Gemfibrozil significantly lowers cynomolgus monkey plasma lipoprotein[a]-protein and liver apolipoprotein[a] mRNA levels.

Ramharack, Randy; Spahr, Mark A.; Hicks, Gary W.; Kieft, Karen A.; Brammer, David W.; Minton, Laura L.; Newton, Roger S.

doi:10.1016/s0022-2275(20)41137-x

Cited by 27 publications

(5 citation statements)

References 57 publications

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“…The physiological role of apoC-III was revealed in apoC-III transgenic animals with reduced VLDL catabolic rate . The utility of fibrates in raising HDL has been tested in both primate models and clinical trials. − Gemfibrozil has been used for clinical studies to demonstrate that elevated HDL levels resulted in a significant reduction of CAD risk. , …”

Section: 41 Fibrates and Other Pparα Agonistsmentioning

confidence: 99%

“…231 The utility of fibrates in raising HDL has been tested in both primate models and clinical trials. [232][233][234][235] Gemfibrozil has been used for clinical studies to demonstrate that elevated HDL levels resulted in a significant reduction of CAD risk. 6,7 The effects on apoA-I are thought to be more direct with many experiments in animals showing significant positive correlation of HDL with apoA-I.…”

Section: Fibrates and Other Pparr Agonistsmentioning

confidence: 99%

See 1 more Smart Citation

HDL: The Metabolism, Function, and Therapeutic Importance

Wang¹,

Briggs²

2003

Chem. Rev.

123

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Section: 41 Fibrates and Other Pparα Agonistsmentioning

confidence: 99%

Section: Fibrates and Other Pparr Agonistsmentioning

confidence: 99%

HDL: The Metabolism, Function, and Therapeutic Importance

Wang¹,

Briggs²

2003

Chem. Rev.

123

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“…To date, little information is available concerning the molecular characterization of nonhuman primate apo(a) proteins. Indeed, only the carboxy-terminal domain of rhesus monkey and the amino-terminal extremity of cynomolgus apo(a)s have been characterized (22,40). The available data indicate that the main properties of apo(a), i.e., its covalent attachment to apoB100 and its ability to bind to fibrin, principally involve the carboxy-terminal domain of the apo(a) protein (1,3,13,26).…”

Section: Discussionmentioning

confidence: 99%

Molecular Cloning of the cDNA Encoding the Carboxy-Terminal Domain of Chimpanzee Apolipoprotein(a): An Asp57 → Asn Mutation in Kringle IV-10 Is Associated with Poor Fibrin Binding

et al. 1998

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Insight into the structural features of human lipoprotein(a) [Lp(a)] which underlie its functional implication in fibrinolysis may be gained from comparative studies of apo(a). Indeed, cloning of rhesus monkey apo(a) has shown that a Trp72 --> Arg mutation in the lysine-binding site (LBS) of KIV-10 leads to loss of lysine-binding properties of the rhesus Lp(a) particle. Consequently, comparative studies of apo(a) sequences in different Old World monkey species should further our understanding of the molecular role of Lp(a) in the fibrinolytic process. In contrast to other Old World monkeys, including rhesus monkey, cynomolgus, and baboon, the chimpanzee exhibits an elevated level of Lp(a) and a distinct isoform distribution as compared to humans [Doucet et al. J. Lipid Res. (1994) 35, 263-270]. Clearly then, the chimpanzee is an interesting animal model for study of the structure, function, and potential pathophysiological roles of Lp(a). We have cloned and sequenced the region of chimpanzee apo(a) cDNA spanning KIV-3 to the stop codon. The global organization of this region is similar to that of human apo(a) with the presence of KV, which is absent in rhesus monkey apo(a). Nucleotide sequence comparison indicates a variation of 1.4% between chimpanzee and man and 5.1% between chimpanzee and rhesus monkey. The differences concerned single base changes. An Asp57 --> Asn mutation was detected in KIV-10; this residue is critical to the LBS of KIV-10 in human apo(a). To verify that the Asp57 --> Asn substitution was specific to apo(a), we have also cloned the cDNA-encoding plasminogen, which exhibited an Asp at the corresponding position in kringle IV. Using an in vitro binding assay, we have demonstrated that chimpanzee Lp(a) exhibits poor lysine-specific interaction with both intact and plasmin-degraded fibrin as compared to its human counterpart. We propose that the Asn57 substitution in KIV-10 of chimpanzee apo(a) is responsible for this property. Chimpanzee Lp(a) therefore represents an appropriate particle with which to explore the potential effects of Lp(a) on the fibrinolytic system, such as the inhibition of plasminogen activation or inhibition of t-PA activity.

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“…(35)(36)(37)]. Both transcriptional and posttranscriptional mechanisms may play roles in regulation of Lp[a] levels by these factors (38)(39)(40)(41)(42)(43)(44)(45)(46)(47).…”

Section: Apolipoprotein [A] (Apo[a]) Is the Unique Glycoprotein Component Of Plasma Lipoprotein [A] (Lp[a]mentioning

confidence: 99%

Determinants of human apolipoprotein [a] secretion from mouse hepatocyte cultures

Wang

Boedeker

Hobbs

et al. 2001

Journal of Lipid Research

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Efforts to develop an in vitro model system to analyze apolipoprotein [a] (apo[a]) gene transcription, mRNA translation, and protein secretion have been complicated by the limited tissue and species distribution of apo[a] and the presence of regulatory DNA sequences remote from the apo[a] transcription start site. In the current study we examined primary hepatocytes cultured from apo[a] transgenic mice as a model system for analyzing apo[a] biogenesis. Hepatocytes from mice transgenic for a yeast artificial chromosome (YAC) encoding the entire apo[a] gene in its own genomic context (YAC-apo[a] hepatocytes) were unable to maintain apo[a] expression beyond 48 h of culture. This suggests that the apo[a] promoter was not active in cultured YAC-apo[a] hepatocytes. In contrast, apo[a] expression was maintained for at least 7 days in hepatocytes cultured from mice transgenic for an apo[a] cDNA under control of the mouse transferrin promoter (transferrin-apo[a] hepatocytes). Pulse-chase experiments established that more than 80% of apo[a] synthesized by both transferrin-apo[a] and YAC-apo[a] hepatocytes was degraded prior to secretion, independently of the coexpression of human apoB. Thus, low secretion efficiency appears to be a general characteristic of human apo[a] proteins in mouse liver. Apo[a] secretion was increased somewhat (from 18% to 32%) in the presence of lipoprotein-containing serum. Transformed cell lines derived from transferrin apo[a] hepatocytes retained characteristics of apo[a] secretion similar to those observed in primary cells. Primary and transformed apo[a] transgenic hepatocytes may provide valuable additional models with which to study posttranslational mechanisms regulating apo[a] secretion. -Wang, J., J. Boedeker, H. H. Hobbs, and A. L. White. Determinants of human apolipoprotein [a] secretion from mouse hepatocyte cultures.

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Gemfibrozil significantly lowers cynomolgus monkey plasma lipoprotein[a]-protein and liver apolipoprotein[a] mRNA levels.

Cited by 27 publications

References 57 publications

HDL: The Metabolism, Function, and Therapeutic Importance

HDL: The Metabolism, Function, and Therapeutic Importance

Molecular Cloning of the cDNA Encoding the Carboxy-Terminal Domain of Chimpanzee Apolipoprotein(a): An Asp57 → Asn Mutation in Kringle IV-10 Is Associated with Poor Fibrin Binding

Determinants of human apolipoprotein [a] secretion from mouse hepatocyte cultures

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