LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice.
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 LXRβ is required to mediate many of the negative side effects of glucocorticoids. Mice lacking LXRβ (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/β knockout mice demonstrated reduced dexamethasone-induced expression of the key hepatic gluconeogenic gene, phosphoenolpyruvate carboxykinase (PEPCK). In perfused liver and primary mouse hepatocytes, LXRβ 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.
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada.
Rucha
R
Patel
Monika
M
Patel
Ricky
R
Tsai
Vicky
V
Lin
Angie L
AL
Bookout
Yuan
Y
Zhang
Lilia
L
Magomedova
Tingting
T
Li
Jessica F
JF
Chan
Conrad
C
Budd
David J
DJ
Mangelsdorf
Carolyn L
CL
Cummins
D000818:Animals; D001483:Base Sequence; D003345:Corticosterone / Q000097:blood; D017931:DNA Primers / Q000235:genetics; D003907:Dexamethasone / Q000009:adverse effects*; D004195:Disease Models, Animal; D015195:Drug Design; D005234:Fatty Liver / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D006946:Hyperinsulinism / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
D017931:DNA Primers; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D003345:Corticosterone