COMPENSATORY RESPONSES TO INHIBITION OF HEPATIC SQUALENE SYNTHASE

The mechanism by which depletion of hepatic cholesterol levels, achiev ed by inhibition of squalene synthase, alters]hepatic LDL receptor, HM G-CoA reductase, and cholesterol 7 alpha-hydroxylase gene expression w as investigated by measuring transcription rates, mRNA stability, rate s of translation, translational efficiency, and levels of sterol respo nse element binding proteins. It was found that the transcription of b oth hepatic LDL receptor and HMG-CoA reductase were increased about tw ofold. The increase in LDL receptor transcription occurred within 2 h after giving 2 mg/kg zaragozic acid A, a potent inhibitor of squalene synthase. This preceded the increase in transcription of HMG-CoA reduc tase that occurred at 4 h. Increases in the stability of both of these mRNAs were also observed. These changes account for the increases in LDL receptor and HMG-CoA reductase mRNA levels previously observed. Th e rate of transcription of hepatic cholesterol 7 alpha-hydroxylase was decreased to about 25% of control within 3 h after administration of zaragozic acid A, which correlates with the decrease in this mRNA. The rates of translation, as determined by pulse labeling, of both hepati c HMG-CoA reductase and LDL receptor were increased two-to threefold. The translational efficiency of these two mRNAs was also increased as judged by polysome profile analysis. There was an increase in mRNA ass ociated with the heaviest polysome fraction and a decrease in that ass ociated with monosomes. No significant change was observed in the leve ls of sterol response element binding protein 2, the form that mediate s induced transcription, in response to zaragozic acid A treatment, in dicating that this protein might not be involved in mediating the obse rved transcriptional changes. An increase in sterol response element b inding protein -1 was observed 30 min after giving zaragozic acid A. T he results suggest that compensatory responses to depletion of squalen e-derived products involve alterations in the rates of transcription, mRNA stability, and translational of key proteins involved in choleste rol homeostasis. (C) 1998 Academic Press.