Impaired peroxisome proliferator-activated receptor gamma function through mutation of a conserved salt bridge (R425C) in familial partial lipodystrophy.

The nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma plays a key role in the regulation of glucose and lipid metabolism in adipocytes by regulating their differentiation, maintenance, and function. A heterozygous mutation in the PPARG gene, which changes an arginine residue at position 425 into a cysteine (R425C), has been reported in a patient with familial partial lipodystrophy subtype 3 (FPLD3). The strong conservation of arginine 425 among nuclear receptors that heterodimerize with retinoic acid X receptor prompted us to investigate the functional consequences of the R425C mutation on PPARgamma function.

An in vitro bioassay to determine individual sensitivity to glucocorticoids: induction of FKBP51 mRNA in peripheral blood mononuclear cells.

Individual variation in sensitivity to glucocorticoids (GCs) poses a dilemma to the clinician. Currently available assays to determine individual sensitivity to GCs either seem imprecise, or they are based on mitogen-activated lymphocytes, although mitogens themselves may affect cellular GC sensitivity. To avoid these disadvantages, we developed an assay based on the GC-induced accumulation of the 51kDa FK506 binding protein (FKBP51) mRNA in unstimulated peripheral blood mononuclear cells (PBMC), measured using real time PCR.

Glucocorticoid-induced increase in lymphocytic FKBP51 messenger ribonucleic acid expression: a potential marker for glucocorticoid sensitivity, potency, and bioavailability.

To reduce the side effects of corticosteroid treatment, the administered dose of glucocorticoids (GCs) should be kept to a minimum while preserving therapeutically needed intracellular levels. Currently available assays to determine individual sensitivity to GCs are either imprecise or based on inhibition by GCs of lymphocyte proliferation following stimulation with phytohemagglutinin or other mitogens, which may influence the GC signal transduction pathway. Using the human lymphoblastoid cell line IM-9 as a model system, we studied whether the GC-induced increase of the mRNA encoding the 51-kDa FK506-binding protein (FKBP51) could be used for the development of a novel assay, ultimately to be used in native human peripheral blood mononuclear cells (PBMCs).