title: Lipin-1 regulates autophagy clearance and intersects with statin drug effects in skeletal muscle.
abstract: LPIN1 encodes lipin-1, a phosphatidic acid phosphatase (PAP) enzyme that catalyzes the dephosphorylation of phosphatidic acid to form diacylglycerol. Homozygous LPIN1 gene mutations cause severe rhabdomyolysis, and heterozygous LPIN1 missense mutations may promote statin-induced myopathy. We demonstrate that lipin-1-related myopathy in the mouse is associated with a blockade in autophagic flux and accumulation of aberrant mitochondria. Lipin-1 PAP activity is required for maturation of autolysosomes, through its activation of the protein kinase D (PKD)-Vps34 phosphatidylinositol 3-kinase signaling cascade. Statin treatment also reduces PKD activation and autophagic flux, which are compounded by diminished mammalian target of rapamycin (mTOR) abundance in lipin-1-haploinsufficent and -deficient muscle. Lipin-1 restoration in skeletal muscle prevents myonecrosis and statin toxicity in vivo, and activated PKD rescues autophagic flux in lipin-1-deficient cells. Our findings identify lipin-1 PAP activity as a component of the macroautophagy pathway and define the basis for lipin-1-related myopathies.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Peixiang
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Division of Neuropathology, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: M Anthony
authors.initials: MA
authors.lastname: Verity
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: reuek@ucla.edu.
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D003402:Creatine Kinase / Q000097:blood; D005260:Female; D057895:Haploinsufficiency / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008055:Lipids / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010711:Phosphatidate Phosphatase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D058546:Class III Phosphatidylinositol 3-Kinases; C089212:protein kinase D; D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C; D003402:Creatine Kinase; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase