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Lipin-1 Regulates Autophagy Clearance and Intersects with Statin Drug Effects in Skeletal Muscle
Open accessAbstract
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.
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“In this model, myopathy/myositis could be aggravated by co-administration of statins, whereas both lipin-1 deficiency and statins were found to attenuate autolysosome maturation.”
From Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management (2015) · cites this paper as [104]
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“Only recently, mice with genetically induced deficiency of lipin-1, a phosphatidic acid phosphatase, were shown to develop myopathy/myositis that was associated with impaired autophagy and the presence of abnormal mitochondria.104”
From Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management (2015) · cites this paper as [104]
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Metadata
- Authors
- Zhang, P., Verity, M. A., & Reue, K.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Reue, Karen
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-08
- Volume
- 20
- Issue
- 2
- Pages
- 267-279
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4170588
- OpenAlex
- W2052660293
- Cited by
- 166
- References
- 60
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 20 · 2023: 10 · 2022: 10 · 2021: 18 · 2020: 17 · 2019: 15 · 2018: 16 · 2017: 8 · 2016: 11 · 2015: 19 · 2014: 4
- FWCI
- 10.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (P01 HL090553, P01 HL028481, P20RR16475)
- National Science Foundation (0920663, MCB 0455318, DBI 0521587, EPS 0236913)
- Kansas State University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- LPIN1, autophagy, statin-induced myopathy, skeletal muscle, phosphatidate phosphohydrolase, protein kinase D, mTOR, mitochondrial accumulation, muscle necrosis, rhabdomyolysis, macroautophagy, diacylglycerol
- MeSH terms
- Animals, Autophagy, Cell Line, Creatine Kinase, Female, Lipids, Mice, Inbred BALB C, Microtubule-Associated Proteins, Mitochondria, Nuclear Proteins, Phosphatidate Phosphatase, Protein Kinase C, Muscle, Skeletal, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Mice, Haploinsufficiency, Class III Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases
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