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

Abstract

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.

Figure 1

Schematic representation of the signaling pathways involved in regulating LDL receptor transcription in hepatic cells. Signals from a variety of extracellular agents converge on p42/44^MAPK cascade to induce LDL receptor transcription. Importantly, degree of p42/ 44^MAPK activation determines the extent of LDL receptor induction. Suppression of LDL receptor receptor transcription by the stress-activated p38^MAPK through modulating p42/44^MAPK cascade may explain stress-induced hypercholesterolemia observed in humans and laboratory animals. Finally, a direct interaction between PKCε and sterols may explain involvement of this kinase in sterol-regulated LDL receptor expression. One exciting possibility is that PKCε induces LDL receptor transcription via SREBPs. Identification of targeted nuclear factors should resolve a number of questions of how and why LDL receptor responds to a wide variety of cellular signals in hepatic cells. Activation is denoted by plus sign, whereas minus sign indicates suppression. CBP, cAMP-response element binding protein.