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Compensatory Responses to Inhibition of Cholesterol Absorption
Author(s) -
Ness Gene Charles
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a83-b
Subject(s) - medicine , endocrinology , hmg coa reductase , cholesterol , reductase , chemistry , hydroxymethylglutaryl coa reductase , ezetimibe , biology , enzyme , biochemistry
Two experimental models that exhibit a high dependency on cholesterol absorption were investigated. These were diabetic and thyroidectomized rats fed 1% cholesterol. Feeding the 1% cholesterol diet to the thyroidectomized rats increased their serum cholesterol levels from 116 to 135 mg/dl while decreasing their low levels of hepatic HMG‐CoA reductase protein to barely detectable levels. Adding 10 mg/kg/day of the cholesterol absorption inhibitor, ezetimibe, to the diet lowered serum cholesterol levels to 85 mg/dl and fully restored hepatic HMG‐CoA reductase protein to normal levels. Hepatic LDL receptor protein was unaffected. Feeding cholesterol to diabetic rats increased serum cholesterol levels to over 500 mg/dl and nearly eliminated hepatic HMG‐CoA reductase protein and mRNA. Administration of ezetimibe lowered serum cholesterol levels to actually less than normal and fully restored hepatic HMG‐CoA reductase protein levels with little effect on hepatic reductase mRNA, indicating a posttranscription site of action. Again hepatic LDL receptor protein levels were unaffected. Changes in hepatic HMG‐CoA reductase expression at a posttranscriptional site appear to be the major compensatory response to inhibition of cholesterol absorption. (Support from Merck/Schering Plough)