A Hypomorphic Mutation in Lpin1 Induces Progressively Improving Neuropathy and Lipodystrophy in the Rat

Abstract

The Lpin1 gene encodes the phosphatidate phosphatase (PAP1) enzyme Lipin 1, which plays a critical role in lipid metabolism. In this study we describe the identification and characterization of a rat model with a mutated Lpin1 gene (Lpin1 1Hubr ), generated by N-ethyl-N-nitrosourea mutagenesis. Lpin1 1Hubr rats are characterized by hindlimb paralysis and mild lipodystrophy that are detectable from the second postnatal week. Sequencing of Lpin1 identified a point mutation in the 5-end splice site of intron 18 resulting in missplicing, a reading frameshift, and a premature stop codon. As this mutation does not induce nonsense-mediated decay, it allows the production of a truncated Lipin 1 protein lacking PAP1 activity.

Lipin-1 Phosphatidic Phosphatase Activity Modulates Phosphatidate Levels to Promote Peroxisome Proliferator-activated Receptor γ (PPARγ) Gene Expression during Adipogenesis

“…Our results are consistent with the characteristics of a rat model carrying a spontaneous mutation that produces a truncated lipin-1 protein lacking the proposed magnesium-binding site, which ablates PAP activity (57). The mutant rats exhibited reduced white adipose tissue weight, reduced adipocyte diameter, and reduced Pparg gene expression beginning at postnatal day 21.…”

Altered Lipid Synthesis by Lack of Yeast Pah1 Phosphatidate Phosphatase Reduces Chronological Life Span

“…These phenotypic changes in lipid metabolism are directly or indirectly coupled to other phenotypes, such as an irregular expansion of the nuclear/ER membrane, marked vacuole fragmentation, and increased fatty acid-induced lipotoxicity (11,29,34,35,38). Similarly, in mammalian cells, loss of lipin PAP activity results in metabolic disorders that include lipodystrophy, insulin resistance, peripheral neuropathy, rhabdomyolysis, and inflammation (30,(93)(94)(95)(96)(97)(98)(99)(100)(101).…”

Cross-talk Phosphorylations by Protein Kinase C and Pho85p-Pho80p Protein Kinase Regulate Pah1p Phosphatidate Phosphatase Abundance in Saccharomyces cerevisiae

“…1A) (10,14). The losses of or defects in mammalian lipin PAP enzymes underlie metabolic disorders that include lipodystrophy and insulin resistance, peripheral neuropathy, myoglobinuria, and inflammation (7,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Together, these observations highlight the importance of PAP in lipid metabolism and cell physiology and the need to understand the genetic and biochemical regulations of the enzyme.…”