ABSTRACT
Although widely prescribed for their potent antiinflammatory actions, glucocorticoid drugs (e.g., dexamethasone) cause undesirable side effects that are features of the metabolic syndrome, including hyperglycemia, fatty liver, insulin resistance, and type II diabetes. Liver x receptors (LXRs) are nuclear receptors that respond to cholesterol metabolites and regulate the expression of a subset of glucocorticoid target genes. Here, we show LXRß is required to mediate many of the negative side effects of glucocorticoids. Mice lacking LXRß (but not LXRα) were resistant to dexamethasone-induced hyperglycemia, hyperinsulinemia, and hepatic steatosis, but remained sensitive to dexamethasone-dependent repression of the immune system. In vivo, LXRα/ß knockout mice demonstrated reduced dexamethasone-induced expression of the key hepatic gluconeogenic gene, phosphoenolpyruvate carboxykinase (PEPCK). In perfused liver and primary mouse hepatocytes, LXRß was required for glucocorticoid-induced recruitment of the glucocorticoid receptor to the PEPCK promoter. These findings suggest a new avenue for the design of safer glucocorticoid drugs through a mechanism of selective glucocorticoid receptor transactivation.
Subject(s)
Dexamethasone/adverse effects , Fatty Liver/chemically induced , Fatty Liver/metabolism , Hyperglycemia/chemically induced , Hyperglycemia/metabolism , Orphan Nuclear Receptors/metabolism , Animals , Base Sequence , Corticosterone/blood , DNA Primers/genetics , Disease Models, Animal , Drug Design , Fatty Liver/genetics , Gene Expression/drug effects , Humans , Hyperglycemia/genetics , Hyperinsulinism/chemically induced , Hyperinsulinism/genetics , Hyperinsulinism/metabolism , In Vitro Techniques , Liver/drug effects , Liver/metabolism , Liver X Receptors , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Orphan Nuclear Receptors/deficiency , Orphan Nuclear Receptors/genetics , Phosphoenolpyruvate Carboxykinase (GTP)/genetics , Promoter Regions, Genetic , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Transcriptional ActivationABSTRACT
Atherosclerosis is a disease characterized by excess cholesterol and inflammation in the blood vessels. The liver X receptors (alpha and beta) are members of the nuclear hormone receptor family that are activated by endogenous cholesterol metabolites. These receptors are widely expressed with a tissue distribution that includes the liver, intestine and macrophage. Upon activation, these receptors have been shown to increase reverse cholesterol transport from the macrophage back to the liver to aid in the removal of excess cholesterol. More recently, they have also been shown to inhibit the inflammatory response in macrophages. These functions are accomplished through direct regulation of gene transcription. Herein, we will describe the key benefits and potential risks of targeting the LXRs for the treatment of atherosclerosis.
