Positional cloning of the combined hyperlipidemia gene Hyplip1

Nat Genet. 2002 Jan;30(1):110-6. doi: 10.1038/ng811. Epub 2001 Dec 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Congenic
  • Carbon Dioxide / metabolism
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Chromosomes, Artificial, Bacterial / genetics
  • Chromosomes, Human, Pair 1 / genetics
  • Citric Acid Cycle / genetics
  • Cloning, Molecular*
  • Codon / genetics
  • Codon, Nonsense
  • Contig Mapping
  • Cosmids / genetics
  • Cricetinae
  • Crosses, Genetic
  • Disease Models, Animal
  • Energy Metabolism / genetics
  • Exons / genetics
  • Fatty Acids / metabolism
  • Haplotypes / genetics
  • Humans
  • Hybrid Cells
  • Hyperlipidemia, Familial Combined / genetics*
  • Hyperlipidemia, Familial Combined / metabolism
  • Ketone Bodies / biosynthesis
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Oxidation-Reduction
  • Thioredoxins / antagonists & inhibitors
  • Triglycerides / blood


  • Carrier Proteins
  • Codon
  • Codon, Nonsense
  • Fatty Acids
  • Ketone Bodies
  • TXNIP protein, human
  • Triglycerides
  • Txnip protein, mouse
  • Carbon Dioxide
  • Thioredoxins

Associated data

  • GENBANK/AF440447