Lipin-1 and lipin-3 together determine adiposity in vivo

Csáki, L; Dwyer, Jennifer R.; Li, Xia; Nguyen, Michael H.; Dewald, Jay; Brindley, David N.; Lusis, Aldons J.; Yoshinaga, Yuko; Jong, Pieter J. de; Fong, Loren G.; Young, Stephen G.; Reue, Karen

doi:10.1016/j.molmet.2013.11.008

Cited by 50 publications

(63 citation statements)

References 37 publications

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“…7A ). Loss of lipin-1-mediated PAP activity caused a strong trend toward accumulation of 18:0-18:1 PA species, but did not affect accumulation of other PA species (51)(52)(53). We found AlbLpin1 Ϫ / Ϫ mice retain suffi cient hepatic PAP activity for robust TG synthesis under fasting and high-fat diet fed conditions.…”

Section: Discussionmentioning

confidence: 70%

Liver-specific loss of lipin-1-mediated phosphatidic acid phosphatase activity does not mitigate intrahepatic TG accumulation in mice

Schweitzer

Chen

Gan

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org states and may be linked to other abnormalities in liver metabolism and function. Indeed, in a subset of individuals, hepatic steatosis can progress to liver injury, dysfunction, and failure. Intrahepatic lipid accumulation is also usually highly correlated with systemic insulin resistance, hyperglycemia, dyslipidemias, and risk of cardiovascular disease. Hepatic steatosis is extremely prevalent in obese individuals, and with the epidemic of obesity, the occurrence of nonalcoholic fatty liver disease has risen dramatically, becoming the most common cause of liver disease in the United States ( 1, 2 ).The primary storage form of lipid is TG, which, in the liver, is predominantly synthesized via the sequential acylation and dephosphorylation of glycerol-3-phosphate. In higher organisms, three genes ( Lpin1 , Lpin2 , and Lpin3 ) encode canonical enzymes that catalyze the Mg 2+ -dependent dephosphorylation of phosphatidic acid (PA) to form diacylglycerol (DAG) at the endoplasmic reticulum ( 3, 4 ). The phosphatidic acid phosphohydrolase (PAP) reaction is not only the penultimate step in TG synthesis, but also a key metabolic branch point. Alterations in PA and DAG concentrations have been linked to regulation of important intracellular signaling cascades including protein kinase C ( 5, 6 ), protein kinase A ( 7 ), ERK MAPK kinase ( 8 ), and the molecular target of rapamycin ( 9-11 ). The regulation of PA and DAG concentrations has potentially important implications for hepatic nutrient homeostasis under conditions of fasting and overnutrition. Indeed, acute RNA interference (RNAi)-mediated depletion of lipin 1 or lipin 2 in mice fed a high-fat diet attenuated hepatic steatosis and led to improvements in hepatic insulin sensitivity ( 12, 13 ).Lipins are not integral membrane proteins, and lipin 1 can translocate into the nucleus and also interact with Abstract Lipin proteins (lipin 1, 2, and 3) regulate glycerolipid homeostasis by acting as phosphatidic acid phosphohydrolase (PAP) enzymes in the TG synthesis pathway and by regulating DNA-bound transcription factors to control gene transcription. Hepatic PAP activity could contribute to hepatic fat accumulation in response to physiological and pathophysiological stimuli. To examine the role of lipin 1 in regulating hepatic lipid metabolism, we generated mice that are defi cient in lipin-1-encoded PAP activity in a liver-specifi c manner (Alb-Lpin1 ؊ / ؊ mice). This allele of lipin 1 was still able to transcriptionally regulate the expression of its target genes encoding fatty acid oxidation enzymes, and the expression of these genes was not affected in Alb-Lpin1 ؊ / ؊ mouse liver. Hepatic PAP activity was signifi cantly reduced in mice with liver-specifi c lipin 1 defi ciency. However, hepatocytes from Alb-Lpin1 ؊ / ؊ mice had normal rates of TG synthesis, and steady-state hepatic TG levels were unaffected under fed and fasted conditions. Furthermore, Alb-Lpin1 ؊ / ؊ mice were not protected from intrahepatic accum...

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Section: Discussionmentioning

confidence: 70%

Liver-specific loss of lipin-1-mediated phosphatidic acid phosphatase activity does not mitigate intrahepatic TG accumulation in mice

Schweitzer

Chen

Gan

et al. 2015

Journal of Lipid Research

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“…27 Considering that humans null for lipin 1 do not have any noticeable lipodystrophy these results suggest that a compensatory mechanism increases adipose PAP activity, possibly through lipin 3 function.…”

Section: Lipinmentioning

confidence: 90%

“…Studies using lipin 3 whole body knockout mice do not reveal any overt phenotypic abnormalities. 27 However, PAP activity from lipin 3KO…”

Section: Lipinmentioning

confidence: 99%

Mechanistic Insight into Phosphoregulation of the Lipin Family

Eaton

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Quietly emerging as essential regulators of lipid metabolism, the lipin protein family consisting of lipin 1, 2 and 3 are phosphatidic acid phosphatases that catalyze the penultimate step in triacylglycerol (TAG) biosynthesis, the conversion of phosphatidic acid to diacylglycerol. In adipocytes, lipin 1 is downstream of the insulin/PI3K/mTOR signaling pathway, and is highly phosphorylated in response to insulin stimulation, which correlates with cytosolic location. The work herein has built upon the prior literature by examining how phosphorylation can alter lipin 1 localization. We have provided evidence that the lipins bind PA by the electrostatic hydrogen-bond switch mechanism through a PA binding domain consisting of nine basic amino acids and that this process is inhibited in a phosphorylation dependent manner, in the case of lipin 1, and independent, in the case of lipin 2. We have made the observation that lipin 1 forms high molecular weight complexes upon membrane binding, which have implications for lipin structure-function. In addition we demonstrate the rhabdomyolysis associated mutations in lipin 1 lead to defective PAP activity, providing a role for its phosphatase activity in the pathogenesis of this acute syndrome.

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“…It is possible and there is some evidence that these enzymes have non-redundant roles in lipid metabolism, and even in other cell functions (75,90,95 domains other than the C1 domains, and is at least partially an integral membrane protein displaying acyl chain specificity among DAG species (103). The class IV enzymes contain MARCKS domains (M), which may render them subject to unique regulation by phosphorylation, and also contain an NLS (104,105).…”

Section: The Lipin Polybasic Domainsmentioning

confidence: 99%

“…These, and maybe yet unknown roles for lipins, are perhaps reasons for the evolution of a long PBD. The nuances surrounding the differences in the molecular regulation of lipins may be indicative of the specialization of their activities, or perhaps speak to their tissue specific functions and necessity for either more lax or alternative regulatory mechanisms (65,75,160).…”

Section: )mentioning

confidence: 99%

Repositioning of Ritanserin for the Inhibition of DGK-Alpha and the Role of the Polybasic Domain in the Phosphoregulation of Lipins 1 and 3

Boroda

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II ABSTRACTThe diversity and multi-functionality of cellular lipids is astounding. At the hub of phospho-and neutral lipid flux are two lipids with many effector proteins: diacylglycerol (DAG) and phosphatidic acid (PA). Enzymes which can simultaneously regulate both of their levels are diacylglycerol kinases (DGKs) and lipins. The former phosphorylates DAG to yield PA and the latter dephosphorylates PA to generate DAG. The work herein approaches the study of DGKs and lipins from two different perspectives.First, we have built upon previous work, which established DGKα as a therapeutic target in glioblastoma multiforme (GBM), and have repositioned ritanserin, a serotonin receptor (5-HTR) antagonist, as a pharmacological tool for attenuating DGK activity. We have also elucidated the polypharmacology of other DGK inhibitors, and shown that they are potent 5-HTR antagonists.Second, we hypothesized that the varying PA-binding domains, or polybasic domains (PBDs), of each lipin are involved in the phosphoregulatory differences among these enzymes. We show, for the first time, that insertion of the lipin 3 PBD in the lipin 1 enzyme eliminates the phosphoregulation of lipin 1. Conversely, the insertion of lipin 1 PBD into the lipin 3 protein allows phosphorylated residues on lipin 3 to negatively regulate its activity in vitro. These data suggest that the differences in the amino acid sequence between PBDs of these two proteins are sufficient to determine whether or not the enzymes can be controlled by intramolecular phosphoregulation III ACKNOWLEDGEMENTS

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Lipin-1 and lipin-3 together determine adiposity in vivo

Cited by 50 publications

References 37 publications

Liver-specific loss of lipin-1-mediated phosphatidic acid phosphatase activity does not mitigate intrahepatic TG accumulation in mice

Liver-specific loss of lipin-1-mediated phosphatidic acid phosphatase activity does not mitigate intrahepatic TG accumulation in mice

Mechanistic Insight into Phosphoregulation of the Lipin Family

Repositioning of Ritanserin for the Inhibition of DGK-Alpha and the Role of the Polybasic Domain in the Phosphoregulation of Lipins 1 and 3

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