Mouse lipin-1 and lipin-2 cooperate to maintain glycerolipid homeostasis in liver and aging cerebellum

Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):E2486-95. doi: 10.1073/pnas.1205221109. Epub 2012 Aug 20.

Abstract

The three lipin phosphatidate phosphatase (PAP) enzymes catalyze a step in glycerolipid biosynthesis, the conversion of phosphatidate to diacylglycerol. Lipin-1 is critical for lipid synthesis and homeostasis in adipose tissue, liver, muscle, and peripheral nerves. Little is known about the physiological role of lipin-2, the predominant lipin protein present in liver and the deficient gene product in the rare disorder Majeed syndrome. By using lipin-2-deficient mice, we uncovered a functional relationship between lipin-1 and lipin-2 that operates in a tissue-specific and age-dependent manner. In liver, lipin-2 deficiency led to a compensatory increase in hepatic lipin-1 protein and elevated PAP activity, which maintained lipid homeostasis under basal conditions, but led to diet-induced hepatic triglyceride accumulation. As lipin-2-deficient mice aged, they developed ataxia and impaired balance. This was associated with the combination of lipin-2 deficiency and an age-dependent reduction in cerebellar lipin-1 levels, resulting in altered cerebellar phospholipid composition. Similar to patients with Majeed syndrome, lipin-2-deficient mice developed anemia, but did not show evidence of osteomyelitis, suggesting that additional environmental or genetic components contribute to the bone abnormalities observed in patients. Combined lipin-1 and lipin-2 deficiency caused embryonic lethality. Our results reveal functional interactions between members of the lipin family in vivo, and a unique role for lipin-2 in central nervous system biology that may be particularly important with advancing age. Additionally, as has been observed in mice and humans with lipin-1 deficiency, the pathophysiology in lipin-2 deficiency is associated with dysregulation of lipid intermediates.

Publication types

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

MeSH terms

  • Aging / physiology*
  • Analysis of Variance
  • Animals
  • Blood Cell Count
  • Blotting, Western
  • Bone and Bones / diagnostic imaging
  • Cerebellum / metabolism
  • Cerebellum / physiology*
  • DNA Primers / genetics
  • Galactosides
  • Gene Expression Profiling
  • Histological Techniques
  • Homeostasis / physiology*
  • Immunohistochemistry
  • Indoles
  • Liver / metabolism
  • Liver / physiology*
  • Locomotion / physiology
  • Mice
  • Mice, Transgenic
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / metabolism*
  • Phosphatidate Phosphatase / deficiency
  • Phosphatidate Phosphatase / metabolism*
  • Phospholipids / metabolism
  • Polymerase Chain Reaction
  • Psychomotor Performance
  • Radiography
  • Reflex, Startle / physiology

Substances

  • DNA Primers
  • Galactosides
  • Indoles
  • Nuclear Proteins
  • Phospholipids
  • Lpin1 protein, mouse
  • Phosphatidate Phosphatase
  • Lipin 2 protein, mouse
  • 5-bromo-4-chloro-3-indolyl beta-galactoside