Positional cloning of the combined hyperlipidemia gene Hyplip1.
Familial combined hyperlipidemia (FCHL, MIM-144250) is a common, multifactorial and heterogeneous dyslipidemia predisposing to premature coronary artery disease and characterized by elevated plasma triglycerides, cholesterol, or both. We identified a mutant mouse strain, HcB-19/Dem (HcB-19), that shares features with FCHL, including hypertriglyceridemia, hypercholesterolemia, elevated plasma apolipoprotein B and increased secretion of triglyceride-rich lipoproteins. The hyperlipidemia results from spontaneous mutation at a locus, Hyplip1, on distal mouse chromosome 3 in a region syntenic with a 1q21-q23 FCHL locus identified in Finnish, German, Chinese and US families. We fine-mapped Hyplip1 to roughly 160 kb, constructed a BAC contig and sequenced overlapping BACs to identify 13 candidate genes. We found substantially decreased mRNA expression for thioredoxin interacting protein (Txnip). Sequencing of the critical region revealed a Txnip nonsense mutation in HcB-19 that is absent in its normolipidemic parental strains. Txnip encodes a cytoplasmic protein that binds and inhibits thioredoxin, a major regulator of cellular redox state. The mutant mice have decreased CO2 production but increased ketone body synthesis, suggesting that altered redox status down-regulates the citric-acid cycle, sparing fatty acids for triglyceride and ketone body production. These results reveal a new pathway of potential clinical significance that contributes to plasma lipid metabolism.
Bodnar
Jackie S
JS
Department of Medicine, University of California, Los Angeles, 47-123 CHS, UCLA School of Medicine, Los Angeles, California 90095, USA.
Chatterjee
Aurobindo
A
Castellani
Lawrence W
LW
Ross
David A
DA
Ohmen
Jeffrey
J
Cavalcoli
James
J
Wu
Chenyan
C
Dains
Katherine M
KM
Catanese
Joe
J
Chu
Michael
M
Sheth
Sonal S
SS
Charugundla
Kanti
K
Demant
Peter
P
West
David B
DB
de Jong
Pieter
P
Lusis
Aldons J
AJ
D000818:Animals; D020296:Animals, Congenic; D002245:Carbon Dioxide / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002952:Citric Acid Cycle / Q000235:genetics; D003001:Cloning, Molecular; D003062:Codon / Q000235:genetics; D018389:Codon, Nonsense; D020451:Contig Mapping; D003360:Cosmids / Q000235:genetics; D006224:Cricetinae; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics; D005091:Exons / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006822:Hybrid Cells; D006950:Hyperlipidemia, Familial Combined / Q000235:genetics* / Q000378:metabolism; D007657:Ketone Bodies / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D013879:Thioredoxins / Q000037:antagonists & inhibitors; D014280:Triglycerides / Q000097:blood
D002352:Carrier Proteins; D003062:Codon; D018389:Codon, Nonsense; D005227:Fatty Acids; D007657:Ketone Bodies; C486715:TXNIP protein, human; D014280:Triglycerides; C445672:Txnip protein, mouse; D002245:Carbon Dioxide; D013879:Thioredoxins