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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
12
|
| pubmed:dateCreated |
1998-3-6
|
| pubmed:abstractText |
Low density lipoprotein (LDL) reduction independent of LDL receptor regulation was investigated using HMG-CoA reductase inhibitors in LDL receptor-deficient mice. In males, LDL cholesterol dose-dependently decreased with atorvastatin treatment after 1 week. As untreated mice grew older, their LDL cholesterol progressively rose above basal levels, but was quelled with atorvastatin treatment. In females, atorvastatin treatment time-dependently decreased LDL cholesterol levels and induced hepatic HMG-CoA reductase activity. Unlike males, cholesterol-lowering effects of the drug were sustained in females. Lovastatin, simvastatin, and pravastatin also reduced total and LDL cholesterol; however, additional studies in females demonstrated that atorvastatin caused the greatest dose-dependent and sustained effect after 2 weeks. In females, hepatic HMG-CoA reductase mRNA inversely correlated with LDL cholesterol lowering, with atorvastatin showing the greatest increase in mRNA levels (17.2-fold), followed by lovastatin (10.7-fold), simvastatin (4.1-fold), and pravastatin (2.5-fold). Atorvastatin effects on lipoprotein production were determined after acute (1 day) or chronic (2 week) treatment prior to intraperitoneal injection of Triton WR1339. Acute treatment reduced cholesterol (-29%) and apoB (-16%) secretion, with no change in triglyceride secretion. In contrast, chronic treatment elevated cholesterol (+20%), apoB (+31%), and triglyceride (+57%) secretion. Despite increased cholesterol and apoB secretion, plasma levels were reduced by 51% and 46%, respectively. Overall, under acute or chronic conditions, apoB paralleled cholesterol secretion rates, and triglyceride to cholesterol secretion ratios were elevated by 38% and 32%, respectively. We propose that atorvastatin limits cholesterol for lipoprotein assembly, which is compensated for by triglyceride enrichment. In addition, with either acute or chronic atorvastatin treatment, apoB-100 secretion was blocked, and compensated for by an increased secretion of apoB-48. The apoB-48 particles produced are cleared by LDL receptor-independent mechanisms, with an overall effect of reducing LDL production in these mice. These studies support the idea that HMG-CoA reductase inhibitors modulate lipoprotein levels independent of LDL receptors, and suggest they may have utility in hyperlipidemias caused by LDLreceptor disorders.
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| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Anticholesteremic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Apolipoproteins B,
http://linkedlifedata.com/resource/pubmed/chemical/Cholesterol,
http://linkedlifedata.com/resource/pubmed/chemical/Cholesterol, LDL,
http://linkedlifedata.com/resource/pubmed/chemical/Hydroxymethylglutaryl CoA Reductases,
http://linkedlifedata.com/resource/pubmed/chemical/Hydroxymethylglutaryl-CoA...,
http://linkedlifedata.com/resource/pubmed/chemical/Lipoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Polyethylene Glycols,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, LDL,
http://linkedlifedata.com/resource/pubmed/chemical/Triglycerides,
http://linkedlifedata.com/resource/pubmed/chemical/tyloxapol
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Dec
|
| pubmed:issn |
0022-2275
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:volume |
38
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
2502-15
|
| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:9458274-Animals,
pubmed-meshheading:9458274-Anticholesteremic Agents,
pubmed-meshheading:9458274-Apolipoproteins B,
pubmed-meshheading:9458274-Cholesterol,
pubmed-meshheading:9458274-Cholesterol, LDL,
pubmed-meshheading:9458274-Female,
pubmed-meshheading:9458274-Hydroxymethylglutaryl CoA Reductases,
pubmed-meshheading:9458274-Hydroxymethylglutaryl-CoA Reductase Inhibitors,
pubmed-meshheading:9458274-Immunoblotting,
pubmed-meshheading:9458274-Lipoproteins,
pubmed-meshheading:9458274-Male,
pubmed-meshheading:9458274-Mice,
pubmed-meshheading:9458274-Mice, Inbred Strains,
pubmed-meshheading:9458274-Polyethylene Glycols,
pubmed-meshheading:9458274-RNA, Messenger,
pubmed-meshheading:9458274-Receptors, LDL,
pubmed-meshheading:9458274-Time Factors,
pubmed-meshheading:9458274-Triglycerides
|
| pubmed:year |
1997
|
| pubmed:articleTitle |
Attenuation of plasma low density lipoprotein cholesterol by select 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in mice devoid of low density lipoprotein receptors.
|
| pubmed:affiliation |
Department of Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
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| pubmed:publicationType |
Journal Article
|