Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Mutations in the lipin-1 gene cause lipodystrophy in fatty liver dystrophy (fld) mice, leading to impaired adipose tissue development, insulin resistance, and altered energy expenditure.
• Lipin-1 is highly expressed in adipose tissue and skeletal muscle.
• Two additional lipin family members, lipin-2 and lipin-3, have unknown functions.

Purpose of the Study:

• To determine the enzymatic activity of lipin-1, lipin-2, and lipin-3.
• To elucidate the biochemical basis of lipodystrophy in lipin-1 deficient mice.

Main Methods:

• Assessed phosphatidate phosphatase type-1 (PAP1) activity in lipin-1 deficient mice.
• Recombinant lipin-2 and lipin-3 were expressed and their PAP1 activity was measured.
• Analyzed tissue-specific expression patterns of the three lipin family members.

Main Results:

• Lipin-1 accounts for all PAP1 activity in white and brown adipose tissue and skeletal muscle.
• Livers of lipin-1-deficient mice showed normal PAP1 activity, suggesting other lipins possess this function.
• Recombinant lipin-2 and lipin-3 demonstrated PAP1 activity, each showing Mg2+-dependent specificity for phosphatidate.
• Distinct tissue expression patterns were observed for the three lipin family members.

Conclusions:

• The three mammalian lipin proteins (lipin-1, lipin-2, and lipin-3) are established as phosphatidate phosphatase type-1 (PAP1) enzymes.
• This study explains the biochemical basis for lipodystrophy observed in lipin-1-deficient fld mice.
• Lipin proteins play a critical role in glycerolipid synthesis and adipose tissue metabolism.