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 features of human lipodystrophy¹, a genetically heterogeneous group of disorders characterized by loss of body fat, fatty liver, hypertriglyceridemia and insulin resistance^2-4. Through positional cloning, we have isolated the gene responsible and characterized two independent mutant alleles, fld and fld^2J. The gene (Lpin1) encodes a novel nuclear protein which we have named lipin. Consistent with the observed reduction of adipose tissue mass in fld and fld^2J mice, wild-type Lpin1 mRNA is expressed at high levels in adipose tissue and is induced during differentiation of 3T3-L1 pre-adipocytes. Our results indicate that lipin is required for normal adipose tissue development, and provide a candidate gene for human lipodystrophy. Lipin defines a novel family of nuclear proteins containing at least three members in mammalian species, and homologs in distantly related organisms from human to yeast.