Rhabdomyolysis-Associated Mutations in Human LPIN1 Lead to Loss of Phosphatidic Acid Phosphohydrolase Activity

Schweitzer, George G.; Collier, Sara L.; Chen, Zhouji; Eaton, James M.; Connolly, Anne M.; Bucelli, Robert C.; Pestronk, Alan; Harris, Thurl E.; Finck, Brian N.

doi:10.1007/8904_2015_440

Cited by 31 publications

(39 citation statements)

References 29 publications

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“…The majority of pathogenic LPIN1 mutations are null alleles that produce no protein product, resulting from nonsense, frame-shift, or deletion mutations [105,106,118,119]. Consistent with this, primary myoblasts from patients exhibit dramatically decreased PAP1 activity [120].…”

Section: Lipin Gene Mutations and Diseasementioning

confidence: 99%

“…A few pathogenic missense LPIN1 alleles have been identified, and have been valuable to dissect the functional deficiency that underlies the observed muscle symptoms. For example, lipin 1 protein bearing the pathogenic missense mutation, Arg725His, retains co-activator function but lacks PAP activity, confirming that the pathology of lipin-1 rhabdomyolysis is a result of PAP deficiency [119]. Another missense mutation (Glu769Gly) was associated with severe myopathy in a heterozygous carrier when treated with statin drugs [105].…”

Section: Lipin Gene Mutations and Diseasementioning

confidence: 99%

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Lipin proteins and glycerolipid metabolism: Roles at the ER membrane and beyond

Zhang

Reue

2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

110

108

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The regulation of glycerolipid biosynthesis is critical for homeostasis of cellular lipid stores and membranes. Here we review the role of lipin phosphatidic acid phosphatase enzymes in glycerolipid synthesis. Lipin proteins are unique among glycerolipid biosynthetic enzymes in their ability to transit among cellular membranes, rather than remain membrane tethered. We focus on the mechanisms that underlie lipin protein interactions with membranes and the versatile roles of lipins in several organelles, including the endoplasmic reticulum, mitochondria, endolysosomes, lipid droplets, and nucleus. We also review the corresponding physiological roles of lipins, which have been uncovered by the study of genetic lipin deficiencies. We propose that the growing body of knowledge concerning the biochemical and cellular activities of lipin proteins will be valuable for understanding the physiological functions of lipin proteins in health and disease.

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Section: Lipin Gene Mutations and Diseasementioning

confidence: 99%

Section: Lipin Gene Mutations and Diseasementioning

confidence: 99%

Lipin proteins and glycerolipid metabolism: Roles at the ER membrane and beyond

Zhang

Reue

2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

110

108

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“…Several pathogenic LPIN1 mutations have been identified, including deletions, nonsense, missense or frame-shift changes in the protein coding sequence. In vitro assessment of a pathogenic missense mutation (R725H) suggests that the disease is related to the loss of lipin 1 PAP enzyme activity, and not related to a deficit in the coactivator function of lipin 1 [64]. The disease is typically asymptomatic until lipin 1-deficient individuals experience metabolic stress such as fever, fasting or anesthesia.…”

Section: Critical Physiological Roles For Glycerolipid Synthesis Enmentioning

confidence: 99%

How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

Wang

Airola

Reue

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Triacylglycerols (TAG) serve as the predominant form of energy storage in mammalian cells, and TAG synthesis influences conditions such as obesity, fatty liver, and insulin resistance. In most tissues, the glycerol 3-phosphate pathway enzymes are responsible for TAG synthesis, and the regulation and function of these enzymes is therefore important for metabolic homeostasis. Here we review the sites and regulation of glycerol-3-phosphate acyltransferase (GPAT), acylglycerol-3-phosphate acyltransferase (AGPAT), lipin/phosphatidic acid phosphatase (PAP), and diacylglycerol acyltransferase (DGAT) enzyme action. We highlight the critical roles that these enzymes play in human health by reviewing Mendelian disorders that result from mutation in the corresponding genes. We also summarize the valuable insights that genetically engineered mouse models have provided into the cellular and physiological roles of GPATs, AGPATs, lipins and DGATs. Finally, we comment on the status and feasibility of therapeutic approaches to metabolic disease that target enzymes of the glycerol 3-phosphate pathway.

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“…Lipin 1 also acts in the nucleus to directly interact with DNAbound transcription factors to regulate gene expression (3)(4)(5)(6). Mutations in the gene encoding lipin 1 (LPIN1) are a common cause of early onset, recurrent pediatric rhabdomyolysis (7)(8)(9)(10)(11)(12)(13)(14)(15), a condition in which damage to skeletal myocytes results in substantial buildup of myocellular proteins in the blood. Severe rhabdomyolysis can cause acute kidney failure and may lead to death.…”

mentioning

confidence: 99%

Loss of lipin 1‐mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice

et al. 2018

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Lipin 1 regulates glycerolipid homeostasis by acting as a phosphatidic acid phosphohydrolase (PAP) enzyme in the triglyceride-synthesis pathway and by regulating transcription factor activity. Mutations in human lipin 1 are a common cause of recurrent rhabdomyolysis in children. Mice with constitutive whole-body lipin 1 deficiency have been used to examine mechanisms connecting lipin 1 deficiency to myocyte injury. However, that mouse model is confounded by lipodystrophy not phenocopied in people. Herein, 2 muscle-specific mouse models were studied: 1) Lpin1 exon 3 and 4 deletion, resulting in a hypomorphic protein without PAP activity, but which preserved transcriptional coregulatory function; and 2) Lpin1 exon 7 deletion, resulting in total protein loss. In both models, skeletal muscles exhibited a chronic myopathy with ongoing muscle fiber necrosis and regeneration and accumulation of phosphatidic acid and, paradoxically, diacylglycerol. Additionally, lipin 1-deficient mice had abundant, but abnormal, mitochondria likely because of impaired autophagy. Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed. These data suggest that mice lacking lipin 1-mediated PAP activity in skeletal muscle may serve as a model for determining the mechanisms by which lipin 1 deficiency leads to myocyte injury and for testing potential therapeutic approaches.-Schweitzer, G. G., Collier, S. L., Chen, Z., McCommis, K. S., Pittman, S. K., Yoshino, J., Matkovich, S. J., Hsu, F.-F., Chrast, R., Eaton, J. M., Harris, T. E., Weihl, C. C., Finck, B. N. Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice.

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Rhabdomyolysis-Associated Mutations in Human LPIN1 Lead to Loss of Phosphatidic Acid Phosphohydrolase Activity

Abstract: Rhabdomyolysis is an acute syndrome due to extensive injury of skeletal muscle. Recurrent rhabdomyolysis is often caused by inborn errors in intermediary metabolism, and recent work has suggested

Cited by 31 publications

References 29 publications

Lipin proteins and glycerolipid metabolism: Roles at the ER membrane and beyond

Lipin proteins and glycerolipid metabolism: Roles at the ER membrane and beyond

How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

Loss of lipin 1‐mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice

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