Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin

Mice carrying mutations in the fatty liver dystrophy (fld) gene have featur es of human lipodystrophy(1), a genetically heterogeneous group of disorder s characterized by loss of body fat, fatty liver hypertriglyceridemia and i nsulin resistance(2-4). Through positional cloning, we have isolated the ge ne responsible and characterized two independent mutant alleles, fld and fl d(2J). The gene (Lpin1) encodes a novel nuclear protein which we have named lipin. Consistent with the observed reduction of adipose tissue mass in fl d and fld(2J) mice, wild-type Lpin1 mRNA is expressed at high levels in adi pose tissue and is induced during differentiation of 3T3-L1 pre-adipocytes. Our results indicate that lipin is required for normal adipose tissue deve lopment, and provide a candidate gene for human lipodystrophy. Lipin define s a novel family of nuclear proteins containing at least three members in m ammalian species, and homologs in distantly related organisms from human to yeast.