InteractiveFly: GeneBrief

Lipin: Biological Overview | References

Gene name - Lipin

Synonyms -

Cytological map position -

Function - enzyme, transcriptional co-activator

Keywords - phosphatidate phosphatase activity, transcriptional co-activator, target of insulin signaling - downstream effector mediating effects of insulin and TORC1 signaling on lipid metabolism - fat body development and function - affects cellular growth

Symbol - Lpin

FlyBase ID: FBgn0263593

Genetic map position - chr2R:4,024,530-4,033,510

Classification - Phosphatidate phosphatase, N-terminal lipin domain

Cellular location - cytoplasmic and nuclear

NCBI links: Precomputed BLAST | EntrezGene
Recent literature
Grillet, M., Dominguez Gonzalez, B., Sicart, A., Pottler, M., Cascalho, A., Billion, K., Hernandez Diaz, S., Swerts, J., Naismith, T. V., Gounko, N. V., Verstreken, P., Hanson, P. I. and Goodchild, R. E. (2016). Torsins are essential regulators of cellular lipid metabolism. Dev Cell. PubMed ID: 27453503
Torsins are developmentally essential AAA+ proteins, and mutation of human torsinA causes the neurological disease DYT1 dystonia. They localize in the ER membranes, but their cellular function remains unclear. This study shows that dTorsin is required in Drosophila adipose tissue, where it suppresses triglyceride levels, promotes cell growth, and elevates membrane lipid content. Human torsinA at the inner nuclear membrane is associated with membrane expansion and elevated cellular lipid content. Furthermore, the key lipid metabolizing enzyme, lipin, is mislocalized in dTorsin-KO cells, and dTorsin increases levels of the lipin substrate, phosphatidate, and reduces the product, diacylglycerol. Finally, genetic suppression of dLipin rescues dTorsin-KO defects, including adipose cell size, animal growth, and survival. These findings identify that torsins are essential regulators of cellular lipid metabolism and implicate disturbed lipid biology in childhood-onset DYT1 dystonia.

Lipin proteins have key functions in lipid metabolism, acting as both phosphatidate phosphatases (PAPs) and nuclear regulators of gene expression. This study shows that the insulin and TORC1 pathways independently control functions of Drosophila dLipin. Reduced signaling through the insulin receptor strongly enhances defects caused by dLipin deficiency in fat body development, whereas reduced signaling through TORC1 leads to translocation of dLipin into the nucleus. Reduced expression of dLipin results in decreased signaling through the insulin receptor-controlled PI3K/Akt pathway and increased hemolymph sugar levels. Consistent with this, downregulation of dLipin in fat body cell clones causes a strong growth defect. The PAP, but not the nuclear activity of dLipin is required for normal insulin pathway activity. Reduction of other enzymes of the glycerol-3 phosphate pathway similarly affects insulin pathway activity, suggesting an effect mediated by one or more metabolites associated with the pathway. Together, these data show that dLipin is subject to intricate control by the insulin and TORC1 pathways and that the cellular status of dLipin impacts how fat body cells respond to signals relayed through the PI3K/Akt pathway (Schmitt, 2015).

Normal growth and the maintenance of a healthy body weight require a balance between food intake, energy expenditure and organismal energy stores. Two signaling pathways, the insulin pathway and the target of rapamycin (TOR) complex 1 (TORC1) pathway, play a critical role in this balancing process. Insulin or, in Drosophila, insulin-like peptides called Dilps are released into the circulatory system upon food consumption and stimulate cellular glucose uptake while promoting storage of surplus energy in the form of triacylglycerol (TAG or neutral fat). Nutrients, in particular amino acids, activate the TORC1 pathway, which stimulates protein synthesis leading to cellular and organismal growth. The two pathways are interconnected to allow crosstalk, but the extent and biological significance of crosstalk seems to be highly dependent on the physiological context and may be different in different animal groups. For instance, tuberous sclerosis protein TSC 2, which together with TSC1 inhibits TORC1 signaling, can be phosphorylated by Akt, the central kinase of the insulin pathway, in both mammals and Drosophila melanogaster. However, phosphorylation of TSC2 by Akt is not required for normal growth and development in Drosophila, whereas in mammalian cells Akt phosphorylation of TSC2 is required for normal TORC1 activity and the resulting activation of ribosomal protein kinase S6K1 (Schmitt, 2015).

Studies in mice have identified one of the three mammalian lipin paralogs, lipin 1, as a major downstream effector mediating effects of insulin and TORC1 signaling on lipid metabolism (Csaki, 2010; Harris, 2011; Peterson, 2011). In both Drosophila and mice, proteins of the lipin family function as key regulators of TAG storage and fat tissue development (Reue, 2009; Ugrankar, 2011). Lipins execute their biological functions through two different biochemical activities, a phosphatidate phosphatase (PAP) activity that converts phosphatidic acid (PA) into diacylglycerol (DAG), and a transcriptional co-regulator activity, mediated by an LxxIL motif located in close proximity to the catalytic motif of the protein (Finck, 2006). The PAP activity of lipin constitutes an essential step in the glycerol-3 phosphate pathway that leads to the production to TAG, which is stored in specialized cells in the form of fat droplets (adipose tissue in mammals and fat body in insects). In addition, the product of the PAP activity of lipin, DAG, is a precursor for the synthesis of membrane phospholipids. As a transcriptional co-regulator, mammalian lipin 1 directly regulates the gene encoding nuclear receptor PPARγ, which regulates mitochondrial fatty acid β-oxidation (Finck, 2006), and the yeast lipin homolog has been shown to regulate genes required for membrane phospholipid synthesis (Schmitt, 2015).

In cultured adipocytes, insulin stimulates phosphorylation of lipin 1 in a rapamycin- sensitive manner, suggesting that phosphorylation is mediated mTORC1. Phosphorylation by mTOR blocks nuclear entry of lipin 1 and, thus, access to target genes. Interestingly, non- phosphorylated lipin 1 that has migrated into the nucleus affects nuclear protein levels, but not mRNA levels, of the transcription factor SREBP1, which is a key regulator of genes involved in fatty acid and cholesterol synthesis. This effect requires the catalytic activity of lipin 1, suggesting that not all nuclear effects of the protein may result from a direct regulation of gene transcription (Peterson, 2011). The lowering of nuclear SREBP protein abundance by lipin 1 counteracts the effects of Akt on lipid metabolism, which activates lipogenesis in a TORC1- dependent manner by activation of SREBP (Schmitt, 2015).

Lipins are not only subject to control by insulin and TORC1 signaling, they also have an effect on the insulin sensitivity of tissues. Lipin 1-deficient mice exhibit insulin resistance and elevated insulin levels, whereas over-expression in adipose tissue increases insulin sensitivity. Similarly, in humans, lipin 1 levels in adipose tissue are inversely correlated with glucose and insulin levels as well as insulin resistance. While these data indicate that adipose tissue expression of lipin 1 is an important determinant of insulin sensitivity, the underlying mechanism remains poorly understood. This study presents evidence that the only Drosophila lipin homolog, dLipin, cell- autonomously controls the sensitivity of the larval fat body to stimulation of the insulin/PI3K/Akt pathway. dLipin mutant larvae have increased hemolymph sugar levels, and larval fat body cells that are deficient of dLipin exhibit a severe growth defect. Loss-of-function and rescue experiments show that dLipin's PAP activity and an intact glycerol-3 phosphate pathway are required for normal insulin pathway activity in fat body cells. Similar to the control of lipin 1 in mammalian cells, the insulin/PI3K pathway controls functions of dLipin in fat tissue development and fat storage, and the TORC1 pathway controls nuclear translocation of dLipin. However, in an apparent contrast to regulation of lipin 1 in mammals, the current data suggest that the two pathways exert at least part of their effects on dLipin independent of one another (Schmitt, 2015).

The data indicated that normal growth of fat body cells depends on sufficient levels of dLipin. Interestingly, cytoplasmic growth seems to be more affected by lack of dLipin than endoreplicative growth, as indicated by an increased nucleocytoplasmic ratio. How does dLipin affect growth? Fat body cells of dLipin mutants and cells in which dLipin is downregulated by RNAi exhibit a striking lack of the second messenger PIP3 in the cell membrane, associated with reduced cellular levels of active Akt. These data indicate that dLipin has an influence on signaling through the canonical InR/PI3K/Akt pathway. PIP2 levels in the cell membrane were unchanged in dLipin-deficient fat body, indicating that lack of PIP3 was not caused by scarcity of the substrate of PI3K. Since RNAi knockdown of dLipin was sufficient to prevent an increase in cell growth induced by overexpression of a constitutively active form of the catalytic subunit of PI3K, Dp110, it seems that disruption of the InR/PI3K/Akt pathway occurs either at the level of PI3K or the PI3K antagonist PTEN (Schmitt, 2015).

The hemolymph of dLipin mutant larvae contains increased levels of sugars, a condition which may result from insulin resistance and/or decreased Dilp levels. The data strongly suggest that insulin resistance at least contributes to increased sugar levels for two reasons. First, reduction of dLipin specifically in the fat body reduces insulin responses in this tissue, but not in other tissues. This suggests that insulin (Dilp) levels are unaffected. Second, mosaic data show that lack of dLipin affects cell growth, which is controlled by the InR/PI3K/Akt pathway, in a cell-autonomous manner. Thus, individual cells that lack dLipin show impaired growth in an otherwise normal physiological background, further supporting the notion that lack of dLipin affects insulin (Dilp) sensitivity, but not insulin signaling itself. Consistent with the current observations in Drosophila, insulin resistance is one of the phenotypes exhibited by fld mice that lack lipin 1 (Reue, 2000). Similar to mice, expression of lipin 1 in humans is positively correlated with insulin sensitivity of liver and adipose tissue. However, mechanisms that mediate effects of lipins on insulin sensitivity are not well understood. The current data show that dLipin's PAP activity is required for normal insulin sensitivity and that reduction of GPAT4 or AGPAT3, two other enzymes of the glycerol-3 phosphate pathway, has similar effects on membrane-associated PIP3 as reduction of dLipin. This suggests that the effect of dLipin on insulin sensitivity is mediated by intracellular changes in metabolites, e.g., TAGs or fatty acids, that are brought about by changed flux through the glycerol-3 phosphate pathway (Schmitt, 2015).

The data show that reduced activity of InR in dLipin-deficient fat body leads to a phenotype that strongly resembles the severe fat body phenotype of dLipin loss-of- function mutants. This observation strongly suggests that reduced signaling through InR further reduces the activity of dLipin. Since reduced activity of InR has no substantial impact on dLipin protein levels, a likely explanation for this effect is that the InR pathway controls the activity of dLipin through post-translational modification. This interpretation is supported by data showing that phosphorylation of dLipin in Drosophila S2 cells responds to insulin stimulation (Bridon, 2012), and it is consistent with a substantial body of evidence showing that mammalian lipin 1 is regulated by phosphorylation in response to insulin signaling. This suggests that functions of the insulin signaling pathway in the regulation of lipins are evolutionarily conserved (Schmitt, 2015).

In contrast to reduced signaling through the InR/PI3K pathway, reduced signaling through TORC1 led to translocation of dLipin into the nucleus. A similar translocation into the cell nucleus has been observed for lipin 1 after loss of TORC1 in mammalian cells (Peterson, 2011). Consistent with the role of TORC1 as a nutrient sensor, nuclear enrichment of dLipin is observed during starvation, and previous work has shown that the presence of dLipin is critical for survival during starvation (Ugrankar, 2011). Together, these data suggest that both dLipin and lipin 1 have essential nuclear, gene-regulatory functions during starvation. What may be the genes controlled by nuclear lipins, and how do they control gene expression? In the mouse, it has been shown that lipin 1 can directly activate the gene encoding nuclear receptor PPARγ and that overexpression of lipin 1 leads to the activation of genes involved in fatty acid transport and β-oxidation, TCA cycle, and oxidative phosphorylation, including many target genes of PPARγ. At the same time, expression of genes involved in fatty acid and TAG synthesis is diminished (Finck, 2006). This suggests that lipins may directly regulate genes to promote the utilization of fat stores during starvation, although gene expression studies are necessary at physiological protein levels that distinguish between the effects of nuclear and cytoplasmic lipin to confirm this hypothesis. Chromatin immunoprecipitation experiments with both yeast and mammalian cells have shown that lipins associate with regulatory regions of target genes, suggesting that nuclear lipins act as transcriptional co-regulators (Finck, 2006; Santos-Rosa, 2005). Interestingly, however, lipin 1 that has translocated into the nucleus can also influence gene expression through an unknown PAP-dependent mechanism that controls nuclear levels of the transcription factor SREBP, which positively controls genes required for sterol and fatty acid synthesis (Peterson, 2011). This suggests that nuclear lipins may use alternate mechanisms to bring about changes in gene expression. It will be interesting to further investigate these mechanisms taking advantage of the large size and the polytene chromosomes of fat body cells in Drosophila (Schmitt, 2015).

Interestingly, robust nuclear translocation of dLipin was observed after reducing TORC1 activity, but no nuclear translocation of dLipin was seen when signaling through the insulin pathway was reduced, neither after moderate (InR DN) or severe reduction (p60). This suggests that the InR/PI3K pathway can control functions of dLipin independent of TORC1 in Drosophila. Two observations further support this proposition. First, reduction of dLipin affects cytoplasmic and endoreplicative growth differently when enhancing growth defects associated with diminished TORC1 activity, leading to an increase in the nucleocytoplasmic ratio. No such increase was observed after reduction of TORC1 alone, suggesting that enhancement of the growth defect is an additive effect that is caused by reduced PI3K/Akt signaling and not by further reduction of TORC1 activity. Second, whereas reduction of TORC1 in the fat body leads to a systemic growth defect, lack of dLipin in the fat body does not affect organismal growth (Ugrankar, 2011) and reduction of dLipin does not affect growth of animals that lack TOR (Schmitt, 2015).

Whereas the data do not indicate that InR/PI3K signaling has an effect on the intracellular distribution of dLipin, insulin stimulates cytoplasmic retention of lipin 1 in mammalian cells in a rapamycin-sensitive manner. This suggests that the effect is mediated by TORC1, which can also regulate lipin 1 in certain cells in a rapamycin-insensitive manner (Peterson, 2011). However, it is noteworthy that lipin 1 contains at least 19 serine and threonine phosphorylation sites, and that some of these sites appear to be recognized by other kinases than TOR. In view of these findings, and considering that not all phosphorylations of lipin 1 stimulated by insulin are sensitive to rapamycin, it cannot be excluded that one or more other insulin-sensitive kinases contribute to the regulation of lipin 1 and other lipins. While data on the insulin and TORC1 regulation of lipin 1 were obtained with cultured cell lines, the current whole-animal data suggest that indeed an additional pathway may exist through which insulin regulates functions of lipins independent of TORC1. It is important to note that genetic studies in Drosophila have provided a number of examples indicating that the insulin and TORC1 pathways act independently of one another when studied in the context of specific tissues during normal development. For instance, activity of the ribosomal protein kinase S6K, which is a major target of TORC1 in both flies and mammals, is unaffected by mutations of insulin pathway components in Drosophila. Furthermore, insulin and TORC1 independently control different aspects of hormone production by the Drosophila ring gland. It will be interesting to see whether whole-animal studies in mammalian systems will reveal a similar, at least partial, independence of insulin and TORC1 signaling in the control of lipins. Specifically, future work will have to address in detail the functional importance of the many phosphorylation sites found in both mammalian and fly lipins, and identify all kinases involved, to determine the extent to which regulation is conserved between fly and mammalian lipins (Schmitt, 2015).

Lipin is a central regulator of adipose tissue development and function in Drosophila melanogaster

Lipins are evolutionarily conserved proteins found from yeasts to humans. Mammalian and yeast lipin proteins have been shown to control gene expression and to enzymatically convert phosphatidate to diacylglycerol, an essential precursor in triacylglcerol (TAG) and phospholipid synthesis. Loss of lipin 1 in the mouse, but not in humans, leads to lipodystrophy and fatty liver disease. This study shows that the single lipin orthologue of Drosophila melanogaster (dLipin) is essential for normal adipose tissue (fat body) development and TAG storage. dLipin mutants are characterized by reductions in larval fat body mass, whole-animal TAG content, and lipid droplet size. Individual cells of the underdeveloped fat body are characterized by increased size and ultrastructural defects affecting cell nuclei, mitochondria, and autophagosomes. Under starvation conditions, dLipin is transcriptionally upregulated and functions to promote survival. Together, these data show that dLipin is a central player in lipid and energy metabolism, and they establish Drosophila as a genetic model for further studies of conserved functions of the lipin family of metabolic regulators (Ugrankar, 2011).

This study shows that the phenotype of Drosophila lipin mutants closely resembles the lipodystrophy phenotype observed in fld mice that carry a mutation in the lipin 1 gene. These mice are characterized by an early defect in adipocyte differentiation and a defect in TAG production later in development (Ugrankar, 2011).

Similarly, fat tissue cells in dLipin mutants do not develop normally and display an array of defects. Adipocytes in fld mice remain immature and accumulate smaller fat droplets than those in normal mice. A similar reduction in the size of fat droplets is observed for dLipin mutants. While the mechanisms that control droplet size are not well understood, the availability of phosphatidylcholine, the major component of the phospholipid monolayer surrounding the TAG core of fat droplets, seems to be a critical factor. Interestingly, studies of yeast indicate that lipins can negatively regulate the synthesis of phosphatidylcholine and other phospholipids by repressing key genes of the biosynthetic pathway. This suggests that the decreased size of lipid droplets in lipin mutants may be driven by an increased ratio of phospholipids to neutral lipids (Ugrankar, 2011).

In contrast to adipose tissue cells of fld mice, fat body cells in dLipin mutants dramatically exceed normal fat body cells in size. Unlike mammalian adipocytes, fat body cells are polytene cells that increase their DNA copy number through endoreplication. The increase in nuclear size that accompanies the increase in cell size indicates that the mutant cells have undergone additional endoreplication cycles and are not the product of cell fusions. The increased growth of the mutant cells may be a secondary effect of dLipin deficiency caused by a mechanism that strives to compensate for the reduced capacity of the fat body tissue to produce and store lipids. In contrast to the situation in C. elegans, where a lack of lipin leads to smaller adult worms (Golden, 2009), reduced fat body mass in dLipin mutants was not associated with a systemic cellular or organismal growth defect. Mutant salivary gland cells and larvae grew to normal size. Since larvae with reduced fat body mass grow more slowly than wild-type larvae, growth to normal size takes more time, explaining the developmental delay that was observed with the dLipin mutants (Ugrankar, 2011).

Transmission electron microscopy data indicate that a lack of dLipin leads not only to increases in the sizes of fat body cells and nuclei but also to ultrastructural changes within the cells. Cell nuclei, autophagosomes, and mitochondria showed changed morphology. Most autophagosomes of the mutant cells contained fewer cytoplasmic components than normal autophagosomes. LysoTracker staining of fat bodies from mutant early-third-instar larvae did not indicate that a premature onset of developmental autophagy, resulting in a depletion of cell organelles, might account for this observation. In mutant wandering larvae, LysoTracker staining indicated high autophagic activity, as it does in wild-type larvae at this stage. While these observations suggest that developmental autophagy is normally initiated in the fat body in dLipin mutants, the TEM data indicate that the mechanism of autophagy might be affected in these animals. A defective mechanism may contribute to the observed increase in cell size (Ugrankar, 2011).

Among the nuclear defects observed were projections and involutions, and occasionally breaks, of the nuclear envelope. These observations are consistent with results obtained by light microscopy of DAPI-stained nuclei that revealed occasional nuclear fragmentation. While nuclear fragmentation is a cytological hallmark of apoptosis, caspase assays and suppression of apoptosis by the cell death inhibitor p35 did not support the conclusion that the cells had entered the apoptotic pathway. Irregular nuclear morphology has also been observed in lipin-deficient yeast and C. elegans cells. In C. elegans, lipin is required for nuclear envelope breakdown during mitosis, and a lack of lipin in yeasts leads to overgrowth of the nuclear envelope. While the mechanistic basis for the defects seen in C. elegans is not known, the evidence obtained with the yeast Saccharomyces cerevisiae supports a direct role of lipin in the transcriptional control of phospholipid biosynthesis. Increased nuclear growth in this species may be the result of an oversupply of phosphatidylcholine and phosphatidylethanolamine after attenuation of the repressive effect of lipin on genes of the biosynthetic pathway. Whether dLipin has a similar effect on phospholipid synthesis in Drosophila remains to be determined. However, the increase in the size and DNA content of mutant fat body cells suggests that overall cell growth, and not a simple increase in phospholipids, is the primary reason for the expansion of the nuclear envelope in this species. Finally, the mitochondria show aberrant morphology, suggesting that these organelles do not function normally in the absence of dLipin. In the vertebrate liver, lipin 1 activates genes required for the β-oxidation of fatty acids and for ATP synthesis by oxidative phosphorylation. Both of these processes take place in the mitochondrial compartment. Mitochondria in the fat bodies of dLipin mutants are characterized by underdeveloped cristae, suggesting that components of the electron transport chain are in limited supply. This observation is consistent with the notion that dLipin in Drosophila has a role in mitochondrial function similar to that of lipin 1 in vertebrate liver. The lysis of mitochondria that was observed in dLipin mutant cells may be a secondary effect of these functional impairments. Mitochondrial dysfunction implies that a lack of dLipin not only affects fat storage but also has a broader impact on energy metabolism that may explain the high lethality observed with the dLipin mutants (Ugrankar, 2011).

dLipin transcript levels are upregulated under starvation conditions and that reduced activity of the gene in the fat body enhances susceptibility to starvation. This does not apply only to reduced activity prior to starvation, as one would expect based on the role of the gene in fat storage. Downregulation of dLipin concomitant with food withdrawal equally leads to diminished starvation resistance. This effect is more pronounced in males than in females, consistent with the stronger starvation-induced upregulation of dLipin transcript levels in males. Why does a gene that is essential for fat synthesis and storage enhance starvation resistance after the cessation of food intake? One possible explanation is more-efficient energy use through improved salvage of fatty acids released during lipolysis (by recycling to TAG). A similar role has been proposed for lipin 1 during starvation in mammalian adipose tissue. In mammalian liver, starvation leads to lipin 1 upregulation. There, lipin activates genes of the fatty acid β-oxidation pathway, bolstering the capacity of the liver to process the increasing supply of free fatty acids derived from adipose tissue. It remains to be seen whether dLipin has a similar role in fly tissues (Ugrankar, 2011).

Drosophila melanogaster lipins are tissue-regulated and developmentally regulated and present specific subcellular distributions

Lipins constitute a novel family of Mg(2+)-dependent phosphatidate phosphatases that catalyze the dephosphorylation of phosphatidic acid to yield diacylglycerol, an important intermediate in lipid metabolism and cell signaling. Whereas a single lipin is detected in less complex organisms, in mammals there are distinct lipin isoforms and paralogs that are differentially expressed among tissues. Compatible with organism tissue complexity, this study shows that the single Drosophila Lpin1 ortholog (CG8709, DmLpin) expresses at least three isoforms (DmLpinA, DmLpinK and DmLpinJ) in a temporal and spatially regulated manner. The highest levels of lipin in the fat body, where DmLpinA and DmLpinK are expressed, correlate with the highest levels of triacylglycerol (TAG) measured in this tissue. DmLpinK is the most abundant isoform in the central nervous system, where TAG levels are significantly lower than in the fat body. In the testis, where TAG levels are even lower, DmLpinJ is the predominant isoform. Together, these data suggest that DmLpinA might be the isoform that is mainly involved in TAG production, and that DmLpinK and DmLpinJ could perform other cellular functions. In addition, it was demonstrated by immunofluorescence that lipins are most strongly labeled in the perinuclear region of the fat body and ventral ganglion cells. In visceral muscles of the larval midgut and adult testis, lipins present a sarcomeric distribution. In the ovary chamber, the lipin signal is concentrated in the internal rim of the ring canal. These specific subcellular localizations of the Drosophila lipins provide the basis for future investigations on putative novel cellular functions of this protein family (Valente, 2010).


Search PubMed for articles about Drosophila Lipin

Bridon, G., Bonneil, E., Muratore-Schroeder, T., Caron-Lizotte, O. and Thibault, P. (2012). Improvement of phosphoproteome analyses using FAIMS and decision tree fragmentation. application to the insulin signaling pathway in Drosophila melanogaster S2 cells. J Proteome Res 11: 927-940. PubMed ID: 22059388

Csaki, L. S. and Reue, K. (2010). Lipins: multifunctional lipid metabolism proteins. Annu Rev Nutr 30: 257-272. PubMed ID: 20645851

Finck, B. N., Gropler, M. C., Chen, Z., Leone, T. C., Croce, M. A., Harris, T. E., Lawrence, J. C., Jr. and Kelly, D. P. (2006). Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell Metab 4: 199-210. PubMed ID: 16950137

Golden, A., Liu, J. and Cohen-Fix, O. (2009). Inactivation of the C. elegans lipin homolog leads to ER disorganization and to defects in the breakdown and reassembly of the nuclear envelope. J Cell Sci 122: 1970-1978. PubMed ID: 19494126

Harris, T. E. and Finck, B. N. (2011). Dual function lipin proteins and glycerolipid metabolism. Trends Endocrinol Metab 22: 226-233. PubMed ID: 21470873

Peterson, T. R., Sengupta, S. S., Harris, T. E., Carmack, A. E., Kang, S. A., Balderas, E., Guertin, D. A., Madden, K. L., Carpenter, A. E., Finck, B. N. and Sabatini, D. M. (2011). mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146: 408-420. PubMed ID: 21816276

Reue, K., Xu, P., Wang, X. P. and Slavin, B. G. (2000). Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene. J Lipid Res 41: 1067-1076. PubMed ID: 19369868

Santos-Rosa, H., Leung, J., Grimsey, N., Peak-Chew, S. and Siniossoglou, S. (2005). The yeast lipin Smp2 couples phospholipid biosynthesis to nuclear membrane growth. EMBO J 24: 1931-1941. PubMed ID: 15889145

Schmitt, S., Ugrankar, R., Greene, S.E., Prajapati, M. and Lehmann, M. (2015). Drosophila lipin interacts with insulin and TOR signaling pathways in the control of growth and lipid metabolism. J Cell Sci [Epub ahead of print]. PubMed ID: 26490996

Ugrankar, R., Liu, Y., Provaznik, J., Schmitt, S. and Lehmann, M. (2011). Lipin is a central regulator of adipose tissue development and function in Drosophila melanogaster. Mol Cell Biol 31: 1646-1656. PubMed ID: 21300783

Valente, V., Maia, R. M., Vianna, M. C. and Paco-Larson, M. L. (2010). Drosophila melanogaster lipins are tissue-regulated and developmentally regulated and present specific subcellular distributions. FEBS J 277: 4775-4788. PubMed ID: 20977671

Biological Overview

date revised: 9 November, 2015

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