Impaired regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation in lovastatin-resistant cells

L-90 cells were selected to grow in the presence of serum lipoproteins and 90 mu M lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A r eductase (HMGR). L-90 cells massively accumulate HMGR, a result of > 10-fol d amplification of the gene and 40-fold rise in mRNA, and also overexpress other enzymes of the mevalonate pathway. Western blot and promoter-lucifera se analyses indicate that transcriptional regulation of sterol-responsive g enes by 25-hydroxycholesterol or mevalonate is normal. Yet, none of these g enes is regulated by lipoproteins, a result of severe impairment in the low density lipoprotein receptor pathway. Moreover, L-90 cells do not accelera te the degradation of HMGR or transfected HMGal chimera in response to 25-h ydroxycholesterol or mevalonate. This aberrant phenotype persists when cell s are grown without lovastatin for up to 37 days. The inability to regulate HMGR degradation is not due to its overproduction since in LP-90 cells, wh ich were selected for lovastatin resistance in lipoprotein-deficient serum, HMGR is overexpressed, yet its turnover is regulated normally. Also, the r apid degradation of transfected cu subunit of T cell receptor is markedly r etarded in L-90 cells. These results show that in addition to gene amplific ation and overexpression of cholesterogenic enzymes, statin resistance can follow loss of regulated HMGR degradation.