Liver X receptors at the intersection of lipid metabolism and atherogenesis.

Abstract

Cholesterol homeostasis is maintained through the coordinated regulation of the trafficking, biosynthesis, absorption, and efflux of cholesterol. From the discovery that atherosclerotic plaques contain >20-fold more cholesterol than healthy aorta, to the identification of mutations in the LDL receptor as the cause of Familial Hypercholesterolemia, to the discovery of the statin drugs, cholesterol metabolism has been a focus of intensive investigation for decades1. Cholesterol is crucial for normal biological functions, including hormone synthesis, bile acid synthesis and maintaining cell membrane fluidity; however, excess circulating cholesterol is associated with CVD, especially when the cholesterol is carried by low-density lipoproteins (LDL). The evidence linking cholesterol to heart disease comes from population studies2-4, genetics, experimental models5, 6, and therapeutic intervention7. Despite tremendous gains in our understanding of CVD, it remains the leading cause of mortality worldwide8. In this review, we focus on molecular mechanisms by which Liver X Receptors (LXRs) mediate physiological responses to cellular and systemic cholesterol overload and the relationship of these pathways to atherogenesis (Figure 1). Figure 1 LXRs exert distinct effects on cholesterol and lipid metabolism in discrete cell types. Globally, LXR activation induces reverse cholesterol transport and reduces atherosclerotic plaque burden. Macrophage LXRs respond to oxidized sterol by increasing ... Transcriptional Regulation of Cholesterol Homeostasis Intracellular cholesterol homeostasis is maintained primarily through the actions of opposing transcription factors: LXRs, which are activated when cells accumulate excess cholesterol, and Sterol Response Element Binding Protein 2 (SREBP-2), which is active when cholesterol levels are low. The intricate details of how the SREBP-2 senses and responds to membrane cholesterol content have been elucidated, and readers are directed to a recent excellent review of this topic 9. LXRs are ligand-activated transcription factors belonging to the nuclear receptor superfamily. There are two highly homologous LXR proteins with distinct tissue expression patterns. LXRβ (NR1H2) is ubiquitously expressed, while LXRα (NR1H3) is highly expressed in liver, intestine, kidney, adipose and macrophages 10-12. Crystal structures of the two LXRs have revealed highly similar ligand binding domains 13-16. Although they appear to respond to the same endogenous sterol ligands 17, in vivo studies suggest that the two LXRs perform distinct physiological roles. This particularly true in the liver where the expression of LXRα dominates. LXRα is uniquely required for the efficient elimination of hepatic cholesterol in mice 18. LXRs form obligate heterodimers with Retinoid X Receptor (RXR) and modulate transcription of target genes via direct DNA binding. The optimal LXR response element is a direct repeat 4 (DR4) motif: repeats of the six base pair sequence AGTTCA separated by four base pairs 10, 12. Under basal conditions, corepressors bind the LXR/RXR heterodimer leading to transcriptional silencing. Ligand binding induces a conformational change in the heterodimer, releasing the corepressors and recruiting coactivators 19, 20. LXRs are activated physiologically by oxidized derivatives of cholesterol, oxysterols, which are synthesized when the cell accumulates excess cholesterol 21-23. Many LXR target genes have been identified in experiments screening for the gene expression consequences of cellular cholesterol loading or synthetic LXR agonist treatment 24.