Hepatic mRNA levels for the LDL receptor and HMG-CoA reductase show coordinate regulation in vivo.
A sensitive solution hybridization assay using autologous cRNA probes was developed with the aim to study the simultaneous regulation of hepatic mRNA levels, on a quantitative basis, for the LDL receptor (LDLr), HMG-CoA reductase, and cholesterol 7 alpha-hydroxylase (Cho-7-hx) in C57BL/6J mice. With the purpose to suppress and stimulate transcript levels respectively, animals received established high fat diets, cholesterol-enriched diets, and a diet supplemented with mevinolin and colestipol. One hundred nineteen animals were investigated in six separate experiments. In spite of an eightfold increase in hepatic cholesterol induced by a high fat diet, the LDLr and the HMG-CoA reductase mRNA levels were only reduced to 60-70% and 25-50% of control values, respectively. When the data from all animals were analyzed, a strong positive correlation was obtained between the mRNA levels for the LDLr and HMG-CoA reductase (r = 0.79, P less than 0.001). A significant relation remained when control animals only were analyzed (n = 42, r = 0.59, P less than 0.001). Cho-7-hx mRNA showed a regulatory pattern that differed from that of the LDLr and HMG-CoA reductase; feeding cholesterol at 1.7% and 5% but not at 0.4% elevated the mRNA levels for Cho-7-hx while the LDLr and HMG-CoA reductase mRNA levels were maximally suppressed already at 0.4% of dietary cholesterol. The results show that the mRNA levels for the LDLr and HMG-CoA reductase are regulated in parallel in the liver in vivo during various metabolic perturbations as well as at normal physiologic conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
Rudling
M
M
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235.
D000818:Animals; D001483:Base Sequence; D002853:Chromatography, Liquid; D003084:Colestipol / Q000494:pharmacology; D004247:DNA; D004032:Diet; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010957:Plasmids; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism*
D012333:RNA, Messenger; D011973:Receptors, LDL; D004247:DNA; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D003084:Colestipol