| First Author | Zhang P | Year | 2014 |
| Journal | Cell Metab | Volume | 20 |
| Issue | 2 | Pages | 267-79 |
| PubMed ID | 24930972 | Mgi Jnum | J:215501 |
| Mgi Id | MGI:5605454 | Doi | 10.1016/j.cmet.2014.05.003 |
| Citation | Zhang P, et al. (2014) Lipin-1 regulates autophagy clearance and intersects with statin drug effects in skeletal muscle. Cell Metab 20(2):267-79 |
| abstractText | 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. |
