Physiological feedback regulation of cholesterol biosynthesis: Role of translational control of hepatic HMG-CoA reductase and possible involvement of oxylanosterols.
Feedback regulation of cholesterol biosynthesis provides a mechanism to adapt to varying cholesterol input while maintaining rather constant serum and tissue cholesterol levels. The molecular mechanisms by which this occurs have been the subject of extensive investigation. This review focuses on the physiological mechanisms by which this regulation occurs. In animals that are sensitive to dietary cholesterol such as Golden Syrian hamsters, feedback regulation occurs mainly at the level of transcription of hepatic HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase). In animals like the Sprague Dawley rat that are resistant to the serum cholesterol raising action of dietary cholesterol, regulation occurs mainly at the level of translation efficiency of hepatic HMG-CoA reductase. Oxylanosterols were shown to effectively decrease translation of HMG-CoA reductase mRNA. Dietary cholesterol acts to significantly lower transcription of squalene epoxidase and lanosterol 14α demethylase favoring accumulation of the putative regulatory oxylanosterol-3β-hydroxylanosterol-8-en-32-al. Thus, decreased transcription of enzymes occurring late in the cholesterol biosynthetic pathway appears to result in decreased translation of hepatic HMG-CoA reductase mRNA. These findings indicate that pronounced physiological feedback regulation of cholesterol biosynthesis in cholesterol resistant animals occurs at the level of translational efficiency without substantial reduction in hepatic HMG-CoA reductase transcription.
['Ness|Gene C|GC|']
D000818:Animals D002784:Cholesterol D002791:Cholesterol, Dietary D025461:Feedback, Physiological D015971:Gene Expression Regulation, Enzymologic D006801:Humans D006903:Hydroxymethylglutaryl CoA Reductases D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors D008099:Liver D023421:Models, Animal D014176:Protein Biosynthesis D011499:Protein Processing, Post-Translational D014158:Transcription, Genetic
Physiological feedback regulation Cholesterol biosynthesis HMG-CoA reductase Oxylanosterols Translational efficiency Lanosterol 14α demethylase