Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase unmask transcriptional regulation of hepatic low-density lipoprotein receptor gene expression by dietary cholesterol.
The mechanism by which dietary cholesterol regulates expression of the hepatic low-density lipoprotein (LDL) receptor was investigated. In a previous study (Arch. Biochem. Biophys. 325, 242-248, 1996), we demonstrated that dietary cholesterol reduces the rate of LDL receptor protein degradation without affecting steady-state levels of receptor protein. In view of these findings, it was expected that dietary cholesterol would decrease the rate of transcription of the hepatic LDL receptor gene, resulting in lower mRNA levels and lower rates of synthesis of LDL receptor protein. Surprisingly, neither the rate of transcription nor the level of LDL receptor mRNA was reduced in response to dietary cholesterol, even though hepatic cholesterol levels were increased twofold. This suggests that under normal conditions, dietary cholesterol does not affect LDL receptor gene expression at the level of transcription. In contrast, feeding 2% cholesterol to rats fed a diet supplemented with 0.04% lovastatin significantly decreased hepatic LDL receptor mRNA levels and transcription rates. These results suggest that lovastatin unmasks transcriptional regulation of the hepatic LDL receptor by dietary cholesterol. The levels of the mature nuclear forms of sterol response element binding proteins-1 and -2 were unaffected despite significant changes in hepatic cholesterol levels, mRNA levels, and transcription rates caused by lovastatin treatment. This suggests that the observed changes in transcription rates may not be mediated by these proteins in rat liver.
Lopez
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Department of Biochemistry and Molecular Biology, College of Medicine and the Institute for Biomolecular Science, University of South Florida, Tampa 33612, USA.
Ness
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D000818:Animals; D015152:Blotting, Northern; D022762:CCAAT-Enhancer-Binding Proteins; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015151:Immunoblotting; D008099:Liver / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000235:genetics*; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
D022762:CCAAT-Enhancer-Binding Proteins; D002791:Cholesterol, Dietary; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011973:Receptors, LDL; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D008148:Lovastatin