A loss-of-function mutation in the hormone-sensitive lipase (HSL) gene is associated with features of the metabolic syndrome, show the results of a new study.

The researchers sequenced genes of the lipolytic pathway in 12 Amish individuals whose levels of triglycerides were either very high or very low. A frameshift deletion in the LIPE gene, which encodes HSL, was present in one of the participants who had high triglyceride levels. Further investigation in a group of 2,730 Amish individuals showed that carriers of the mutation had higher serum triglyceride levels, hepatic fat content and fasting insulin, and lower levels of HDL cholesterol than noncarriers.

Both heterozygous and homozygous individuals with the mutation had increased insulin resistance and increased risk of developing type 2 diabetes mellitus (T2DM). Individuals homozygous for the mutation had small adipocytes and increased inflammation. “These data support a key role for HSL in regulation of lipid and glucose metabolism in humans,” comments Coleen Damcott, senior author of the study. “Our findings also suggest that disruption of HSL downregulates PPARγ-responsive signalling pathways, perhaps through decreased production of endogenous ligands for PPARγ and/or RXRα.”

Damcott hopes that this research will help unveil mechanisms and pathways useful in predicting which patients will be more responsive to PPARγ agonists. “In addition, our results suggest activation of HSL as a potential experimental approach to treating dyslipidaemia and glucose intolerance in patients with the metabolic syndrome and T2DM.”