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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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Citations
Cites
Autophagy in the Pathogenesis of Disease
Levine, B., & Kroemer, G. (2008) · Cell · doi:10.1016/j.cell.2007.12.018 · Cited by 7,069
LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.
Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., Kominami, E., Ohsumi, Y., & Yoshimori, T. (2000) · The EMBO Journal · doi:10.1093/emboj/19.21.5720 · Cited by 6,605
Methods in Mammalian Autophagy Research
Mizushima, N., Yoshimori, T., & Levine, B. (2010) · Cell · doi:10.1016/j.cell.2010.01.028 · Cited by 4,497
Cellular and Molecular Regulation of Muscle Regeneration
CHARGÉ, S. B. P., & Rudnicki, M. A. (2004) · Physiological Reviews · doi:10.1152/physrev.00019.2003 · Cited by 2,691
Kimura, S., Noda, T., & Yoshimori, T. (2007) · Autophagy · doi:10.4161/auto.4451 · Cited by 2,278
SLCO1B1 Variants and Statin-Induced Myopathy — A Genomewide Study
(2008) · New England Journal of Medicine · doi:10.1056/nejmoa0801936 · Cited by 2,043 · cited 1×
“The underlying mechanisms for statin myotoxicity are not understood, but there is evidence that underlying genetic variations may predispose some individuals (Link et al., 2008; Mangravite et al., 2013; Needham andMastaglia, 2014).”
Termination of autophagy and reformation of lysosomes regulated by mTOR
Yu, L., McPhee, C. K., Zheng, L., Mardones, G. A., Rong, Y., Peng, J., Mi, N., Zhao, Y., Liu, Z., Wan, F., et al. (2010) · Nature · doi:10.1038/nature09076 · Cited by 1,544
Thompson, P. D., Clarkson, P., & Karas, R. H. (2003) · JAMA · doi:10.1001/jama.289.13.1681 · Cited by 1,463
mTOR Complex 1 Regulates Lipin 1 Localization to Control the SREBP Pathway
Peterson, T. R., Sengupta, S., Harris, T. E., Carmack, A. E., Kang, S. A., Balderas, E., Guertin, D. A., Madden, K. L., Carpenter, A. E., Finck, B. N., et al. (2011) · Cell · doi:10.1016/j.cell.2011.06.034 · Cited by 1,293
Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis
He, C., Bassik, M. C., Moresi, V., Sun, K., Wei, Y., Zou, Z., An, Z., Loh, J., Fisher, J., Sun, Q., et al. (2012) · Nature · doi:10.1038/nature10758 · Cited by 1,136
Liang, C., Lee, J.-S., Inn, K.-S., Gack, M. U., Li, Q., Roberts, E. A., Vergne, I., Deretic, V., Feng, P., Akazawa, C., et al. (2008) · Nature Cell Biology · doi:10.1038/ncb1740 · Cited by 792
LAMP proteins are required for fusion of lysosomes with phagosomes
Huynh, K. K., Eskelinen, E., Scott, C. C., Malevanets, A., Saftig, P., & Grinstein, S. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601511 · Cited by 619
The PX domains of p47phox and p40phox bind to lipid products of PI(3)K
Kanai, F., Liu, H., Field, S. J., Akbary, H., Matsuo, T., Brown, G. E., Cantley, L. C., & Yaffe, M. B. (2001) · Nature Cell Biology · doi:10.1038/35083070 · Cited by 611
Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin
Péterfy, M., Phan, J., Xu, P., & Reue, K. (2001) · Nature Genetics · doi:10.1038/83685 · Cited by 604
Self-citationStatin-associated myopathy with normal creatine kinase levels
Phillips, P. S., Haas, R. H., Bannykh, S., Hathaway, S., Gray, N. L., Kimura, B. J., Vladutiu, G. D., England, J. D. F., & and the Scripps Mercy Clinical Research Center* (2002) · Annals of Internal Medicine · doi:10.7326/0003-4819-137-7-200210010-00009 · Cited by 565
Lipin 1 is an inducible amplifier of the hepatic PGC-1α/PPARα regulatory pathway
Finck, B. N., Gropler, M. C., Chen, Z., Leone, T. C., Croce, M. A., Harris, T. E., Lawrence, J. C., & Kelly, D. P. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.08.005 · Cited by 563
The Saccharomyces cerevisiae Lipin Homolog Is a Mg2+-dependent Phosphatidate Phosphatase Enzyme*
Han, G., Wu, W. I., & Carman, G. M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m600425200 · Cited by 559
Role of Diacylglycerol in PKD Recruitment to the TGN and Protein Transport to the Plasma Membrane
Baron, C. L., & Malhotra, V. (2002) · Science · doi:10.1126/science.1066759 · Cited by 414
Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function
Jaber, N. L., Dou, Z., Chen, J., Catanzaro, J. M., Jiang, Y.-P., Ballou, L. M., Selinger, E. S., Ouyang, X., Lin, R. Z., Zhang, J., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1112848109 · Cited by 399
Three Mammalian Lipins Act as Phosphatidate Phosphatases with Distinct Tissue Expression Patterns
Donkor, J., Sarıahmetoğlu, M., Dewald, J. W., Brindley, D. N., & Reue, K. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m610745200 · Cited by 381
Self-citationMitochondria removal by autophagy
Wang, K., & Klionsky, D. J. (2011) · Autophagy · doi:10.4161/auto.7.3.14502 · Cited by 380
Lipin, a lipodystrophy and obesity gene
Phan, J., & Reue, K. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2004.12.002 · Cited by 308
Self-citationThe muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity
Hanai, J., Cao, P., Tanksale, P., Imamura, S., Koshimizu, E., Zhao, J., Kishi, S., Yamashita, M., Phillips, P. S., Sukhatme, V. P., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32741 · Cited by 281
A statin-dependent QTL for GATM expression is associated with statin-induced myopathy
Mangravite, L. M., Engelhardt, B. E., Medina, M. W., Smith, J. D., Brown, C. D., Chasman, D. I., Mecham, B. H., Howie, B., Shim, H., Naidoo, D., et al. (2013) · Nature · doi:10.1038/nature12508 · Cited by 224
Fatty Acids Suppress Autophagic Turnover in β-Cells
Las, G., Serada, S. B., Wikström, J. D., Twig, G., & Shirihai, O. S. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.242412 · Cited by 220
Mutations in LPIN1 Cause Recurrent Acute Myoglobinuria in Childhood
Zeharia, A., Shaag, A., Houtkooper, R. H., Hindi, T., de Lonlay, P., Erez, G., Hubert, L., Saada, A., de Keyzer, Y., Eshel, G. M., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.09.002 · Cited by 219
Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin
Huffman, T. A., Mothe‐Satney, I., & Lawrence, J. C. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.022634399 · Cited by 217
Harris, T. E., Huffman, T. A., Chi, A., Shabanowitz, J., Hunt, D. F., Kumar, A. T., & Lawrence, J. C. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m609537200 · Cited by 216
PPAR control: it's SIRTainly as easy as PGC
Sugden, M. C., Caton, P., & Holness, M. J. (2009) · Journal of Endocrinology · doi:10.1677/joe-09-0359 · Cited by 196
A Diacylglycerol-Dependent Signaling Pathway Contributes to Regulation of Antibacterial Autophagy
Shahnazari, S., Yen, W.-L., Birmingham, C. L., Shiu, J., Namolovan, A., Zheng, Y. T., Nakayama, K., Klionsky, D. J., & Brumell, J. H. (2010) · Cell Host & Microbe · doi:10.1016/j.chom.2010.07.002 · Cited by 165
Tan, S. H., Shui, G., Zhou, J., Li, J. J., Bay, B., Wenk, M. R., & Shen, H. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.294157 · Cited by 165
Phosphatidate phosphatase, a key regulator of lipid homeostasis
Pascual, F. L., & Carman, G. M. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2012.08.006 · Cited by 161
MCL‐1 is a stress sensor that regulates autophagy in a developmentally regulated manner
Germain, M., Nguyen, A. P., Le Grand, J. N., Arbour, N., Vanderluit, J. L., Park, D. S., Opferman, J. T., & Slack, R. S. (2011) · The EMBO Journal · doi:10.1038/emboj.2010.327 · Cited by 159
Mice lacking microRNA 133a develop dynamin 2–dependent centronuclear myopathy
Liu, N., Bezprozvannaya, S., Shelton, J. M., Frisard, M. I., Hulver, M. W., McMillan, R. P., Wu, Y., Voelker, K. A., Grange, R. W., Richardson, J. A., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci46267 · Cited by 156
Lipins, lipinopathies, and the modulation of cellular lipid storage and signaling
Csaki, L. S., Dwyer, J. R., Fong, L. G., Tontonoz, P., Young, S. G., & Reue, K. (2013) · Progress in Lipid Research · doi:10.1016/j.plipres.2013.04.001 · Cited by 146
Self-citationPKD is a kinase of Vps34 that mediates ROS-induced autophagy downstream of DAPk
Eisenberg‐Lerner, A., & Kimchi, A. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.149 · Cited by 137
LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood
Michot, C., Hubert, L., Brivet, M., Meırleır, L. D., Valayannopoulos, V., Müller‐Felber, W., Ramesh, V., de Baulny, H. O., Desguerre, I., Altuzarra, C., et al. (2010) · Human Mutation · doi:10.1002/humu.21282 · Cited by 132
Tyrosine Phosphorylation of Protein Kinase D in the Pleckstrin Homology Domain Leads to Activation
Störz, P., Döppler, H. R., Johannes, F., & Toker, A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213224200 · Cited by 119
Vergnes, L., Chin, R. G., Young, S. G., & Reue, K. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.184754 · Cited by 111
Self-citationDiacylglycerol Is Required for the Formation of COPI Vesicles in the Golgi-to-ER Transport Pathway
Fernández‐Ulibarri, I., Vilella, M., Lázaro‐Diéguez, F., Sarri, E., Martínez, S. E., Jiménez, N., Claro, E., Mérida, I., Burger, K. N. J., & Egea, G. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-04-0334 · Cited by 109
Statin myotoxicity: a review of genetic susceptibility factors
Needham, M., & Mastaglia, F. L. (2014) · Neuromuscular Disorders · doi:10.1016/j.nmd.2013.09.011 · Cited by 108
Kim, H. B., Kumar, A. T., Wang, L., Liu, G., Keller, S. R., Lawrence, J. C., Finck, B. N., & Harris, T. E. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01671-09 · Cited by 108
Lipin Is a Central Regulator of Adipose Tissue Development and Function in Drosophila melanogaster
Ugrankar, R., Liu, Y., Provaznik, J., Schmitt, S., & Lehmann, M. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.01335-10 · Cited by 107
Eaton, J. M., Mullins, G. R., Brindley, D. N., & Harris, T. E. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.441493 · Cited by 97
Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise‐induced myalgia
Michot, C., Hubert, L., Romero, N. B., Gouda, A. S., Mamoune, A., Mathew, S. A., Kirk, E. P., Viollet, L., Rahman, S., Bekri, S., et al. (2012) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-012-9461-6 · Cited by 93
Early Stages of Golgi Vesicle and Tubule Formation Require Diacylglycerol
Asp, L., Kartberg, F., Fernández-Rodrı́guez, J., Smedh, M., Elsner, M., Laporte, F., Bárcena, M., Jansen, K. A., Valentijn, J. A., Koster, A. J., et al. (2008) · Molecular Biology of the Cell · doi:10.1091/mbc.e08-03-0256 · Cited by 83
Zhang, P., Takeuchi, K., Csaki, L. S., & Reue, K. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.296681 · Cited by 74
Self-citationThe spectrum of statin myopathy
Mohassel, P., & Mammen, A. L. (2013) · Current Opinion in Rheumatology · doi:10.1097/01.bor.0000434673.85515.89 · Cited by 69
Michot, C., Mamoune, A., Vamecq, J., Bui, M. T., Hsieh, L., Testet, E., Lainé, J., Hubert, L., Dessein, A., Fontaine, M., et al. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.07.021 · Cited by 66
Ching, J. K., Elizabeth, S., Ju, J.-S., Lusk, C., Pittman, S. K., & Weihl, C. C. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds524 · Cited by 65
Fatal Rhabdomyolysis in 2 Children with LPIN1 Mutations
Bergounioux, J., Brassier, A., Rambaud, C., Bustarret, O., Michot, C., Hubert, L., Arnoux, J. B., Laquerrière, A., Bekri, S., Galene-Gromez, S., et al. (2012) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2012.02.033 · Cited by 59
Alcoholic Rhabdomyolysis: An Experimental Model in the Rat
Haller, R. G., & Drachman, D. B. (1980) · Science · doi:10.1126/science.7189294 · Cited by 48
Yeast Pah1p Phosphatidate Phosphatase Is Regulated by Proteasome-mediated Degradation
Pascual, F. L., Hsieh, L., Soto-Cardalda, A., & Carman, G. M. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.550103 · Cited by 48
Cho, K.-J., Hill, M. M. C., Chigurupati, S., Du, G., Parton, R. G., & Hancock, J. F. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.00989-10 · Cited by 44
Infantile Pompe's disease, lipid storage, and partial carnitine deficiency
Verity, M. A. (1991) · Muscle & Nerve · doi:10.1002/mus.880140509 · Cited by 32
Self-citationJensen, T. E., Maarbjerg, S., Rose, A. J., Leitges, M., & Richter, E. A. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90610.2008 · Cited by 29
Protein kinase D controls voluntary-running-induced skeletal muscle remodelling
Ellwanger, K., Kienzle, C., Lutz, S., Jin, Z., Wiekowski, M., Pfizenmaier, K., & Haußer, A. (2011) · Biochemical Journal · doi:10.1042/bj20101980 · Cited by 18
Cai, K., & Sewer, M. B. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m035634 · Cited by 17
Shibasaki, M., Kurokawa, K., Katsura, M., & Ohkuma, S. (2009) · Synapse · doi:10.1002/syn.20612 · Cited by 7
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The interplay between cell signalling and the mevalonate pathway in cancer
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Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart
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Schirris, T. J. J., Renkema, G. H., Ritschel, T., Voermans, N. C., Bilos, A., van Engelen, B. G. M., Brandt, U., Koopman, W. J. H., Beyrath, J., Rodenburg, R. J., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.08.002 · Cited by 235
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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