Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein energy wasting, a state of decreased stores of body protein and fat, is a risk factor for mortality in advanced chronic kidney disease (CKD). Little is known about the mechanism underlying loss of fat in CKD. Accumulation of asymmetric dimethylarginine (ADMA) is prevalent in advanced CKD. Here we assessed the effect of ADMA on cellular perturbation in cultured 3T3-L1 adipocytes. Exposure of adipocytes to ADMA induced lipolysis and decreased perilipin A, with no alteration of lipases expression or activity. ADMA treatment also upregulated the expression of inflammatory adipocytokines via activation of nuclear factor-kappaB (NF-kappaB). Blocking the inflammatory responses with NF-kappaB inhibitor partly inhibited the ADMA-induced lipolysis. Furthermore, ADMA treatment triggered endoplasmic reticulum (ER) stress, revealed by phosphorylation of PKR-like eukaryotic initiation factor 2alpha kinase, eukaryotic translational initiation factor 2alpha, c-Jun NH2-terminal kinase, and overexpression of glucose-regulated protein 78. Treatment with ER stress inhibitor completely abolished the ADMA-induced lipolysis and inflammatory responses. Moreover, conditioned medium from the ADMA-treated adipocytes increased protein degradation in cultured C2C12 myotubes, suggesting that the ADMA-induced adipocyte perturbation may promote skeletal muscle proteolysis. These data suggest that elevated ADMA promoted the adipocyte perturbation through induction of ER stress, which might have implication for protein energy wasting in CKD.
 ...
PMID:Asymmetrical dimethylarginine triggers lipolysis and inflammatory response via induction of endoplasmic reticulum stress in cultured adipocytes. 1920 51

Muscle atrophy remains a significant concern in multiple inflammatory conditions, including injury, sepsis, cachexia, and HIV-associated wasting. Herein, we show that inflammatory stressors, including TNF-alpha, IFN-gamma, or lipopolysaccharide, potently induced the novel expression of the RNA editor ADAR1, an observation not previously described in muscle cells. We also observed that cytokine stimulation suppressed muscle-associated microRNAs, an observation also not previously demonstrated. To map potential effects of ADAR1 induction in the muscle program, we conducted knockdown and overexpression studies in the mouse C2C12 muscle precursor cell (MPC) line and in primary human MPCs. We show that knockdown of stress-induced ADAR1 increased inflammation-mediated declines in the muscle differentiation markers Myogenin and myosin heavy chain, and knockdown reduced levels of active phosphorylated Akt (phospho-Akt), but had no effect on microRNA transcript levels, suggesting a role for ADAR1 in buffering inflammatory stress effects on myogenic transcription and protein synthesis pathways. In addition, overexpression of recombinant ADAR1 suppressed active phosphorylated double-stranded RNA (dsRNA)-dependent protein kinase (phospho-PKR), consistent with a role for ADAR1 in limiting inflammation-driven catabolic atrophy pathways. Collectively, these data identify a novel regulatory role for ADAR1 activation under inflammatory stress to both promote muscle protein synthesis pathways and limit atrophy pathways.
 ...
PMID:The RNA editor gene ADAR1 is induced in myoblasts by inflammatory ligands and buffers stress response. 2059 Jun 75