Liver X receptors (LXRs). Part II: non-lipid effects, role in pathology, and therapeutic implications.

Liver X receptors (LXRs) alpha and ss belong to a group of nuclear receptors which, after ligand binding, regulate gene transcription. Their natural agonists are oxidized cholesterol derivatives (oxysterols). The main function of LX receptors is the regulation of cholesterol metabolism. In the first part of this work we discussed the structure and mechanism of action of LXRs, their agonists and antagonists, the regulation of LXR expression, and their role in cholesterol and lipid metabolism. In the present article we describe other roles of LXRs. Agonists of these receptors increase insulin sensitivity and stimulate insulin secretion. Activation of LXRs inhibits inflammation and autoimmune reactions. Moreover, pharmacological studies and genetic manipulations indicate that these receptors inhibit atherogenesis. LX receptors are also involved in the regulation of renin secretion, inhibit the formation of amyloid ss in the central nervous system, regulate gonadal function and steroidogenesis both in gonads and in adrenals, influence the proliferation and differentiation of keratinocytes, and inhibit the proliferation of tumor cells. Changes in the expression of these receptors and in the level of their agonists are observed in many diseases. Taking into account the multiple roles of LX receptors, their agonists may be applied in the future in the treatment of many disorders, including diabetes, inflammatory diseases, atherosclerosis, Alzheimer's disease, and hypogonadism. However, possible side effects should be taken into account, including enhancement of lipogenesis, hypertriglyceridemia, and liver steatosis. The function of LX receptors is also modulated by many currently used drugs such as statins, fibrates, and thazolidinedione derivatives.