Acylglycerophosphate acyltransferase 4 (AGPAT4) is a mitochondrial lysophosphatidic acid acyltransferase that regulates brain phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol levels

Bradley, Ryan M.; Marvyn, Phillip M.; Henao, Juan J. Aristizabal; Mardian, Emily B.; George, Steve; Aucoin, Marc G.; Duncan, Robin E.

doi:10.1016/j.bbalip.2015.09.005

Cited by 38 publications

(59 citation statements)

References 45 publications

(64 reference statements)

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“…Regardless, since PtdOH is a common precursor for both TAG and phospholipid synthesis, knowledge of the regulation of AGPAT enzymes is of interest for understanding fasting-mediated adaptations throughout the body. This knowledge is also relevant to current efforts to understand the in vivo function of the individual Agpat homologues, since these enzymes all synthesize the common product PtdOH, but appear to support different down-stream pathways for complex lipid formation [8]. In the current work, we report novel findings that fasting induces specific profiles of gene expression of Agpat1-5 in mouse liver, heart, and whole brain.…”

Section: Agpatmentioning

confidence: 68%

“…Understanding the implications of this work is currently limited by a lack of studies on the functional role of the different AGPAT/LPAAT enzymes in vivo. For example, our group has determined that Agpat4 deficiency reduces the content of PC, PE, and PI in mouse brain without affecting TAG stores [8], while others have found changes in TAG content with loss of Agpat2 in adipose tissue [13,14,35]. This indicates that the AGPAT/LPAAT enzymes likely produce PtdOH in support of specific and well-defined glycerolipid synthesis pathways.…”

Section: Resultsmentioning

confidence: 99%

“…Total RNA was isolated, and RT-PCR was performed as we have previously described [8]. Expression of Agpat1, Agpat2, Agpat3, Agpat4, Agpat5, and 18s were performed using PerfeCTA qPCR FastMix (Quanta Biosciences, Gaithersburg, MD, USA), and Taqman gene expression assays (Agpat1: Mm00479700_m1, Agpat2: Mm00458880_m1, Agpat3: Mm00474003_m1, Agpat4: Mm00509777_ml, Agpat5: Mm00546668_m1, Life Technologies, Burlington, ON, Canada, and 18S: cat#4319413E, Applied Biosystems, Mississauga, Ontario, Canada).…”

Section: Rna Extraction and Real-time Reverse Transcription Pcr (Rt-mentioning

confidence: 99%

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Acute Fasting Induces Expression of Acylglycerophosphate Acyltransferase (AGPAT) Enzymes in Murine Liver, Heart, and Brain

Bradley

Mardian

Moes

et al. 2017

Lipids

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During fasting, cells increase uptake of non-esterified fatty acids (NEFA) and esterify excess into phosphatidic acid (PtdOH), the common precursor of both triacylglycerols and phospholipids, using acylglycerophosphate acyltransferases/lysophosphatidic acid acyltransferases (AGPAT/LPAAT). Knowledge of the regulation of AGPAT enzymes is important for understanding fasting adaptations. Total RNA was isolated from liver, heart, and whole brain tissue of C57BL/6J mice fed ad libitum, or fasted for 16 h. Following fasting, induction of Agpat2, 3, 4, and 5 was observed in the liver, Agpat2 and 3 in heart tissue, and Agpat1, 2, and 3 in whole brain tissue. As a result, the relative abundance profile of the individual homologues within specific tissues was found to be significantly altered depending on the nutritive state of the animal. These data demonstrate tissue-specific effects of fasting on the regulation of different Agpat that are implicated in supporting unique downstream glycerolipid synthesis pathways.

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Section: Agpatmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Rna Extraction and Real-time Reverse Transcription Pcr (Rt-mentioning

confidence: 99%

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Acute Fasting Induces Expression of Acylglycerophosphate Acyltransferase (AGPAT) Enzymes in Murine Liver, Heart, and Brain

Bradley

Mardian

Moes

et al. 2017

Lipids

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“…Our results displayed that CP could reduce the palmitic acids levels and adjust PC content to improve lipid utilization and protect hepatic steatosis. PE is directly associated with diabetes and dyslipidemia and PC/PE ratio is closely correlated with the accumulation of hepatic TG content (Bradley et al, 2015; Ling et al, 2017). Our results showed that the levels of PE were elevated in CP-treated diabetic mice, indicating CP can reduce TG accumulation.…”

Section: Discussionmentioning

confidence: 99%

Cyclocarya paliurus Leaves Tea Improves Dyslipidemia in Diabetic Mice: A Lipidomics-Based Network Pharmacology Study

et al. 2018

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Hyperlipidemia and hepatic steatosis afflict over 75% of patients with type 2 diabetes, causing diabetic dyslipidemia. Cyclocarya paliurus (CP) leaf is a herbal tea which has long been consumed by the Chinese population, particularly people suffering from obesity and diabetes. CP appears to exhibit a hypolipidemic effect in lipid loaded mice (Kurihara et al., 2003), although the detailed mechanisms and active ingredients for this hypolipidemic effect have not yet been answered. In this study, we investigated the beneficial effects of CP and predicted the mechanisms by utilizing lipidomics, serum-pharmacochemistry and network pharmacology approaches. Our results revealed that serum and hepatic levels of total triglyceride (TG), total cholesterol (T-CHO), low-density lipoproteins (LDL) and high-density lipoproteins (HDL), as well as 30 lipids including cholesterol ester (CE), diglyceride (DG), phosphatidylethanolamine (PE), phosphatidylcholine (PC), and sphingomyelin (SM) in CP-treated mice were improved in comparison with untreated diabetic mice. In parallel, 14 phytochemical compounds of CP were determined in mice serum after CP administration. Mechanistically, the network pharmacology analysis revealed the predicted targets of CP’s active ingredients ALOX12, APP, BCL2, CYP2C9, PTPN1 and linked lipidome targets PLD2, PLA2G(s), and PI3K(s) families could be responsible for the CP effects on diabetic dyslipidemia. In conclusion, this study revealed the beneficial effects of CP on diabetic dyslipidemia are achieved by reducing accumulation of hepatic lipid droplets and regulating circulatory lipids in diabetic mice, possibly through PI3K signaling and MAPK signaling pathways. GRAPHICAL ABSTRACTWork flow of the evaluation of the effects and mechanisms of Cyclocarya paliurus leaves tea on dyslipidemia in diabetic mice.

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“…We and others have studied the enzymatic and biochemical functions of LPAAT␦/ AGPAT4, which are present at ubiquitously high levels in whole mouse brain (5-7) and in multiple mouse brain subregions (6). In previous work, we reported that Lpaat␦ deficiency in mouse brain is compensated for by induction of Lpaat␣, -␤, -␥, and -(Agpat1, -2, -3, and -5), which serves to maintain total brain levels of PA but, interestingly, does not functionally compensate for loss of the enzyme (6).…”

mentioning

confidence: 99%

Mice Deficient inlysophosphatidic acid acyltransferase delta(Lpaatδ)/acylglycerophosphate acyltransferase 4(Agpat4) Have Impaired Learning and Memory

Bradley

Mardian

Bloemberg

et al. 2017

Molecular and Cellular Biology

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We previously characterized LPAATδ/AGPAT4 as a mitochondrial lysophosphatidic acid acyltransferase that regulates brain levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI). Here, we report that δ mice display impaired spatial learning and memory compared to wild-type littermates in the Morris water maze and our investigation of potential mechanisms associated with brain phospholipid changes. Marker protein immunoblotting suggested that the relative brain content of neurons, glia, and oligodendrocytes was unchanged. Relative abundance of the important brain fatty acid docosahexaenoic acid was also unchanged in phosphatidylserine, phosphatidylglycerol, and cardiolipin, in agreement with prior data on PC, PE and PI. In phosphatidic acid, it was increased. Specific decreases in ethanolamine-containing phospholipids were detected in mitochondrial lipids, but the function of brain mitochondria in δ mice was unchanged. Importantly, we found that δ mice have a significantly and drastically lower brain content of the -methyl-d-asparate (NMDA) receptor subunits NR1, NR2A, and NR2B, as well as the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1, compared to wild-type mice. However, general dysregulation of PI-mediated signaling is not likely responsible, since phospho-AKT and phospho-mTOR pathway regulation was unaffected. Our findings indicate thatδ deficiency causes deficits in learning and memory associated with reduced NMDA and AMPA receptors.

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Acylglycerophosphate acyltransferase 4 (AGPAT4) is a mitochondrial lysophosphatidic acid acyltransferase that regulates brain phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol levels

Cited by 38 publications

References 45 publications

Acute Fasting Induces Expression of Acylglycerophosphate Acyltransferase (AGPAT) Enzymes in Murine Liver, Heart, and Brain

Acute Fasting Induces Expression of Acylglycerophosphate Acyltransferase (AGPAT) Enzymes in Murine Liver, Heart, and Brain

Cyclocarya paliurus Leaves Tea Improves Dyslipidemia in Diabetic Mice: A Lipidomics-Based Network Pharmacology Study

Mice Deficient inlysophosphatidic acid acyltransferase delta(Lpaatδ)/acylglycerophosphate acyltransferase 4(Agpat4) Have Impaired Learning and Memory

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