CETP expression reverses the reconstituted HDL-induced increase in VLDL

Effect of open-label infusion of an apoA-I-containing particle (CER-001) on RCT and artery wall thickness in patients with FHA

“…Similar effects have been reported upon apoA-I infusion in experimental models (29)(30)(31). The VLDL-c increase in response to apoA-I infusion has been attributed to both increased CETP-mediated cholesterol exchange between HDL-c and VLDL-c leading to higher VLDL-c, as well as to enhanced hepatic VLDL production refl ecting an increased cholesterol fl ux toward the liver ( 29,31 ). However, the observations that the increase in VLDL-c was confi ned to unesterifi ed cholesterol in our participants, together with previous observations that CER-001 also increased VLDL-c in mice, which are naturally CETP-defi cient ( 30,32 ), argue against a CETP-driven mechanism, and hint toward an increased VLDL secretion.…”

“…Similar effects have been reported upon apoA-I infusion in experimental models (29)(30)(31). The VLDL-c increase in response to apoA-I infusion has been attributed to both increased CETP-mediated cholesterol exchange between HDL-c and VLDL-c leading to higher VLDL-c, as well as to enhanced hepatic VLDL production refl ecting an increased cholesterol fl ux toward the liver ( 29,31 ).…”

Male apoE*3-Leiden.CETP mice on high-fat high-cholesterol diet exhibit a biphasic dyslipidemic response, mimicking the changes in plasma lipids observed through life in men

“…; Wang et al. ) were housed individually and fed a synthetic HFCD diet containing 60% fat in energy and 0.25% cholesterol in weight (D12429, Research Diets) in a light (lights on at 7:00 AM–lights off at 7:00 PM) and temperature‐controlled (21°C) facility. Prior to the start of the experimental period, mice were co‐housed with siblings and fed chow ad libitum with unlimited access to drinking water.…”

“…Similarly, while mice carry most of their plasma cholesterol in high‐density lipoprotein (HDL), humans have a large LDL‐c fraction (Wang et al. ). To mitigate these species‐specific differences, we make use of “humanized” apoE*3‐Leiden.CETP (E3L.CETP) mice, in which the apoE*3‐Leiden transgene confers reduced clearance of triglyceride‐rich lipoprotein (i.e., chylomicron‐ and VLDL‐remnants), and the cholesteryl ester transfer protein (CETP) transgene further adds to a cholesterol profile more closely resembling that of humans (Westerterp et al.…”

Effect of repeated apoA-IMilano/POPC infusion on lipids, (apo)lipoproteins, and serum cholesterol efflux capacity in cynomolgus monkeys

“…We propose that the infusion of MDCO-216 has likewise led to enhanced production and secretion of apoE in the monkeys. Other researchers ( 46,47 ) have shown that apoE is able to cause effl ux of FC and PL from macrophages, thus producing apoE-containing nascent HDL in an ABCA1-dependent increased delivery of cholesterol and phospholipids to the liver, described in other animal models to lead to increased VLDL production ( 35,36 ), or alternatively, of decreased VLDL clearance as observed after administration of high doses of reconstituted HDL to apoE knockout mice ( 37 ) or apoE3-Leiden mice ( 38 ).…”