• Jessica S Albert, Laura M Yerges-Armstrong, Richard B Horenstein, Toni I Pollin, Urmila T Sreenivasan, Sumbul Chai, William S Blaner, Soren Snitker, Jeffrey R O'Connell, Da-Wei Gong, Richard J Breyer, Alice S Ryan, John C McLenithan, Alan R Shuldiner, Carole Sztalryd, and Coleen M Damcott.
• From the Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
• N. Engl. J. Med.. 2014 Jun 12;370(24):2307-15.

BackgroundLipolysis regulates energy homeostasis through the hydrolysis of intracellular triglycerides and the release of fatty acids for use as energy substrates or lipid mediators in cellular processes. Genes encoding proteins that regulate energy homeostasis through lipolysis are thus likely to play an important role in determining susceptibility to metabolic disorders.MethodsWe sequenced 12 lipolytic-pathway genes in Old Order Amish participants whose fasting serum triglyceride levels were at the extremes of the distribution and identified a novel 19-bp frameshift deletion in exon 9 of LIPE, encoding hormone-sensitive lipase (HSL), a key enzyme for lipolysis. We genotyped the deletion in DNA from 2738 Amish participants and performed association analyses to determine the effects of the deletion on metabolic traits. We also obtained biopsy specimens of abdominal subcutaneous adipose tissue from 2 study participants who were homozygous for the deletion (DD genotype), 10 who were heterozygous (ID genotype), and 7 who were noncarriers (II genotype) for assessment of adipose histologic characteristics, lipolysis, enzyme activity, cytokine release, and messenger RNA (mRNA) and protein levels.ResultsCarriers of the mutation had dyslipidemia, hepatic steatosis, systemic insulin resistance, and diabetes. In adipose tissue from study participants with the DD genotype, the mutation resulted in the absence of HSL protein, small adipocytes, impaired lipolysis, insulin resistance, and inflammation. Transcription factors responsive to peroxisome-proliferator-activated receptor γ (PPAR-γ) and downstream target genes were down-regulated in adipose tissue from participants with the DD genotype, altering the regulation of pathways influencing adipogenesis, insulin sensitivity, and lipid metabolism.ConclusionsThese findings indicate the physiological significance of HSL in adipocyte function and the regulation of systemic lipid and glucose homeostasis and underscore the severe metabolic consequences of impaired lipolysis. (Funded by the National Institutes of Health and others).

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