{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:39:47Z","timestamp":1792813187946,"version":"4.5.0"},"reference-count":58,"publisher":"National Academy of Sciences","issue":"37","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,9,11]]},"abstract":"<jats:p>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\u2013deficient 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\u2013deficient 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\u2013deficient 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.<\/jats:p>","DOI":"10.1073\/pnas.1205221109","type":"journal-article","created":{"date-parts":[[2012,8,21]],"date-time":"2012-08-21T00:30:12Z","timestamp":1345509012000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":86,"title":["Mouse lipin-1 and lipin-2 cooperate to maintain glycerolipid homeostasis in liver and aging cerebellum"],"prefix":"10.1073","volume":"109","author":[{"given":"Jennifer R.","family":"Dwyer","sequence":"first","affiliation":[{"name":"Molecular Biology Institute, University of California, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy","family":"Donkor","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peixiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren S.","family":"Csaki","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Vergnes","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica M.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Dewald","sequence":"additional","affiliation":[{"name":"Department of Cell Signaling, University of Alberta, Edmonton, AB, Canada T6G 2H7;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David N.","family":"Brindley","sequence":"additional","affiliation":[{"name":"Department of Cell Signaling, University of Alberta, Edmonton, AB, Canada T6G 2H7;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Atti","sequence":"additional","affiliation":[{"name":"School of Dentistry, University of California, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sotirios","family":"Tetradis","sequence":"additional","affiliation":[{"name":"School of Dentistry, University of California, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Yoshinaga","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital Oakland Research Institute, Oakland, CA 94609; 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