Liver X Receptor-Mediated Gene Regulation and Cholesterol Homeostasis in Brain: Relevance to Alzheimers Disease Therapeutics

Guoqing      Cao; Kelly   R.   Bales; Ronald   B.   DeMattos; Steven   M.   Paul

Abstract

Liver X receptors (LXRα and LXRβ ) are oxysterol receptors that function as master transcription factors mediating cholesterol homeostasis in the periphery. LXRs regulate the levels of the ABCA1 and ABCG1 cholesterol transporters as well as apolipoproteins (apoE and apoC) in various cells thereby affecting cholesterol transport and metabolism. In the brain, LXRs regulate ABCA1 in both neurons and glia resulting in cholesterol efflux from these cells. In addition, the expression of apolipoprotein E (apoE), synthesized primarily by astrocytes and microglia, is also upregulated by LXR agonists. As both apoE and the ABCA1 transporter are intimately involved in amyloid-β peptide (Aβ ) transport and clearance, activation of these genes by LXR agonists in brain may have a significant impact on Aβ deposition and amyloid/ neuritic plaque formation. Furthermore, LXR activation has been shown to have significant anti-inflammatory properties. Taken together, these findings suggest that brain-penetrable LXR agonists or modulators may be useful therapeutic agents for the treatment and (or) prevention of Alzheimers disease.

Keywords: Nuclear hormone receptors, cholesterol, amyloid, ABCA1, apolipoprotein E, glia

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