Retinoid X Receptor Heterodimers in the Metabolic Syndrome
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The excellent review of nuclear receptors by Shulman and Mangelsdorf (Aug. 11 issue)1 mentioned that the study of patients with mutations in PPAR, the gene encoding peroxisome-proliferator–activated receptor (PPAR), which is rare, can yield corroborating and new insights into the metabolic syndrome. However, it is important to acknowledge that all reported cases of the metabolic syndrome involving heterozygous germ-line loss-of-function PPAR mutations2,3,4,5 concurrently have familial partial lipodystrophy type 3 (FPLD3). Given the role of PPAR in adipogenesis, it seems reasonable that adipose tissue is repartitioned from peripheral to central stores in patients with such mutations. The metabolic syndrome in patients with mutant PPAR might be a consequence of fat loss or redistribution, as in other genetic and acquired forms of lipodystrophy,6 of some direct effects of defective or deficient PPAR within metabolic pathways, or both. Therefore, germ-line PPAR mutations in patients with FPLD3 provide an interesting and possibly informative monogenic model system that may be helpful in elucidating acquired-lipodystrophy syndromes.
Robert A. Hegele, M.D.
Robarts Research Institute
London, ON N6A 5K8, Canada
hegele@robarts.ca
References
Shulman AI, Mangelsdorf DJ. Retinoid X receptor heterodimers in the metabolic syndrome. N Engl J Med 2005;353:604-615.
Agarwal AK, Garg A. A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab 2002;87:408-411.
Hegele RA, Cao H, Frankowski C, Mathews ST, Leff T. PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes 2002;51:3586-3590.
Savage DB, Tan GD, Acerini CL, et al. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. Diabetes 2003;52:910-917.
Al-Shali K, Cao H, Knoers N, Hermus AR, Tack CJ, Hegele RA. A single-base mutation in the peroxisome proliferator-activated receptor gamma4 promoter associated with altered in vitro expression and partial lipodystrophy. J Clin Endocrinol Metab 2004;89:5655-5660.
Garg A. Acquired and inherited lipodystrophies. N Engl J Med 2004;350:1220-1234.
Robert A. Hegele, M.D.
Robarts Research Institute
London, ON N6A 5K8, Canada
hegele@robarts.ca
References
Shulman AI, Mangelsdorf DJ. Retinoid X receptor heterodimers in the metabolic syndrome. N Engl J Med 2005;353:604-615.
Agarwal AK, Garg A. A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab 2002;87:408-411.
Hegele RA, Cao H, Frankowski C, Mathews ST, Leff T. PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes 2002;51:3586-3590.
Savage DB, Tan GD, Acerini CL, et al. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. Diabetes 2003;52:910-917.
Al-Shali K, Cao H, Knoers N, Hermus AR, Tack CJ, Hegele RA. A single-base mutation in the peroxisome proliferator-activated receptor gamma4 promoter associated with altered in vitro expression and partial lipodystrophy. J Clin Endocrinol Metab 2004;89:5655-5660.
Garg A. Acquired and inherited lipodystrophies. N Engl J Med 2004;350:1220-1234.