Putative Metabolic Effects of the Liver X Receptor (LXR)

Abstract

The nuclear receptors liver X receptor (LXR)␣ and LXR␤ are sensors of cholesterol metabolism and lipid biosynthesis. They have recently been found to be regulators of inflammatory cytokines, suppressors of hepatic glucose production, and involved in different cellsignaling pathways. LXR␣ is a target gene of the peroxisome proliferator-activated receptor-␥, a target of drugs used in treating elevated levels of glucose seen in diabetes. Furthermore, insulin induces LXR␣ in hepatocytes, resulting in increased expression of lipogenic enzymes and suppression of key enzymes in gluconeogenesis, including PEPCK. LXR seems to have an important role in the regulation of glucocorticoid action and a role in the overall energy homeostasis suggested by its putative regulatory effect on leptin and uncoupling protein 1. The physiological roles of LXR indicate that it is an interesting potential target for drug treatment of diabetes. Diabetes 53 (Suppl. 1):S36 -S42, 2004 T ype 2 diabetes accounts for Ͼ90% of the cases of diabetes and is caused by defective insulin secretion and insulin resistance. Type 2 diabetes is often of polygenic origin, but the molecular defects are still not fully known. However, the genetic background of maturity-onset type diabetes of the young is known.A class of nuclear receptors has recently become the focus for its important role in cholesterol, lipid, and carbohydrate metabolism, namely the liver X receptor (LXR). A number of recent studies have shown that LXR is a key player in these biological functions. The main target tissues for LXR action are liver and adipose tissue, where its function has been carefully studied, but LXR has recently been suggested to be involved in lipid and carbohydrate metabolism in muscle as well. Important target tissues of insulin action are also liver, muscle, and adipose tissue, where insulin stimulates the uptake of excess glucose from blood and inhibits hepatic glucose production. A salient feature of type 2 diabetes is insulin resistance in these tissues, which leads to hyperglycemia and hyperlipidemia, both pathological conditions where, based on recent studies, LXR may be a key player. The LXR subfamily consists of two members, LXR␣ and LXR␤, which are activated by oxysterols. Whereas LXR␤ is ubiquitously expressed, high expression of LXR␣ is restricted to liver, adipose tissue, small intestine, and macrophages. LXR target genes have been shown to be involved in lipid and cholesterol metabolism, glucose homeostasis, and inflammatory response (Table 1). This review will focus on physiological roles of LXR and highlight why LXR could be an important potential target for drug treatment of lipid and carbohydrate disorders. LXR IN CHOLESTEROL AND LIPID METABOLISMThe phenotypes of LXR knockout mice generated in our laboratory and by Mangelsdorf and colleagues have shown that LXR is important for cholesterol and lipid metabolism (1,2). These were the first of many articles reporting LXR as a sensor for metabolites of lipid and cholesterol metabolism. Thus, Mangelsdorf ...

Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

“…In recent years our laboratory has established that fetal brown adipocytes constitute an ideal system for studying molecular mechanisms of insulin resistance and for testing novel approaches to overcome or bypass such resistance. One such approach is ligand activation of nuclear receptors, which can regulate glucose metabolism in multiple tissues including adipose tissue [3][4][5]. Accordingly, we decided to explore and compare the effect of nuclear receptor agonists on glucose uptake in brown adipocytes.…”

“…NR1HRs are activated by naturally produced oxysterols, including (22R)-hydroxycholesterol, (24,25S)-epoxycholesterol, and 27-hydroxycholesterol, as well as by synthetic compounds such as T0901317 and GW3965 [1,2]. Although NR1HR function has been elucidated in detail with respect to cholesterol and lipid metabolism, new findings have indicated that NR1HR is an important regulator of glucose metabolism in liver and adipose tissue [3][4][5]. Recent studies have reported low plasma glucose, improved glucose tolerance and increased glucose-induced insulin secretion by islets in genetic and dietary models of type 2 diabetes treated with synthetic NR1HR agonists [6][7][8].…”

Nuevos receptores nucleares heterodiméricos: reguladores metabólicos con impacto en fisiopatología y su proyección terapéutica en dislipidemias y diabetes mellitus

“…Se ha reportado que algunos RNH tendrían, además, participación fisioló-gica en el metabolismo de los carbohidratos 4,5 , la respuesta inflamatoria local [6][7][8] , la regeneración tisular 9 , la diferenciación celular 10 , la apoptosis 10 y el envejecimiento, ampliando su potencial impacto en la patogenia y el tratamiento de diversas enfermedades.…”

“…Sin embargo, y al igual que PPARß/δ, estos receptores nucleares también han sido implicados en la regulación de procesos tales como la inflamación, el metabolismo de los carbohidratos y la homeostasis energética 5 .…”

“…Por otro lado, se ha reportado en modelos murinos de resistencia insulínica que agonistas sintéticos de LXRα, incrementan significativamente la sensibilidad a esta hormona y reducen paralelamente la glicemia, tanto por reducción en la producción hepática de glucosa 37,40 como por mayor captación tisular de glucosa dependiente de los transportadores GLUT1 y GLUT4 5 .…”