate the expression of various genes during the monocyte-macrophage differentiation process. Immunoblot analysis with anti-human ACAT-1 antibodies revealed that ACAT-1 protein was increased by 2.6-fold, using 1,25-(OH) 2 D 3 at a physiological concentration (100 pM). ACAT-1 protein was also increased when using 9-cis -RA, but only at relatively high concentrations (0.1-1 M). Northern blot analysis revealed that among the four ACAT-1 mRNA transcripts (2.8, 3.6, 4.2, and 7.0 kb) examined, only the 2.8-and 3.6-kb transcripts were selectively increased. On the basis of enzyme assays in vitro, ACAT activity was increased 3.0-fold by using 100 nM 1,25-(OH) 2 D 3 , and 1.8-fold by using 1 M 9-cis -RA.Together, our results suggest that 1,25-(OH) 3 participates in ACAT-1 gene expression during the monocyte-macrophage differentiation process. -Maung, K. K., A. Miyazaki, H. Nomiyama, C. C. Y. Chang, T-Y. Chang, and S. Horiuchi. Induction of acyl-coenzyme A:cholesterol acyltransferase-1 by 1,25-dihydroxyvitamin D 3 or 9-cis -retinoic acid in undifferentiated THP-1 cells.
designated as ACAT-1). Using affinity purified antibodies raised against N-terminal portion of human ACAT-1 protein, we performed immunohistochemical localization studies, and showed that the ACAT-1 protein was highly expressed in the atherosclerotic lesions of human aorta. We also performed cell-specific localization studies using double immunostaining, and showed that ACAT-1 was predominantly expressed in macrophages, but not in smooth muscle cells. We then used cell culture system in vitro to monitor the ACAT-1 expression in differentiating monocytesmacrophages. The ACAT-1 protein content increased by up to 10-fold when monocytes spontaneously differentiate into macrophages. This increase occurred within the first two days of culturing the monocytes, and reached a plateau level within four days of culturing, indicating that the increase in ACAT-1 protein content is an early event during the monocyte differentiation process. The ACAT-1 protein expressed in the differentiating monocytemacrophages was shown to be active by enzyme assay in vitro. The high levels of ACAT-1 present in macrophages maintained in culture can explain the high ACAT-1 content found in the atheroslerotic lesions. Our results thus support the idea that ACAT-1 plays an important role in the differentiating monocytes, and in forming the macrophage foam cells during the development of human atherosclerosis.
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