Remodeling of HDL by CETP in vivo and by CETP and hepatic lipase in vitro results in enhanced uptake of HDL CE by cells expressing scavenger receptor B-I

Abstract

The transport of HDL cholesteryl esters (CE) from plasma to the liver involves a direct uptake pathway, mediated by hepatic scavenger receptor B-I (SR-BI), and an indirect pathway, involving the exchange of HDL CE for triglycerides (TG) of TG-rich lipoproteins by cholesteryl ester transfer protein (CETP). We carried out HDL CE turnover studies in mice expressing human CETP and/or human lecithin:cholesterol acyltransferase (LCAT) transgenes on a background of human apoA-I expression. The fractional clearance of HDL CE by the liver was delayed by LCAT transgene, while the CETP transgene increased it. However, there was no incremental transfer of HDL CE radioactivity to the TG-rich lipoprotein fraction in mice expressing CETP, suggesting increased direct removal of HDL CE in the liver. To evaluate the possibility that this might be mediated by SR-BI, HDL isolated from plasma of the different groups of transgenic mice was incubated with SR-BI transfected or control CHO cells. HDL isolated from mice expressing CETP showed a 2-to 4-fold increase in SR-BImediated HDL CE uptake, compared to HDL from mice lacking CETP. The addition of pure CETP to HDL in cell culture did not lead to increased selective uptake of HDL CE by cells. However, when human HDL was enriched with TG by incubation with TG-rich lipoproteins in the presence of CETP, then treated with hepatic lipase, there was a significant enhancement of HDL CE uptake. Thus, the remodeling of human HDL by CETP, involving CE-TG interchange, followed by the action of hepatic lipase (HL), leads to the enhanced uptake of HDL CE by cellular SR-BI. These observations suggest that in animals such as humans in which both the selective uptake and CETP pathways are active, the two pathways could operate in a synergistic fashion to enhance reverse cholesterol transport. -Collet, X., A. R. Tall, H. Serajuddin, K. Guendouzi, L. Royer, H. Oliveira, R. Barbaras, X-c. Jiang, and O. L. Francone. Remodeling of HDL by CETP in vivo and by CETP and hepatic lipase in vitro results in enhanced uptake of HDL CE by cells expressing scavenger receptor B-I.

Elevated cholesteryl ester transfer protein (CETP) activity, a major determinant of the atherogenic dyslipidemia, and atherosclerotic cardiovascular disease in South Asians

“…Smaller HDL particles have been shown to be cleared more rapidly from the circulation than normal HDL particles, thereby decreasing circulating HDL levels. 30,[44][45][46][47] Smaller cholesterol-depleted HDL particles also appear to be less able to carry out the anti-atherogenic functions of HDL, including antioxidant and anti-inflammatory activities and protection against cellular accumulation of cholesterol in the arterial wall. 48,49 In the case of LDL, smaller LDL particles are less readily able to bind to hepatic LDL receptors, the efficient mechanism of LDL particle clearance, thereby raising circulating LDL levels.…”

Hepatic lipase overexpression lowers remnant and LDL levels by a noncatalytic mechanism in LDL receptor-deficient mice

“…Furthermore, catalytically inactive HL reduced HDL-C and apoA-I (ϳ30%, did not reach statistical significance) in Ldlr Ϫ/Ϫ mice on a chow diet but had no effect on these levels in Ldlr Ϫ/Ϫ mice on a Western diet. The catalytically inactive HL could affect HDL levels of the chow-fed mice by serving as a ligand, concentrating the particles at the cell surface and facilitating direct uptake (via HSPG-syndecan-1) (28,41,42) or selective uptake mediated by the B1 scavenger receptor (43,44). It is conceivable that the absence of reduced HDL levels in Western diet-fed mice reflects displacement of HDL from HL S145G by high levels of apoB-containing lipoproteins, as has been described for the homologous enzyme lipoprotein lipase (45).…”

Triglyceride enrichment of HDL does not alter HDL-selective cholesteryl ester clearance in rabbits

“…HL bound to proteoglycan sulfate at hepatocytes promotes the selective uptake of HDL CE by a number of mechanisms (14), including via the SR-B1 receptor (23,27). Indeed, Collet et al (12) demonstrated that HDL CE uptake in vitro is enhanced in TGenriched human HDL upon treatment with HL.…”

“…1 To whom correspondence should be addressed at Toronto General Hospital, 200 Elizabeth St., Room EN11-229, Toronto, Ontario, Canada M5G 2C4. e-mail: gary.lewis@uhn.on.ca HDL isolated from CE transfer protein (CETP)/apoA-I transgenic mice showed a significant increase in SR-B1mediated HDL CE uptake in Chinese hamster ovary cells compared with control HDL isolated from apoA-I transgenic mice (12). The authors of the second study attributed the increase in HDL CE uptake to remodeling of HDL by CETP-mediated CE-TG interchange.…”