Null Mutation in Hormone-Sensitive Lipase Gene and Risk of Type 2 Diabetes  

Oleh:

Albert, Jessica S. ; Yerges-Armstrong, Laura M. ; Horenstein, Richard B. ; Pollin, Toni I. ; Sreenivasan, Urmila T.

Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: The New England Journal of Medicine (keterangan: ada di Proquest) vol. 370 no. 24 (Jun. 2014), page 2307-2315.
Topik: Null Mutation; Hormone-Sensitive Lipase Gene; Risk of Type 2 Diabetes

Ketersediaan

Perpustakaan FK Nomor Panggil: N08.K.2014.01 Non-tandon: 1 (dapat dipinjam: 0) Tandon: tidak ada

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Isi artikel

Background Lipolysis 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. Methods We 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. Results Carriers 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 ? (PPAR-?) 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. Conclusions These 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.

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