Null Mutation in Hormone-Sensitive Lipase Gene and Risk of Type 2 Diabetes
What is the role of impaired lipolysis in risk for hyperlipidemia and type 2 diabetes?
In 24 Old Order Amish subjects with extremely elevated fasting triglyceride levels, 12 genes in the lipolytic pathway were sequenced. A novel frameshift deletion was identified in exon 9 of the gene encoding hormone-sensitive lipase (HSL). Association analyses between the mutation and metabolic traits were then performed in 2,738 Amish participants. Abdominal subcutaneous adipose tissue was analyzed in a small subgroup.
Subjects with the HSL mutation showed dyslipidemia, insulin resistance, diabetes, and hepatic steatosis. Adipose tissue from subjects homozygous for the mutation showed impaired lipolysis, insulin resistance, inflammation, small adipocytes, and down-regulation of PPAR gamma-responsive transcription factors.
The authors concluded that these findings demonstrate the significance of HSL in adipocyte function and the regulation of systemic lipid and glucose homeostasis.
HSL is a ubiquitously expressed intracellular lipase with many lipid substrates. A previous mouse model of HSL deficiency showed accumulation of lipids within adipocytes with miminal or no systemic abnormalities in lipid or glucose homeostasis. The current human study showed small adipocytes in subjects with HSL deficiency and a much more severe systemic phenotype including dyslipidemia, insulin resistance, and ectopic lipid storage. This difference suggests important differences between mice and humans in lipoprotein metabolism, as has been noted with other lipid-storage regulatory genes. This study establishes a critical role for impaired lipolysis in the regulation of lipid and glucose homeostasis in humans, and also suggests that activation of HSL may serve as a therapeutic strategy in some patients with dyslipidemia and diabetes.
Keywords: Inflammation, Hyperlipidemias, Diabetes Mellitus, Type 2, Transcription Factors, Insulin Resistance, Glucose, Mutation, Dyslipidemias, Subcutaneous Fat, Abdominal, PPAR gamma, Sterol Esterase, Homeostasis, Lipolysis
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