IN-VIVO LDL-RECEPTOR AND HMG-COA REDUCTASE REGULATION IN HUMAN-LYMPHOCYTES AND ITS ALTERATIONS DURING AGING

The LDL receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) r eductase play primary roles in the regulation of cellular cholesterol metabolism. To investigate the transcriptional regulation of lipid met abolism under physiological conditions ex vivo and its alterations dur ing aging, we analyzed both the activity and mRNA concentration of the LDL receptor and HMG-CoA reductase in freshly isolated lymphocytes fr om healthy young and elderly donors. Data from fluorescent reverse tra nscriptase-polymerase chain reaction indicated that not only plasma LD L but also plasma HDL downregulates lymphocyte LDL receptor mRNA. Down regulation by HDL was three times more effective than that by LDL and presumably involved specific HDL binding sites. There was coordinate r egulation of HMG-CoA reductase mRNA with LDL receptor mRNA that was in dependent of plasma lipoprotein concentrations, Despite elevated plasm a concentrations of LDL, lymphocytes from elderly donors paradoxically expressed increased levels of the LDL receptor (P = .030) and HMG-CoA reductase mRNA (p = .062). The age-related dysregulation of the LDL r eceptor was predominantly due to impaired downregulation by plasma LDL rather than by HDL. Thus, not only LDL but also HDL and age significa ntly influences the transcriptional regulation of the LDL receptor in extrahepatic cells in vivo.