Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes.
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).
Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
Jessica S
JS
Albert
Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
Laura M
LM
Yerges-Armstrong
Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
Richard B
RB
Horenstein
Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
Toni I
TI
Pollin
Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
Urmila T
UT
Sreenivasan
Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
Sumbul
S
Chai
Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
William S
WS
Blaner
Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
Soren
S
Snitker
Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
Jeffrey R
JR
O'Connell
Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
Da-Wei
DW
Gong
Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
Richard J
RJ
Breyer
Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
Alice S
AS
Ryan
Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
John C
JC
McLenithan
Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
Alan R
AR
Shuldiner
Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
Carole
C
Sztalryd
Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center - all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).
Coleen M
CM
Damcott
D000328:Adult; D000368:Aged; D061365:Amish / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D050171:Dyslipidemias / Q000235:genetics / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008066:Lipolysis / Q000235:genetics*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008875:Middle Aged; D010375:Pedigree; D002787:Sterol Esterase / Q000235:genetics*
D002787:Sterol Esterase