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

Abstract

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 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. 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. (Funded by the National Institutes of Health and others).

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

“…Similarly as in AKO/cTg mice, the obesity-resistant phenotype could be partially prevented by PPAR-γ agonist treatment (8). Recently, the first report on human individuals suffering from HSL deficiency confirmed the mouse findings and showed that the lack of HSL leads to decreased PPAR-γ target gene expression and partial lipodystrophy in affected patients (38). Collectively, these data suggest that lipolysis is required for functional PPAR-γ signaling, normal lipogenesis, and TG synthesis.…”

Nicotinic acid timed to feeding reverses tissue lipid accumulation and improves glucose control in obese Zucker rats[S]

“…Because the products of lipolysis are thought to provide ligands for PPAR activation (39), sustained and robust antilipolytic therapy might reduce the activation of PPAR. Depending on its magnitude, this could undermine the beneficial effects by impairing adipose tissue function and perturbing systemic metabolic control, as seen in humans with insufficiencies of functional PPAR or HSL (40,41). However, we found that expression of PPAR2 as well as several regulated genes [perilipin 1 (42), CD36 (43), and FABP4 (44)] in adipose tissue was unaffected by NiAc treatment.…”

Complex Genetics of Type 2 Diabetes and Effect Size: What have We Learned from Isolated Populations?

“…LIPE encodes hormone-sensitive lipase (HSL), and primarily hydrolyzes stored triglycerides to free fatty acids in adipose tissue and heart, whereas in steroidogenic tissues, it converts cholesteryl esters to free cholesterol for steroid hormone production. Analysis of the 19-bp frameshift deletion in 2,738 Amish subjects identified an effect on T2D (OR = 1.80 for subjects heterozygous for the deletion compared to subjects without deletion despite similar BMI), dyslipidemia, hepatic steatosis, and systemic insulin resistance [118]. All four subjects who were homozygous for the deletion were diagnosed with T2D before the age of 50 years [118].…”

“…A study in the Old Order Amish analyzed sequence data from 12 lipolytic-pathway genes in subjects whose fasting triglyceride levels were at the extremes of the distribution, and identified a 19-bp frameshift deletion in exon 9 of LIPE, a key enzyme for lipolysis [118]. LIPE encodes hormone-sensitive lipase (HSL), and primarily hydrolyzes stored triglycerides to free fatty acids in adipose tissue and heart, whereas in steroidogenic tissues, it converts cholesteryl esters to free cholesterol for steroid hormone production.…”