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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.  To identify genetic regulators of lipolysis, we sequenced 12 lipolytic-pathway genes in Amish subjects with extreme high or low 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 then genotyped this deletion in 2,738 additional Amish subjects and observed that carriers of the mutation had dyslipidemia, hepatic steatosis, systemic insulin resistance, and diabetes, and that the mutation resulted in the absence of HSL protein, small adipocytes, impaired lipolysis, insulin resistance, and inflammation.

Key Findings

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.


  • Albert JS, Yerges-Armstrong LM, Horenstein RB, Pollin TI, Sreenivasan UT, Chai S, Blaner WS, Snitker S, O’Connell JR, Gong DW, Breyer RJ 3rd, Ryan AS, McLenithan JC, Shuldiner AR, Sztalryd C, Damcott CM. Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes. N Engl J Med. 2014 Jun 12;370(24):2307-15. PMID: 24848981; PMCID: PMC4096982.

Read More: New England Journal of Medicine

Research Details

  • Research Center: Mid-Atlantic, Maryland
  • Center Contribution: The Mid-Atlantic NORC provided support to this study for access to the Amish biobank, subject recruitment, clinical assessment, sequencing, and genotyping.

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