The role of thyroid hormone (TH) in the development and function of the central nervous system (CNS) has been known for many years. However, the role of liver X receptors (LXRs) in TH function and protection against neuronal degeneration was not recognized until recently. The relationship between thyroid hormone receptors (TRs) and LXRs became apparent with the cloning of steroid hormone receptors, leading to the discovery of the nuclear receptor superfamily. This family includes not only receptors for classical steroid hormones but also many newly discovered ligand-activated nuclear receptors. LXRs and TRs regulate overlapping pathways in lipid and carbohydrate metabolism, as well as in overall CNS development and function. These CNS pathways include neuronal migration during cortical and cerebellar layering, myelination, oligodendrocyte maturation, microglial activation, and astrocyte functions. Furthermore, LXRs likely have unique functions, as evidenced by the inability of TH to compensate for microglial activation, oligodendrocyte maturation, spinal motor neuron death, and degeneration of retinal and cochlear neurons in LXRβ knockout mice. The common and unique functions of these two receptors are the subject of this review. We analyzed some of the most relevant literature on the regulation and function of LXRs and TRs and investigated why both receptors are required in the human body. We conclude that LXRs and TRs do not represent parallel pathways but rather constitute a single pathway through which the TH endocrine system regulates cholesterol homeostasis. Subsequently, LXRs, activated by cholesterol metabolites, function as a paracrine/autocrine system that modulates the target cell response to TH.
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