Mouse lipin-1 and lipin-2 cooperate to maintain glycerolipid homeostasis in liver and aging cerebellum

Dwyer, Jennifer R.; Donkor, Jimmy; Zhang, Peixiang; Csáki, L; Vergnes, Laurent; Lee, Jessica M.; Dewald, Jay; Brindley, David N.; Atti, Elisa; Tetradis, Sotirios; Yoshinaga, Yuko; Jong, Pieter J. de; Fong, Loren G.; Young, Stephen G.; Reue, Karen

doi:10.1073/pnas.1205221109

Cited by 81 publications

(95 citation statements)

References 54 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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“…Speaking of glycolysis, in chronic liv-er injury, energy production will change from mitochondrial respiration to glycolysis which plays a key role in energy metabolism in the liver (Nishikawa et al, 2014). The liver is the main organ for the metabolism of glucose and lipid (Bou Khalil et al, 2010;Hammond et al, 2002) and when lesion occurs, the liver may dysfunction including abnormal glycolysis/gluconeogenesis and glycerolipid metabolism (Prentki and Madiraju, 2008;Dwyer et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of CCl<sub>4</sub>-induced liver fibrosis with combined transcriptomic and proteomic analysis

et al. 2016

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-The classic toxicity of carbon tetrachloride (CCl 4 ) is to induce liver lesion and liver fibrosis. Liver fibrosis is a consequence of chronic liver lesion, which can progress into liver cirrhosis even hepatocarcinoma. However, the toxicological mechanisms of CCl 4 -induced liver fibrosis remain not fully understood. We combined transcriptomic and proteomic analysis and biological network technology, predicted toxicological targets and regulatory networks of CCl 4 in liver fibrosis. Wistar rats were treated with CCl 4 for 9 weeks. Histopathological changes, hydroxyproline (Hyp) contents, serum ALT and AST in the CCl 4 -treated group were significantly higher than that of CCl 4 -untreated group. CCl 4 -treated and -untreated liver tissues were examined by microarray and iTRAQ. The results showed that 3535 genes (fold change ≥ 1.5, P < 0.05) and 1412 proteins (fold change ≥ 1.2, P < 0.05) were differentially expressed. Moreover, the integrative analysis of transcriptomics and proteomics data showed 523 overlapped proteins, enriched in 182 GO terms including oxidation reduction, response to oxidative stress, inflammatory response, extracellular matrix organization, etc. Furthermore, KEGG pathway analysis showed that 36 pathways including retinol metabolism, PPAR signaling pathway, glycolysis/gluconeogenesis, arachidonic acid metabolism, metabolism of xenobiotics by cytochrome P450 and drug metabolism. Network of protein-protein interaction (PPI) and key function with their related targets were performed and the degree of network was calculated with Cytoscape. The expression of key targets such as CYP4A3, ALDH2 and ALDH7A1 decreased after CCl 4 treatment. Therefore, the toxicological mechanisms of CCl 4 -induced liver fibrosis may be related with multi biological process, pathway and targets which may provide potential protection reaction mechanism for CCl 4 detoxication in the liver.

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“…Studies in cell culture as well as lipin 2 knock-out mice show that the expression of lipin 1 and 2 is inversely correlated, most likely via a post-transcriptional mechanism (6,9,33). Cells appear to adapt to the loss of lipin 1 PAP activity by increasing PAP activity through the induction of lipin 2.…”

Section: Discussionmentioning

confidence: 99%

Lipin 2 Binds Phosphatidic Acid by the Electrostatic Hydrogen Bond Switch Mechanism Independent of Phosphorylation

Eaton

Takkellapati

Lawrence

et al. 2014

Journal of Biological Chemistry

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Background: Lipin 2 is a phosphatidic acid phosphatase (PAP) responsible for DAG formation at the ER membrane during lipogenesis. Results: A combination of biochemical approaches is used to characterize lipin 2 phosphatase activity and regulation. Conclusion: The electrostatic charge of PA regulates activity, but phosphorylation does not.Significance: These findings demonstrate differential regulation of PAP activity within the lipin family.

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Mouse lipin-1 and lipin-2 cooperate to maintain glycerolipid homeostasis in liver and aging cerebellum

Cited by 81 publications

References 54 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

Mechanisms of CCl<sub>4</sub>-induced liver fibrosis with combined transcriptomic and proteomic analysis

Lipin 2 Binds Phosphatidic Acid by the Electrostatic Hydrogen Bond Switch Mechanism Independent of Phosphorylation

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