AGPAT2 deficiency impairs adipogenic differentiation in primary cultured preadipocytes in a non-autophagy or apoptosis dependent mechanism

Fernández‐Galilea, Marta; Tapía, Pablo; Cautivo, Kelly M.; Morselli, Eugenia; Cortés, Víctor

doi:10.1016/j.bbrc.2015.09.128

Cited by 19 publications

(10 citation statements)

References 20 publications

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“…Using this approach, we observed that AGPAT1/2 DKO impaired lipid droplet formation (Supplementary Fig. 3c–e ) as shown previously 20 , 21 , confirming disruption of AGPAT1/2 function. To monitor the impact of single KO and AGPAT1/2 DKO on HCV replication, cells were infected with an HCV reporter virus and viral replication was determined by using luciferase assay.…”

Section: Resultssupporting

confidence: 87%

Convergent use of phosphatidic acid for hepatitis C virus and SARS-CoV-2 replication organelle formation

et al. 2021

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Double membrane vesicles (DMVs) serve as replication organelles of plus-strand RNA viruses such as hepatitis C virus (HCV) and SARS-CoV-2. Viral DMVs are morphologically analogous to DMVs formed during autophagy, but lipids driving their biogenesis are largely unknown. Here we show that production of the lipid phosphatidic acid (PA) by acylglycerolphosphate acyltransferase (AGPAT) 1 and 2 in the ER is important for DMV biogenesis in viral replication and autophagy. Using DMVs in HCV-replicating cells as model, we found that AGPATs are recruited to and critically contribute to HCV and SARS-CoV-2 replication and proper DMV formation. An intracellular PA sensor accumulated at viral DMV formation sites, consistent with elevated levels of PA in fractions of purified DMVs analyzed by lipidomics. Apart from AGPATs, PA is generated by alternative pathways and their pharmacological inhibition also impaired HCV and SARS-CoV-2 replication as well as formation of autophagosome-like DMVs. These data identify PA as host cell lipid involved in proper replication organelle formation by HCV and SARS-CoV-2, two phylogenetically disparate viruses causing very different diseases, i.e. chronic liver disease and COVID-19, respectively. Host-targeting therapy aiming at PA synthesis pathways might be suitable to attenuate replication of these viruses.

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Section: Resultssupporting

confidence: 87%

Convergent use of phosphatidic acid for hepatitis C virus and SARS-CoV-2 replication organelle formation

et al. 2021

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“…The glycerophosphate pathway is an important pathway for de novo synthesis of triglycerides, and AGPAT2 plays a key role in the synthesis of glycerolipid and triglyceride. As a precursor of de novo synthesis of major glycerides (Bradley et al, 2017), it is highly expressed in adipose tissue and liver and can catalyze the formation of triglycerides (Fernandez-Galilea et al, 2015). AGPAT2 mutation can lead to congenital systemic adipotrophic diabetes (GCL), which is characterized by adipose tissue deficiency, insulin resistance, diabetes, and hyperlipidemia (Oswiecimska et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

The Effect of Silibinin on Protein Expression Profile in White Adipose Tissue of Obese Mice

et al. 2020

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Objective: To investigate the effect of silibinin on the protein expression profile of white adipose tissue (WAT) in obese mice by using Tandem Mass Tag (TMT) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Methods: According to experimental requirements, 36 C57BL/6JC mice were randomly divided into normal diet group (WC group), high fat diet group (WF group), and high fat diet + silibinin group (WS group). WS group was intragastrically administered with 54 mg/ kg body weight of silibinin, and the WC group and the WF group were intragastrically administered with equal volume of normal saline. Serum samples were collected to detect fasting blood glucose and blood lipids. IPGTT was used to measure the blood glucose value at each time point and calculate the area under the glucose curve. TMT combined with LC-MS/MS were used to study the expression of WAT, and its cellular processes, biological processes, corresponding molecular functions, and related network molecular mechanisms were analyzed by bioinformatics. Finally, RT-PCR and LC-MS/MS were used to detect the mRNA and protein expressions of FABP5, Plin4, GPD1, and AGPAT2, respectively. Results: Although silibinin did not reduce the mice's weight, it did improve glucose metabolism. In addition, silibinin decreased the concentration of TC, TG, and LDL-C and increased the concentration of HDL-C in the serum of mice. In the WF/WS group, 182 differentially expressed proteins were up-regulated and 159 were down-regulated. While in the WS/WF group, 362 differentially expressed proteins were up-regulated and 176 were down-regulated. Further analysis found that these differential proteins are mainly distributed in the peroxisome proliferation-activated receptor (PPAR), lipolysis of fat cells, metabolism of glycerides, oxidative phosphorylation, and other signaling pathways, and participate in cell processes and lipid metabolism through catalysis and integration functions. Specifically, silibinin reduced the expression of several key factors such as FABP5, Plin4, GPD1, and AGPTA2.

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“…2 a, b), indicating regulatory changes in PPARγ and C/EBPα genes to be reflected in both chromatin accessibility and transcript abundance. AGPAT2 , which induces the expression of PPARγ and C/EBPα [ 45 ], as well as critical genes governing adipocyte function such as ADIPOQ , PLIN1 , SLC2A4 , FABP4 and LPL were also up-regulated in PCOS cells with peak expression level at days 7–12 following peak chromatin accessibility generally at day 3 (Fig. 2 , Additional file: Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Dynamic changes in chromatin accessibility, altered adipogenic gene expression, and total versus de novo fatty acid synthesis in subcutaneous adipose stem cells of normal-weight polycystic ovary syndrome (PCOS) women during adipogenesis: evidence of cellular programming

et al. 2020

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Background Normal-weight polycystic ovary syndrome (PCOS) women exhibit adipose resistance in vivo accompanied by enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with accelerated lipid accumulation per cell in vitro. The present study examines chromatin accessibility, RNA expression and fatty acid (FA) synthesis during SC abdominal ASC differentiation into adipocytes in vitro of normal-weight PCOS versus age- and body mass index-matched normoandrogenic ovulatory (control) women to study epigenetic/genetic characteristics as well as functional alterations of PCOS and control ASCs during adipogenesis. Results SC abdominal ASCs from PCOS women versus controls exhibited dynamic chromatin accessibility during adipogenesis, from significantly less chromatin accessibility at day 0 to greater chromatin accessibility by day 12, with enrichment of binding motifs for transcription factors (TFs) of the AP-1 subfamily at days 0, 3, and 12. In PCOS versus control cells, expression of genes governing adipocyte differentiation (PPARγ, CEBPα, AGPAT2) and function (ADIPOQ, FABP4, LPL, PLIN1, SLC2A4) was increased two–sixfold at days 3, 7, and 12, while that involving Wnt signaling (FZD1, SFRP1, and WNT10B) was decreased. Differential gene expression in PCOS cells at these time points involved triacylglycerol synthesis, lipid oxidation, free fatty acid beta-oxidation, and oxidative phosphorylation of the TCA cycle, with TGFB1 as a significant upstream regulator. There was a broad correspondence between increased chromatin accessibility and increased RNA expression of those 12 genes involved in adipocyte differentiation and function, Wnt signaling, as well as genes involved in the triacylglycerol synthesis functional group at day 12 of adipogenesis. Total content and de novo synthesis of myristic (C14:0), palmitic (C16:0), palmitoleic (C16:1), and oleic (C18:1) acid increased from day 7 to day 12 in all cells, with total content and de novo synthesis of FAs significantly greater in PCOS than controls cells at day 12. Conclusions In normal-weight PCOS women, dynamic chromatin remodeling of SC abdominal ASCs during adipogenesis may enhance adipogenic gene expression as a programmed mechanism to promote greater fat storage.

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AGPAT2 deficiency impairs adipogenic differentiation in primary cultured preadipocytes in a non-autophagy or apoptosis dependent mechanism

Cited by 19 publications

References 20 publications

Convergent use of phosphatidic acid for hepatitis C virus and SARS-CoV-2 replication organelle formation

Convergent use of phosphatidic acid for hepatitis C virus and SARS-CoV-2 replication organelle formation

The Effect of Silibinin on Protein Expression Profile in White Adipose Tissue of Obese Mice

Dynamic changes in chromatin accessibility, altered adipogenic gene expression, and total versus de novo fatty acid synthesis in subcutaneous adipose stem cells of normal-weight polycystic ovary syndrome (PCOS) women during adipogenesis: evidence of cellular programming

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