The ATP-binding cassette transporter 1 (ABCA1) has recently been identified as a key regulator of high-density lipoprotein (HDL) metabolism, which is defective in familial HDL-deficiency syndromes such as Tangier disease. ABCA1 functions as a facilitator of cellular cholesterol and phospholipid efflux, and its expression is induced during cholesterol uptake in macrophages. To assess the role of macrophage ABCA1 in atherosclerosis, we generated lowdensity lipoprotein (LDL) receptor knockout (LDLr ؊/؊ ) mice that are selectively deficient in leukocyte ABCA1 (ABCA1 ؊/؊ ) by using bone marrow transfer (ABCA1 ؊/؊ 3 LDLr ؊/؊ ). Here we demonstrate that ABCA1 ؊/؊ 3 LDLr ؊/؊ chimeras develop significantly larger and more advanced atherosclerotic lesions compared with chimeric LDLr ؊/؊ mice with functional ABCA1 in hematopoietic cells. Targeted disruption of leukocyte ABCA1 function did not affect plasma HDL cholesterol levels. The amount of macrophages in liver and spleen and peripheral blood leukocyte counts is increased in the ABCA1 ؊/؊ 3 LDLr ؊/؊ chimeras. Our results provide evidence that leukocyte ABCA1 plays a critical role in the protection against atherosclerosis, and we identify ABCA1 as a leukocyte factor that controls the recruitment of inflammatory cells.

We describe the 2-year follow-up of an open-label trial (CT-AMT-011-01) of AAV1-LPL S447X gene therapy for lipoprotein lipase deficiency (LPLD), an orphan disease associated with chylomicronemia, severe hypertriglyceridemia, metabolic complications and potentially lifethreatening pancreatitis. The LPL S447X gene variant, in an adeno-associated viral vector of serotype 1 (alipogene tiparvovec), was administered to 14 adult LPLD patients with a prior history of pancreatitis. Primary objectives were to assess the long-term safety of alipogene tiparvovec and achieve a ≥40% reduction in fasting median plasma triglyceride (TG) at 3-12 weeks compared with baseline. Cohorts 1 (n=2) and 2 (n=4) received 3 × 10 11 gc/kg, and cohort 3 (n=8) received 1 × 10 12 gc/kg. Cohorts 2 and 3 also received immunosuppressants from the time of alipogene tiparvovec administration and continued for 12 weeks. Alipogene tiparvovec was well tolerated, without emerging safety concerns for 2 years. Half of the patients demonstrated a ≥40% reduction in fasting TG between 3-12 weeks. TG subsequently returned to baseline, although sustained LPL S447X expression and long-term changes in TG-rich lipoprotein characteristics were noted independently of the effect on fasting plasma TG.

Scavenger receptor class B, type I (SRBI) is a key regulator of high density lipoprotein (HDL) metabolism.It facilitates the efflux of cholesterol from cells in peripheral tissues to HDL and mediates the selective uptake of cholesteryl esters from HDL in the liver. We investigated the effects of SRBI deficiency in the arterial wall and in the liver using SRBI-deficient mice and wild-type littermates fed a Western-type diet. The SRBIdeficient mice showed massive accumulation of cholesterol-rich HDL in the circulation, reflecting impaired delivery to the liver. Strikingly, SRBI deficiency did not alter hepatic cholesterol (ester) content nor did it affect the expression of key regulators of hepatic cholesterol homeostasis, including HMG-CoA reductase, the low density lipoprotein receptor, and cholesterol 7␣-hydroxylase. However, a ϳ40% reduction in biliary cholesterol content was observed, and the expression of ABCG8 and ABCG5, ATP half-transporters implicated in the transport of sterols from the liver to the bile, was attenuated by 70 and 35%, respectively. In contrast to the situation in the liver, SRBI deficiency did result in lipid deposition in the aorta and atherosclerosis. Vascular mRNA analysis showed increased expression of inflammatory markers as well as of genes involved in cellular cholesterol homeostasis. Our data show that, although hepatic cholesterol homeostasis is maintained upon feeding a Western-type diet, SRBI deficiency is associated with de-regulation of cholesterol homeostasis in the arterial wall that results in an increased susceptibility to atherosclerosis.

IntroductionThe LDL receptor plays a critical role in the regulation of plasma LDL levels by mediating approximately two thirds of LDL clearance (1-3). Loss of LDL receptor function leads to decreased LDL catabolism and elevated LDL levels (4). LDL receptor levels are affected by diet, hormones, and most dramatically, by mutations in the LDL receptor locus that lead to familial hypercholesterolemia (FH).Early studies of LDL metabolism in patients with FH revealed that in addition to the LDL clearance defect, they overproduce LDL (5, 6) and relatively small VLDL particles (7). VLDL is the metabolic precursor of LDL and is converted to LDL through the action of lipoprotein lipase, a triacylglycerol lipase that acts upon VLDL while it circulates in the bloodstream (8). Increased production of VLDL can lead to increased LDL simply by providing more precursor. In addition, impaired clearance of VLDL remnants can lead to LDL overproduction (9).A long-standing paradox in the lipoprotein field is posed by the cholesterol-lowering drugs known as statins. These drugs inhibit 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, a tightly regulated step in the cholesterol biosynthetic pathway (10). Cells respond to the dearth of cholesterol by upregulating transcription of cholesterol-regulated genes, including the LDL receptor (11). Statins are ineffective in patients homozygous for null alleles of the LDL receptor (12). It has therefore been inferred that statins act by increasing LDL catabolism via upregulation of the LDL receptor. Paradoxically, statins do not always affect the LDL clearance rate. Rather, in many clinical studies (13)(14)(15) and animal studies (16,17), statins decrease VLDL and/or LDL production (reviewed in ref. 18).The post-translational fate of apoB, the major protein component of VLDL, can be explained by multiple mechanisms. In human and rat hepatoma cell lines, a large proportion of newly synthesized apoB is degraded within the secretory pathway (19). Thus, the rate of apoB secretion, and hence, VLDL secretion, from the liver is determined by the proportion of apoB that escapes coor post-translational degradation (20,21). In addition, reuptake of newly secreted lipoproteins has also been proposed to regulate the net output of apoB (22).How can the presence or absence of a functional LDL receptor affect the production of lipoproteins? We addressed this question by studying apoB secretion in cultured hepatocytes isolated from wild-type mice and mice lacking a functional LDL receptor (Ldlr -/-). Similar to FH, previous studies with Ldlr -/-mice revealed a decrease in LDL clearance (23) and a marked increase in plasma apoB levels (23-26). Our results with primary hepatocytes from these animals indicate that the LDL receptor is involved Jaap Twisk and Donald L. Gillian-Daniel contributed equally to this work.Received for publication October 6, 1999, and accepted in revised form December 28, 1999. Familial hypercholesterolemia is caused by mutations in the LDL receptor gene (Ldlr). Elevated plasma LDL ...