Identification of a novel lipase gene mutated in lpd mice with hypertriglyceridemia and associated with dyslipidemia in humans.
Triglyceride (TG) metabolism is crucial for whole body and local energy homeostasis and accumulating evidence suggests an independent association between plasma TG concentration and increased atherosclerosis risk. We previously generated a mouse insertional mutation lpd (lipid defect) whose phenotype included elevated plasma TG and hepatic steatosis. Using shotgun sequencing (approximately 500 kb) and bioinformatics, we have now identified a novel lipase gene lpdl (lpd lipase) within the lpd locus, and demonstrate the genetic disruption of exon 10 of lpdl in the lpd mutant locus. lpdl is highly expressed in the testis and weakly expressed in the liver of 2-week old mice. Human LPDL cDNA was subsequently cloned, and was found to encode a 460AA protein with 71% protein sequence identity to mouse lpdl and approximately 35% identity to other known lipases. We next sequenced the human LPDL gene exons in hypertriglyceridemic subjects and normal controls, and identified seven SNPs within the gene exons and six SNPs in the adjacent introns. Two hypertriglyceridemic subjects were heterozygous for a rare DNA variant, namely 164G>A (C55Y), which was absent from 600 normal chromosomes. Two other coding SNPs were associated with variation in plasma HDL cholesterol in independent normolipidemic populations. Using bioinformatics, we identified another novel lipase designated LPDLR (for 'LPDL related lipase'), which had 44% protein sequence identity with LPDL. Together with the phospholipase gene PSPLA1, LPDL and LPDLR form a new lipase gene subfamily, which is characterized by shortened lid motif. Study of this lipase subfamily may identify novel molecular mechanisms for plasma and/or tissue TG metabolism.
Department of Experimental Therapeutics, Toronto General Research Institute, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada. x.wen@utoronto.ca
Xiao-Yan
XY
Wen
Robert A
RA
Hegele
Jian
J
Wang
Ding Yan
DY
Wang
Joseph
J
Cheung
Michael
M
Wilson
Maryam
M
Yahyapour
Yahong
Y
Bai
Lihua
L
Zhuang
Jennifer
J
Skaug
T Kue
TK
Young
Philip W
PW
Connelly
Ben F
BF
Koop
Lap-Chee
LC
Tsui
A Keith
AK
Stewart
D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics* / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000201:enzymology / Q000235:genetics*; D008049:Lipase / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010802:Phylogeny; D013737:Testis / Q000473:pathology
D008049:Lipase