LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice

Patel, Rucha; Patel, Monika; Tsai, Ricky; Lin, Vicky Y.; Bookout, Angie L.; Zhang, Yuan; Magomedova, Lilia; Li, Tingting; Chan, Jessica F; Budd, Conrad; Mangelsdorf, David J.; Cummins, Carolyn L.

doi:10.1172/jci41681

Cited by 106 publications

(83 citation statements)

References 82 publications

(84 reference statements)

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“…In Vivo Dex Treatment-Female 8-week-old mice were intraperitoneally injected with Dex (1 mg/kg body weight/daily, 5 days) (41). The symptoms of hepatic steatosis and the levels of immune cells were analyzed on day 6.…”

Section: Methodsmentioning

confidence: 99%

Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells

Liu

Wei

Shi

et al. 2016

Journal of Biological Chemistry

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Glucocorticoids (GCs) used as inflammation suppressors have harmful side effects, including induction of hepatic steatosis. The underlying mechanisms of GC-promoted dysregulation of lipid metabolism, however, are not fully understood. GCs could facilitate the accumulation of myeloid-derived suppressor cells (MDSC) in the liver of animals, and the potential role of MDSCs in GC-induced hepatic steatosis was therefore investigated in this study. We demonstrated that granulocytic (G)-MDSC accumulation mediated the effects of GCs on the fatty liver, in which activating transcription factor 3 (ATF3)/S100A9 signaling plays an important role. ATF3-deficient mice developed hepatic steatosis and displayed expansion of G-MDSCs in the liver and multiple immune organs, which shared high similarity with the phenotype observed in GC-treated wild-type littermates. Adoptive transfer of GC-induced or ATF3-deficient G-MDSCs promoted lipid accumulation in the liver, whereas depletion of G-MDSCs alleviated these effects. Mechanistic studies showed that in MDSCs, ATF3 was transrepressed by the GC receptor GR through direct binding to the negative GR-response element. S100A9 is the major transcriptional target of ATF3 in G-MDSCs. Silencing S100A9 clearly alleviated G-MDSCs expansion and hepatic steatosis caused by ATF3 deficiency or GC treatment. Our study uncovers an important role of G-MDSCs in GC-induced hepatic steatosis, in which ATF3 may have potential therapeutic implications.

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Section: Methodsmentioning

confidence: 99%

Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells

Liu

Wei

Shi

et al. 2016

Journal of Biological Chemistry

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“…To avoid the confounding effects of insulin on lipogenesis, we explored the role of LXR in insulinopenic models of DN induced by streptozotocin (STZ). For the first animal model, based on Lxrα/β −/− mice with STZinduced diabetes, we used male Lxrα/β −/− and matching wild-type mice (C57Bl/6:129SvEv) [30], which were maintained on chow (2016 Teklad Global rodent diet; Harlan Teklad, Mississauga, ON, Canada). At 8 weeks, mice were given daily i.p.…”

Section: Methodsmentioning

confidence: 99%

“…Kidney lipid analysis Tissues were digested in chloroform : methanol (2:1) with a 20:1 volume to tissue ratio, and processed as described previously [30].…”

Section: Methodsmentioning

confidence: 99%

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Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice

et al. 2013

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Aims/hypothesis Liver X receptors (LXRs) α and β are nuclear hormone receptors that are widely expressed in the kidney. They promote cholesterol efflux from cells and inhibit inflammatory responses by regulating gene transcription. Here, we hypothesised (1) that LXR deficiency would promote renal decline in a mouse model of diabetes by accelerating intraglomerular cholesterol accumulation and, conversely, (2) that LXR agonism would attenuate renal decline in diabetes.Methods Diabetes was induced with streptozotocin (STZ) and maintained for 14 weeks in Lxrα/β +/+ (Lxrα, also known as Nr1h3; Lxrβ, also known as Nr1h2) and Lxrα/β −/− mice. In addition, STZ-injected DBA/2J mice were treated with vehicle or the LXR agonist N ,N -dimethyl-hydroxycholenamide (DMHCA) (80 mg/kg daily) for 10 weeks. To determine the role of cholesterol in diabetic nephropathy (DN), mice were placed on a Western diet after hyperglycaemia developed. Results Even in the absence of diabetes, Lxrα/β −/− mice exhibited a tenfold increase in the albumin:creatinine ratio and a 40-fold increase in glomerular lipid accumulation compared with Lxrα/β +/+ mice. When challenged with diabetes, Lxrα/β −/− mice showed accelerated mesangial matrix expansion and glomerular lipid accumulation, with upregulation of inflammatory and oxidative stress markers. In the DN-sensitive STZ DBA/2J mouse model, DMHCA treatment significantly decreased albumin and nephrin excretion (by 50% each), glomerular lipids and plasma triacylglycerol (by 70%) and cholesterol (by 48%); it also decreased kidney inflammatory and oxidative stress markers compared with vehicle-treated mice. Conclusions/interpretation These data support the idea that LXR plays an important role in the normal and diabetic kidney, while showing that LXR, through its inhibitory effect on inflammation and cholesterol accumulation in glomeruli, could also be a novel therapeutic target for DN.

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“…Although some of these GC target genes are regulated ubiquitously, others appear to be cell-type selective, suggesting cooperation between GR and tissue-specific factors or cofactors (17). Indeed, it has been shown that transcriptional regulators such as liver X-receptor β (LXRβ) can contribute specifically to hyperglycemia, hyperinsulinemia, and hepatic steatosis but not to the immunological system responses elicited by GC (18) and that Kruppel-like factor 15 (KLF15) selectively prevents GC-induced muscle atrophy (19). Although it has been shown that GR regulates adipocyte metabolism (12) and that GCs affect adiposity and energy expenditure both centrally (20)(21)(22) and peripherally, the detailed mechanisms underlying these metabolic changes are incompletely understood.…”

mentioning

confidence: 99%

Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

Mueller

2016

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents, but their chronic use leads to undesirable side effects such as excessive expansion of adipose tissue. We have recently shown that the forkhead box protein A3 (Foxa3) is a calorie-hoarding factor that regulates the selective enlargement of epididymal fat depots and suppresses energy expenditure in a nutritional- and age-dependent manner. It has been demonstrated that Foxa3 levels are elevated in adipose depots in response to high-fat diet regimens and during the aging process; however no studies to date have elucidated the mechanisms that control Foxa3’s expression in fat. Given the established effects of GCs in increasing visceral adiposity and in reducing thermogenesis, we assessed the existence of a possible link between GCs and Foxa3. Computational prediction analysis combined with molecular studies revealed that Foxa3 is regulated by the glucocorticoid receptor (GR) in preadipocytes, adipocytes, and adipose tissues and is required to facilitate the binding of the GR to its target gene promoters in fat depots. Analysis of the long-term effects of dexamethasone treatment in mice revealed that Foxa3 ablation protects mice specifically against fat accretion but not against other pathological side effects elicited by this synthetic GC in tissues such as liver, muscle, and spleen. In conclusion our studies provide the first demonstration, to our knowledge, that Foxa3 is a direct target of GC action in adipose tissues and point to a role of Foxa3 as a mediator of the side effects induced in fat tissues by chronic treatment with synthetic steroids.

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LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice

Cited by 106 publications

References 82 publications

Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells

Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells

Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice

Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

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