Selective glucocorticoid receptor modulation prevents and reverses non-alcoholic fatty liver disease in male mice

Koorneef, Lisa L; Heuvel, José K. van den; Kroon, Jan; Boon, Mariëtte R.; Hoen, Peter A.C. ‘t; Hettne, Kristina; Velde, Nienke M van de; Kolenbrander, Kelsey B; Streefland, Trea C M; Mol, Isabel M.; Sips, Hetty C M; Kiełbasa, Szymon M.; Mei, Hailiang; Belanoff, Joseph K.; Pereira, Alberto M.; Oosterveer, Maaike H.; Hunt, Hazel; Rensen, Patrick C.N.; Meijer, Onno C.

doi:10.1210/en.2018-00671

Cited by 31 publications

(32 citation statements)

References 49 publications

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“…In addition, synthetic modulators of glucocorticoid receptor can attenuate obesity and inflammation and reverse fatty liver in experimental animals. 129,130 Much further work is required for a better understanding of the role of the 11β-HSD1 and 11β-HSD2 in glucocorticoid action.…”

Section: Importance Of Cortisol and Cortisone Interconversion To Glucmentioning

confidence: 99%

<p>Glucocorticoid-Induced Fatty Liver Disease</p>

Rahimi

Rajpal

Ismail‐Beigi

2020

DMSO

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Glucocorticoids (GCs) are commonly used at high doses and for prolonged periods (weeks to months) in the treatment of a variety of diseases. Among the many side effects are increased insulin resistance with disturbances in glucose/insulin homeostasis and increased deposition of lipids (mostly triglycerides) in the liver. Here, we review the metabolic pathways of lipid deposition and removal from the liver that become altered by excess glucocorticoids. Pathways of lipid deposition stimulated by excess glucocorticoids include 1) increase in appetite and high caloric intake; 2) increased blood glucose levels due to GC-induced stimulation of gluconeogenesis; 3) stimulation of de novo lipogenesis that is augmented by the high glucose and insulin levels and by GC itself; and 4) increased release of free fatty acids from adipose stores and stimulation of their uptake by the liver. Pathways that decrease hepatic lipids affected by glucocorticoids include a modest stimulation of verylow-density lipoprotein synthesis and secretion into the circulation and inhibition of βoxidation of fatty acids. Role of 11β-hydroxysteroid dehydrogenases-1 and-2 and the reversible conversion of cortisol to cortisone on intracellular levels of cortisol is examined. In addition, GC control of osteocalcin expression and the effect of this bone-derived hormone in increasing insulin sensitivity are discussed. Finally, research focused on gaining a better understanding of the dose and duration of treatment with glucocorticoids, which leads to increased triglyceride deposition in the liver, and the reversibility of the condition is highlighted.

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Section: Importance Of Cortisol and Cortisone Interconversion To Glucmentioning

confidence: 99%

<p>Glucocorticoid-Induced Fatty Liver Disease</p>

Rahimi

Rajpal

Ismail‐Beigi

2020

DMSO

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“…The primary role of glucocorticoids in the liver is to regulate hepatic energy homeostasis and control hepatic influx and the efflux of lipids [30,31]. Moreover, both liver steatosis and fibrosis have been shown to be promoted by substantial glucocorticoid exposure and receptor antagonism [32]. In addition, glucocorticoids were found to be potent modulators of the IGF system, as they were able to reduce the local expression of IGF1 [33].…”

Section: Glucocorticoids Participate In Iugr Liver Metabolismmentioning

confidence: 99%

Liver transcriptome profiling and functional analysis of intrauterine growth restriction (IUGR) piglets reveals a genetic correction and sexual-dimorphic gene expression during postnatal development

et al. 2020

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Background Intrauterine growth restriction (IUGR) remains a major problem associated with swine production. Thus, understanding the physiological changes of postnatal IUGR piglets would aid in improving growth performance. Moreover, liver metabolism plays an important role in the growth and survival of neonatal piglets. Results By profiling the transcriptome of liver samples on postnatal Days 1, 7, and 28, our study focused on characterizing the growth, function, and metabolism in the liver of IUGR neonatal piglets. Our study demonstrates that the livers of IUGR piglets were associated with a series of complications, including inflammatory stress and immune dysregulation; cytoskeleton and membrane structure disorganization; dysregulated transcription events; and abnormal glucocorticoid metabolism. In addition, the abnormal liver function index in the serum [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total protein (TP)], coupled with hepatic pathological and ultrastructural morphological changes are indicative of liver damage and dysfunction in IUGR piglets. Moreover, these results reveal the sex-biased developmental dynamics between male and female IUGR piglets, and that male IUGR piglets may be more sensitive to disrupted metabolic homeostasis. Conclusions These observations provide a detailed reference for understanding the mechanisms and characterizations of IUGR liver functions, and suggest that the potential strategies for improving the survival and growth performance of IUGR offspring should consider the balance between postnatal catch-up growth and adverse metabolic consequences. In particular, sex-specific intervention strategies should be considered for both female and male IUGR piglets.

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“…28 Corticosterone concentration was measured by ELISA according to the manufacturer's protocol (Corticosterone EIA, Immunodiagnostics). These samples were used to determine plasma concentrations of P1NP and TRAP using enzyme immunoassay kits (IDS) according to manufacturer's instructions.…”

Section: P1np Trap and Corticosterone Measurementsmentioning

confidence: 99%

Circadian disruption by shifting the light‐dark cycle negatively affects bone health in mice

et al. 2019

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The past decade, it has become evident that circadian rhythms within metabolically active tissues are very important for physical health. However, although shift work has also been associated with an increased risk of fractures, circadian rhythmicityhas not yet been extensively studied in bone. Here, we investigated which genes are rhythmically expressed in bone, and whether circadian disruption by shifts in lightdark cycle affects bone turnover and structure in mice. Our results demonstrate diurnal expression patterns of clock genes (Rev-erbα, Bmal1, Per1, Per2, Cry1, Clock), as well as genes involved in osteoclastogenesis, osteoclast proliferation and function (Rankl, Opg, Ctsk), and osteocyte function (c-Fos) in bone. Weekly alternating lightdark cycles disrupted rhythmic clock gene expression in bone and caused a reduction in plasma levels of procollagen type 1 amino-terminal propeptide (P1NP) and tartrate-resistant acidic phosphatase (TRAP), suggestive of a reduced bone turnover.These effects coincided with an altered trabecular bone structure and increased cortical mineralization after 15 weeks of light-dark cycles, which may negatively affect

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Selective glucocorticoid receptor modulation prevents and reverses non-alcoholic fatty liver disease in male mice

Cited by 31 publications

References 49 publications

<p>Glucocorticoid-Induced Fatty Liver Disease</p>

<p>Glucocorticoid-Induced Fatty Liver Disease</p>

Liver transcriptome profiling and functional analysis of intrauterine growth restriction (IUGR) piglets reveals a genetic correction and sexual-dimorphic gene expression during postnatal development

Circadian disruption by shifting the light‐dark cycle negatively affects bone health in mice

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