Inhibited Insulin Signaling in Mouse Hepatocytes Is Associated with Increased Phosphatidic Acid but Not Diacylglycerol

Zhang, Chongben; Hwarng, Gwen; Cooper, Daniel E.; Grevengoed, Trisha J.; Eaton, James M.; Natarajan, Viswanathan; Harris, Thurl E.; Coleman, Rosalind A.

doi:10.1074/jbc.m114.602789

Cited by 24 publications

(17 citation statements)

References 52 publications

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“…In contrast to the lack of differences in PA levels observed in our deficiency model, the overexpression of Pld1 in a whole cell system increases the total PA level39. Elevated PA levels in Pld1 -overexpressing hepatocytes inhibit Akt by disrupting mTORC239, which localizes to the plasma membrane40. Based on the different localization patterns of mTORC2 and PLD1, the lysosomal deficiency of PA probably does not regulate insulin-stimulated Akt via mTORC2.…”

Section: Discussioncontrasting

confidence: 57%

“…Indeed, other PA-generating enzymes, such as GPAT/AGPAT and DGK, are localized on the endoplasmic reticulum and mitochondrial membranes37 and are unlikely to regulate the lysosomal PA level. In contrast to the lack of differences in PA levels observed in our deficiency model, the overexpression of Pld1 in a whole cell system increases the total PA level39. Elevated PA levels in Pld1 -overexpressing hepatocytes inhibit Akt by disrupting mTORC239, which localizes to the plasma membrane40.…”

Section: Discussionmentioning

confidence: 58%

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Phospholipase D1 deficiency in mice causes nonalcoholic fatty liver disease via an autophagy defect

Hur

Park

Dall’Armi

et al. 2016

Sci Rep

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Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides (TG) as lipid droplets in the liver. Although lipid-metabolizing enzymes are considered important in NAFLD, the involvement of phospholipase D1 (PLD1) has not yet been studied. Here, we show that the genetic ablation of PLD1 in mice induces NAFLD due to an autophagy defect. PLD1 expression was decreased in high-fat diet-induced NAFLD. Subsequently, PLD1 deficiency led to an increase in hepatic TGs and liver weight. Autophagic flux was blocked in Pld1−/− hepatocytes, with decreased β-oxidation rate, reduced oxidation-related gene expression, and swollen mitochondria. The dynamics of autophagy was restored by treatment with the PLD product, phosphatidic acid (PA) or adenoviral PLD1 expression in Pld1−/− hepatocytes, confirming that lysosomal PA produced by PLD1 regulates autophagy. Notably, PLD1 expression in Pld1−/− liver significantly reduced hepatic lipid accumulation, compared with Pld1−/− liver. Thus, PLD1 plays an important role in hepatic steatosis via the regulation of autophagy.

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Section: Discussioncontrasting

confidence: 57%

Section: Discussionmentioning

confidence: 58%

Phospholipase D1 deficiency in mice causes nonalcoholic fatty liver disease via an autophagy defect

Hur

Park

Dall’Armi

et al. 2016

Sci Rep

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“…Moreover, DGKθ is highly expressed in the cerebellum and hippocampus in the adult rat brain . Furthermore, overexpression of DGKθ mainly increased the amount of 18:1/18:1‐PA in mouse primary hepatocytes . Therefore, these results imply that the abnormal aggregation of the α‐syn protein results from 18:1/18:1‐PA production by DGKθ in the brain.…”

Section: Discussionmentioning

confidence: 80%

Dioleoyl‐phosphatidic acid selectively binds to α‐synuclein and strongly induces its aggregation

et al. 2017

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α-Synuclein (α-syn), which causally links to Parkinson's disease, binds to vesicles containing phosphatidic acid (PA). However, the effects of the fatty acyl chains of PA on its ability to bind to α-syn protein remain unclear. Intriguingly, we reveal that among several PA species, 18:1/18:1-PA is the most strongly bound PA to the α-syn protein. Moreover, 18:1/18:1-PA more strongly enhances secondary structural changes from the random coil form to the α-helical form than 16:0/18:1-PA. Furthermore, 18:1/18:1-PA more markedly accelerates generation of multimeric and proteinase K-resistant α-syn protein compared to 16:0/18:1-PA. These results indicate that among phospholipids examined so far, 18:1/18:1-PA demonstrates the strongest binding to α-syn, as well as the most effective enhancement of its secondary structural changes and aggregation formation.

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“…We detected that hepatocytes and 3T3 fibroblasts accumulate fully saturated PAs in response to SCD inhibition. Interestingly, recent studies have demonstrated that hepatic fully saturated PAs such as 16:0/16:0-PA, but not unsaturated PAs derived from de novo glycerolipid synthesis, inhibit the mTOR complex 2, leading to insulin resistance (60,61). Therefore, fully saturated PAs may not only play a critical role in vascular calcification, but also in many other cardiometabolic diseases.…”

Section: Discussionmentioning

confidence: 99%

Saturated phosphatidic acids mediate saturated fatty acid–induced vascular calcification and lipotoxicity

Masuda¹,

Miyazaki–Anzai²,

Keenan³

et al. 2015

Journal of Clinical Investigation

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R e s e a R c h a R t i c l e 4 5 4 4jci.org Volume 125 Number 12 December 2015 IntroductionVascular calcification is a major complication in patients who are aging, have diabetes, or have chronic kidney disease (CKD) and is an active process that differentiates vascular smooth muscle cells (VSMCs) into osteoblast-like cells (1, 2). This process is highly regulated by transcription factors involved in osteogenic differentiation, such as RUNX2, MSX2, and ATF4 (3-5). Several in vitro and in vivo studies have shown lipids to play a causative role in the pathogenesis of vascular calcification in addition to inorganic phosphate, inflammatory cytokines, and oxidative stress (6-13). Treatment with unsaturated fatty acids (UFAs) inhibits vascular mineralization and osteogenic differentiation (14, 15), whereas oxidized lipids, such as oxysterols and oxidized phospholipids, elicit procalcific effects in vascular cells (9,16,17). In addition to this evidence, we also previously reported that saturated fatty acids (SFAs) and calcium simultaneously accumulate during osteogenic differentiation of vascular cells (18,19). Ectopic accumulation of excess lipids, called lipotoxicity, plays a central role in the pathogenesis of cardio-metabolic diseases, including diabetes, obesity, atherosclerosis, and vascular calcification (20-24). However, evidence from a number of experimental systems is emerging, stating that SFAs and UFAs have distinct contributions to lipotoxicity (25,26). SFAs such as palmitic acid (16:0) and stearic acid (18:0) induce apoptosis, oxidative stress, and ER stress in a variety of mammalian cell lines (including hepatocytes, macrophages, and VSMCs), whereas UFAs such as oleic acid have no or minimal lipotoxic properties (5,(25)(26)(27)(28)(29)(30). In addition, cotreatment with UFAs blocks SFA-mediated lipotoxic effects (25,29). However, the specific metabolite of SFAs that induces lipotoxicity, the mechanism underlying SFA-mediated lipotoxicity, and how UFAs block SFA-mediated lipotoxicity are largely unknown.Proper intracellular SFA and UFA balance is controlled by a lipogenic enzyme called stearoyl-CoA desaturase (SCD) (31,32). SCD catalyzes the conversion of SFAs to monounsaturated FAs, mainly 16:0 into palmitoleate (16:1n-7), and 18:0 into oleate (18:1n-9) (33,34). This introduction of a double bond markedly impacts several chemical properties, including a decrease in melting point and an increase in solubility. The activation of SCD therefore neutralizes SFA-mediated lipotoxicity (5, 25). The expression of SCD is highly regulated by a number of hormonal and dietary factors (33,(35)(36)(37). Recently, we found that the accumulation of SFAs by either supplementation with exogenous SFAs or inhibition of SCD induces mineralization of VSMCs (5,19). In addition, SFA-mediated lipotoxicity and vascular calcification were completely blocked by an acyl-CoA synthetase inhibitor and were attenuated by the shRNA-mediated inhibition of fatty acid elongase-6 (Elovl6) (5), suggesting that stearoyl-CoA (18:0-CoA) or its ...

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Inhibited Insulin Signaling in Mouse Hepatocytes Is Associated with Increased Phosphatidic Acid but Not Diacylglycerol

Cited by 24 publications

References 52 publications

Phospholipase D1 deficiency in mice causes nonalcoholic fatty liver disease via an autophagy defect

Phospholipase D1 deficiency in mice causes nonalcoholic fatty liver disease via an autophagy defect

Dioleoyl‐phosphatidic acid selectively binds to α‐synuclein and strongly induces its aggregation

Saturated phosphatidic acids mediate saturated fatty acid–induced vascular calcification and lipotoxicity

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