Human apolipoprotein A-I forms small high density lipoprotein particles in rats in vivo

Ha, Y.C.; Trifunovic, Zlatan; Howlett, Geoffrey J.

doi:10.1016/0005-2760(92)90049-2

Cited by 6 publications

(2 citation statements)

References 23 publications

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“…This result was not surprising, as it has been previously reported that ApoAI can inhibit both lipoprotein lipase and hepatic lipase in vitro. 10,35 Examples of ApoAI-targeting agents inducing transient triglyceridemia exist in multiple studies, including ApoAI mimetic peptides dosed into mice 10 and hApoAI administered to humans 11 ,25,36 and rats, 15 and RVX-208 administered to monkeys. 5 Although the exact mechanism and physiological impacts of this phenomenon are not well understood, caution needs to be taken and an optimal therapeutic window needs to be defined in clinical development of rHDL.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13][14] These approaches have resulted in favorable effects, such as increased plasma HDL or improvement in HDL function in vitro and in preclinical species. 5,7,15,16 However, positive effects in animals do not always translate to the clinic. For example, RVX-208, while inducing a large increase in HDL in nonhuman primates, 5 only modestly increased circulating ApoAI and HDL in humans, and dose was limited by increased circulating liver transaminases 17 ; similarly, L4F, an ApoAI mimetic peptide with efficacy in preclinical models, 18 failed to improve HDL function in humans.…”

Section: Introductionmentioning

confidence: 99%

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Reconstituted HDL Elicits Marked Changes in Plasma Lipids Following Single-Dose Injection in C57Bl/6 Mice

Chen

O’Neill

Meurer

et al. 2011

J Cardiovasc Pharmacol Ther

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High-density lipoprotein (HDL)-targeting therapies, including reconstituted HDL (rHDL), are attractive agents for treating dyslipidemia and atherosclerosis, as they may increase HDL levels and enhance therapeutic activities associated with HDL, including reverse cholesterol transport (RCT). Using CSL-111, a rHDL consisting of native human apolipoprotein AI (hApoAI) and phospholipids, we characterized the acute effects of rHDL administration in C57Bl/6 mice to (i) further our understanding of the mechanism of action of rHDL, and (ii) evaluate the usefulness of the mouse as a preclinical model for HDL-targeting therapies. After a single injection of CSL-111, there was a dose- and time-dependent increase of hApoAI, human pre-β HDL, total cholesterol, and triglycerides in serum, consistent with the effects of CSL-111 in humans. However, unlike in humans, there was no measurable increase in cholesteryl esters. Evaluated ex vivo, the ATP binding cassette A1 (ABCA1)- and scavenger receptor type BI (SR-BI)-dependent cholesterol efflux capacity of serum from CSL-111-treated mice was increased compared with serum from vehicle-treated animals. Fractionation by size exclusion chromatography of lipoproteins in serum from treated mice revealed hApoAI in particles the size of endogenous HDL and slightly larger, cholesterol-enriched particles of all sizes, including sizes distinct from endogenous HDL or CSL-111 itself, and triglyceride-enriched particles the size of very-low-density lipoprotein (VLDL). These results suggest that in mouse blood CSL-111 is remodeled and generates enhanced cholesterol efflux capacity which increases mobilization of free cholesterol from peripheral tissues. Our findings complement the previous reports on CSL-111 in human participants and provide data with which to evaluate the potential utility of mouse models in mechanistic studies of HDL-targeting therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reconstituted HDL Elicits Marked Changes in Plasma Lipids Following Single-Dose Injection in C57Bl/6 Mice

Chen

O’Neill

Meurer

et al. 2011

J Cardiovasc Pharmacol Ther

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Alteration in rat apolipoprotein C-III gene expression and lipoprotein composition during inflammation

Shen

Howlett

1993

Inflammation

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A cloned rat apolipoprotein (apo) C-III cDNA was used as a hybridization probe to measure apo C-III mRNA levels in rats after induction of inflammation. Hepatic apo C-III mRNA levels decrease to a minimum value of 46% of normal 72 h after the induction of inflammation. The changes observed are very similar to the changes in mRNA levels of rat apo A-IV, while the hepatic mRNA levels for apo A-I and apo C-I during inflammation remain relatively constant. Alterations in apo C-III gene expression during inflammation were associated with changes in lipoprotein particle size and composition. A decrease of approximately twofold in the amount of apo C-III-containing HDL particles was found in rats 24 h after the induction of inflammation. The average size of apo C-III-containing HDL particles in rats during inflammation is significantly larger than that of the control group. A decrease in the concentration of apo A-I-containing HDL particles was also observed in these rats. The results indicate altered apolipoprotein gene expression associated with alterations in the size and composition of HDL particles.

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Drug control of reverse cholesterol transport

Franceschini¹,

Werba²,

Calabresi³

1994

Pharmacology & Therapeutics

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Human apolipoprotein A-I forms small high density lipoprotein particles in rats in vivo

Cited by 6 publications

References 23 publications

Reconstituted HDL Elicits Marked Changes in Plasma Lipids Following Single-Dose Injection in C57Bl/6 Mice

Reconstituted HDL Elicits Marked Changes in Plasma Lipids Following Single-Dose Injection in C57Bl/6 Mice

Alteration in rat apolipoprotein C-III gene expression and lipoprotein composition during inflammation

Drug control of reverse cholesterol transport

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