Circulating Levels Of HDL Research Articles

ABCA1-dependent lipid efflux to apolipoprotein A-I mediates HDL particle formation and decreases VLDL secretion from murine hepatocytes

High levels of expression of the ATP binding cassette transporter A1 (ABCA1) in the liver and the need to over- or underexpress hepatic ABCA1 to impact plasma HDL levels in mice suggest a major role of the liver in HDL formation and in determining circulating HDL levels. Cultured murine hepatocytes were used to examine the role of hepatic ABCA1 in mediating the lipidation of apolipoprotein A-I (apoA-I) for HDL particle formation. Exogenous apoA-I stimulated cholesterol efflux to the medium from wild-type hepatocytes, but not from ABCA1-deficient (abca1(-/-)) hepatocytes. ApoA-I induced the formation of new HDL particles and enhanced the lipidation of endogenously secreted murine apoA-I in ABCA1-expressing but not abca1(-/-) hepatocytes. ABCA1-dependent cholesterol mobilization to apoA-I increased new cholesterol synthesis, indicating depletion of the regulatory pool of hepatocyte cholesterol during HDL formation. Secretion of triacylglycerol and apoB was decreased following apoA-I incubation with ABCA1-expressing but not abca1(-/-) hepatocytes. These results support a major role for hepatocyte ABCA1 in generating a critical pool of HDL precursor particles that enhance further HDL generation and passive cholesterol mobilization in the periphery. The results also suggest that diversion of hepatocyte cholesterol into the "reverse" cholesterol transport pathway diminishes cholesterol availability for apoB-containing lipoprotein secretion by the liver.

098 Smoking, Atherosclerosis, and MCP‐1 Expression

The inflammatory events of atherosclerosis involve monocytes, endothelial cells, smooth muscle cells, and several cytokines, including chemokines. Atherosclerosis begins with recruitment of circulating monocytes to sites of blood vessel injury. In the vessel wall, these cells are activated to become macrophages that scavenge toxic material such as oxidized LDL and transition into “foam cells” which will eventually lead to plaque formation. Tobacco smoke is known to exacerbate cardiovascular disease but the mechanisms by which this occurs are not known. The chemokine MCP‐1 is involved in recruiting monocytes to the injured blood vessel wall and is commonly found in atherosclerotic plaques. Our data show that both “first‐hand” and “second‐hand” cigarette smoke stimulate MCP‐1 production in cultured primary human aortic endothelial cells (EC), suggesting that cigarette smoke may contribute to plaque formation by stimulating aortic EC to produce MCP‐1 in blood vessels after smoke injury. To test whether MCP‐1 links smoking and cardiovascular disease, we are studying the expression of this molecule in mice that are either transgenic for human ApoB or are null for MCP‐1 or its receptor, CCR2, by exposing the mice to smoke in a way that closely resembles human smoking. Blood samples from the mice were tested for carboxyhemoglobin, triglycerides, LDL and HDL, and MCP‐1 at successive weeks after initiation of smoking and the aortas isolated to analyze for plaque size and MCP‐1 expression in the tissue. The carboxyhemoglobin test shows that the mice are exposed to smoke. Plasma MCP‐1 and HDL levels are reduced in the smoking groups, whereas LDL, triglyceride, and total cholesterol remain unchanged. On one hand, the decrease in circulating HDL levels suggests that the reason smokers develop atherosclerosis may be because the rate of cholesterol clearance is slowed down. On the other hand, a decrease in circulating MCP‐1 level may reflect that this chemokine accumulates in blood vessel walls, conferring stronger ability for attraction of monocytes.This work is supported by TRDRP and Phillip Morris.

Estrogen-induced regulation of the ATP-binding cassette transporter A1 (ABCA1) in mice: a possible mechanism of atheroprotection by estrogen.

Estrogens are suggested to be antiatherogenic by affecting the vessel wall components. Since ABCA1 was recently shown to be atheroprotective, it was examined if estrogen-induced atheroprotection occurs partly via the regulation of the ABCA1. Since hepatic ABCA1 expression was also suggested to contribute to the bulk HDL levels, regulation of the ABCA1 under conditions of high or low levels of HDL were investigated in mice expressing normal or elevated levels of apoAI. To delineate whether estrogen's effect occurs via estrogen receptor-alpha-mediated pathway, the estrogen receptor-alpha-deficient (ER-alpha)-/- mice were also administered either placebo or beta-estradiol for 5 consecutive days. Estrogen treatments decreased circulating HDL levels by 30%, but increased hepatic and intestinal ABCA1 mRNA by 2- and 1.5-fold, respectively. Hepatic ABCA1 mRNA also increased in the ER-alpha-/- mice by 3-fold. These results suggest that estrogen, despite lowering the levels of HDL, it up-regulated the hepatic ABCA1 mRNA, and in the absence of ER-alpha, ER-beta could compensate for ER-alpha. To study whether HDL levels correlate with the ABCA1 expression, wild-type (WT) and the apoAI transgenic (A1-Tg) mice were fed high fat (HF) diet with or without cholic acid (CA) for 3 weeks. One group of mice was treated with fenofibrate, known to elevate HDL levels. CA without HF decreased HDL levels, while fenofibrate increased HDL levels. However, neither CA nor fenofibrate altered hepatic ABCA1 mRNA levels. HF diet increased the hepatic ABCA1 mRNA 1.8-fold in WT, but lowered ABCA1 mRNA by 2-fold in A1-Tg mice, suggesting that ABCA1 levels did not correlate with circulating HDL levels, while basal levels of HDL influenced ABCA1 expression. These data show for the first time that estrogen's antiatherogenic effects may occur via ABCA1-mediated pathway, and circulating HDL levels may influence expression of ABCA1.

ATP binding cassette transporter A1--key roles in cellular lipid transport and atherosclerosis.

ATP-binding cassette transporter A1 (ABCA1) was recently recognized as the mutant molecule responsible for Tangier disease with low HDL levels, accumulation of cholesteryl esters in tissues, and increased risk of cardiovascular disease. Extensive studies for the past 2 years have recognized the critical role of ABCA1 in cholesterol and phospholipid trafficking. Since the removal of cholesterol from tissues is a key step in the prevention of atherosclerosis, significant attention has been focused on this molecule. Natural ABCA1 mutations in Tangier disease (TD) patients and WHAM chickens together with induced mutation in ABCA1 knock-out mice unequivocally established the important role of ABCA1 in maintaining circulating HDL levels and promoting cholesterol efflux from the arterial wall. Mice lacking ABCA1 showed similar phenotypes observed in Tangier disease patients with low levels of HDL. Further understanding of the roles of ABCA1 in lipid transport and atherosclerosis became clear from studies with ABCA1 transgenic mice. These mice showed enhanced cholesterol efflux from macrophages and reduced atherosclerotic lesion formation. The promoter of the ABCA1 gene has been mapped to a large extent, with the exception of cAMP response element. The present review summarizes recent developments on the role of ABCA1 in cholesterol efflux and prevention of atherosclerosis. Given the antiatherogenic properties of ABCA1, this molecule can serve as an appropriate target for developing drugs to treat individuals with low levels of HDL.