Mouse lipin-1 and lipin-2 cooperate to maintain glycerolipid homeostasis in liver and aging cerebellum.
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.
Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
Jennifer R
JR
Dwyer
Jimmy
J
Donkor
Peixiang
P
Zhang
Lauren S
LS
Csaki
Laurent
L
Vergnes
Jessica M
JM
Lee
Jay
J
Dewald
David N
DN
Brindley
Elisa
E
Atti
Sotirios
S
Tetradis
Yuko
Y
Yoshinaga
Pieter J
PJ
De Jong
Loren G
LG
Fong
Stephen G
SG
Young
Karen
K
Reue
D000375:Aging / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001772:Blood Cell Count; D015153:Blotting, Western; D001842:Bone and Bones / Q000000981:diagnostic imaging; D002531:Cerebellum / Q000378:metabolism / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D005697:Galactosides; D020869:Gene Expression Profiling; D006652:Histological Techniques; D006706:Homeostasis / Q000502:physiology*; D007150:Immunohistochemistry; D007211:Indoles; D008099:Liver / Q000378:metabolism / Q000502:physiology*; D008124:Locomotion / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D010711:Phosphatidate Phosphatase / Q000172:deficiency / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011597:Psychomotor Performance; D011859:Radiography; D013216:Reflex, Startle / Q000502:physiology
D017931:DNA Primers; D005697:Galactosides; D007211:Indoles; D009687:Nuclear Proteins; D010743:Phospholipids; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase; C540254:Lipin 2 protein, mouse; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside