Role of mitogen-activated protein kinases and protein kinase C in regulating low-density lipoprotein receptor...

The cell signaling pathways that culminate in induction of low-density lipoprotein (LDL) receptor transcription in response to a variety of extracellular and intracellular signals are beginning to be defined. Evidence is accumulating that LDL receptor transcription is under complex regulation and that a major pathway of induction by cytokines, growth factors, anisomycin, and phorbol esters involves the extracellular/mitogen-activated protein kinase (p42/44MAPK) cascade. In fact, degree of p42/44MAPK activation determines the extent of LDL receptor induction. The suppression of LDL receptor expression by stress-activated p38MAPK via p42/44MAPK provides a potential mechanism for stress-induced hypercholesterolemia observed in humans and animals. Moreover, endogenous signals such as cholesterol regulate LDL receptor transcription through a different signaling cascade involving protein kinase Cepsilon isoform (PKCepsilon). The ability of cholesterol to directly bind PKCepsilon in an isoform-specific manner strongly supports its role in sensing the cellular cholesterol levels. The emerging picture from the above studies is that regulation of LDL receptor transcription results from the activity of a number of interlinked regulatory molecules and pathways, rather than from a single linear series of events. These studies will provide the necessary framework for understanding differential responses within human populations to atherosclerosis following high-fat/cholesterol diet. This information may also provide new strategies to modulate specific gene expression with the hope to develop novel therapies for the treatment of hypercholesterolemia.