Molecular regulation of urea cycle function by the liver glucocorticoid receptor

Abstract

ObjectiveOne of the major side effects of glucocorticoid (GC) treatment is lean tissue wasting, indicating a prominent role in systemic amino acid metabolism. In order to uncover a novel aspect of GCs and their intracellular-receptor, the glucocorticoid receptor (GR), on metabolic control, we conducted amino acid and acylcarnitine profiling in human and mouse models of GC/GR gain- and loss-of-function.MethodsBlood serum and tissue metabolite levels were determined in Human Addison's disease (AD) patients as well as in mouse models of systemic and liver-specific GR loss-of-function (AAV-miR-GR) with or without dexamethasone (DEX) treatments. Body composition and neuromuscular and metabolic function tests were conducted in vivo and ex vivo, the latter using precision cut liver slices.ResultsA serum metabolite signature of impaired urea cycle function (i.e. higher [ARG]:[ORN + CIT]) was observed in human (CTRL: 0.45 ± 0.03, AD: 1.29 ± 0.04; p < 0.001) and mouse (AAV-miR-NC: 0.97 ± 0.13, AAV-miR-GR: 2.20 ± 0.19; p < 0.001) GC/GR loss-of-function, with similar patterns also observed in liver. Serum urea levels were consistently affected by GC/GR gain- (∼+32%) and loss (∼−30%) -of-function. Combined liver-specific GR loss-of-function with DEX treatment revealed a tissue-autonomous role for the GR to coordinate an upregulation of liver urea production rate in vivo and ex vivo, and prevent hyperammonaemia and associated neuromuscular dysfunction in vivo. Liver mRNA expression profiling and GR-cistrome mining identified Arginase I (ARG1) a urea cycle gene targeted by the liver GR.ConclusionsThe liver GR controls systemic and liver urea cycle function by transcriptional regulation of ARG1 expression.

Mutations and common variants in the human arginase 1 (ARG1) gene: Impact on patients, diagnostics, and protein structure considerations

“…In fetal rat, cortisol has been shown to stimulate liver ARG1 after an intraperitoneal injection (Husson & Vaillant, ). In patients with Addison's disease, which exhibit a loss of function of the liver glucocorticoid receptor (GR) after acute withdrawal from treatment and in mouse models of systemic and liver‐specific GR loss‐of‐function (AVV‐miR‐GR), an increased ratio arginine/(ornithine+citrulline) was observed (Okun et al., ). Furthermore, liver mRNA expression profiling identified ARG1 as a target of GR (Okun et al., ).…”

“…In patients with Addison's disease, which exhibit a loss of function of the liver glucocorticoid receptor (GR) after acute withdrawal from treatment and in mouse models of systemic and liver‐specific GR loss‐of‐function (AVV‐miR‐GR), an increased ratio arginine/(ornithine+citrulline) was observed (Okun et al., ). Furthermore, liver mRNA expression profiling identified ARG1 as a target of GR (Okun et al., ). This study concluded that liver glucocorticoid/GR controls the urea cycle function by transcriptional regulation of ARG1 expression (Okun et al., ).…”

An endocrine-hepato-muscular metabolic cycle links skeletal muscle atrophy and hyperglycemia in type 2 diabetes

“…Glucocorticoids are known to have direct effects on skeletal muscle to induce muscle atrophy, despite intact liver GR signaling 24,25 . Therefore, although the liver GR was not a critical component 43 , our results demonstrate that blocking the previously observed 65 increase in liver ALT activity could confer an abrogation in the muscle atrophy upon synthetic glucocorticoid treatment. The lack of effects of the liver GR action might be explained by the partial action of liver-GR silencing on the upregulation of liver ALT expression ( Fig.…”

“…The muscle atrophy, and related weakness, in T2D could be reversed by a silencing of the upregulation of liver alanine catabolism, an intriguing result. Such a result is not unfounded however, as some prior studies have linked liver metabolic control with systemic protein turnover and skeletal muscle phenotype 43,44 . Similar to our studies in mice ( Fig.…”

Mechanistic insights on metabolic dysfunction in PTSD: Role of glucocorticoid receptor sensitivity and energy deficit

“…The reduced availability of ATP can thus limit formation of carbamoyl phosphate and its subsequent reaction with ornithine, thereby leading to accumulation of ornithine (p=0.01) and reduced levels of citrulline and arginine (trend), as observed in our data. Further, elevated arginase expression is shown to be associated with increased inflammatory cytokines and GC activity 46 , which could further lead to a lower urea cycle flux, reduced arginine levels and subsequent nitric oxide production. This is also supported by a significant positive association between cortisol suppression and ornithine (ρ=0.223, p=0.004, q=0.015) and a trend of causal association between hs-CRP and arginine ( =- 0.05, p=0.05, q=0.145, τ 2 =0.211).…”