Ellagic acid ameliorates AKT-driven hepatic steatosis in mice by suppressing <i>de novo</i> lipogenesis <i>via</i> the AKT/SREBP-1/FASN pathway

Zhang, Cong; Hu, Junjie; Sheng, Lei; Yuan, Ming; Wu, Yong; Chen, Liang; Wang, Guihong; Qiu, Zhenpeng

doi:10.1039/c9fo00284g

Cited by 43 publications

(33 citation statements)

References 42 publications

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“…Upon binding to EGFR, EGF activates PI3K/Akt, PLC-γ1 and MEK/ERK1/2 pathways [37][38][39]. Previous studies have shown that inhibition of the Akt/mTOR pathway in GMECs decreases the expressions of genes related to fatty acid synthesis, such as FASN, ACC and SCD1 genes [40,41]. In our study, suppression of Akt activity by its specific inhibitor MK2206 resulted in the downregulation of mRNA levels of FASN and SCD1 genes in GMECs.…”

Section: Plc-γ1 and Pi3k/akt Signaling Is Involved In The Lipid Metabsupporting

confidence: 61%

Epidermal Growth Factor Stimulates Fatty Acid Synthesis Mainly via PLC-γ1/Akt Signaling Pathway in Dairy Goat Mammary Epithelial Cells

Huang

Dai

et al. 2020

Animals

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EGF acts as a ligand of the EGF receptor (EGFR) to activate the EGFR-mediated signaling pathways and is involved in the regulation of cell physiology. However, the roles of EGFR mediated signaling pathways in the regulation of lipid metabolism in goat mammary epithelial cells (GMECs) are poorly understood. To evaluate the impact of EGF on GMECs, the triglyceride (TG) content and lipid droplet were detected, using TG assay and immunofluorescence. Further, expression of lipogenic genes, the protein kinase B (Akt), phospholipase C-γ1 (PLC-γ1) and extracellular signal-regulated kinases (ERK)1/2 signaling pathways were measured by real-time polymerase chain reaction and Western blot, respectively. The results showed that the mRNA expression of EGFR gene was significantly upregulated in lactating goat mammary gland tissues compared to non-lactation period (p < 0.05). TG contents in EGF-treated GMECs were significantly increased (p < 0.05), and an increase of lipid droplets was also detected. In vitro studies demonstrated that the mRNA levels of lipogenesis-related FASN, ACC, SCD1, LXRa, LXRb and SP1 genes were positively correlated to the mRNA level of EGFR gene shown by gene overexpression and silencing (p < 0.05). The phosphorylations of Akt, ERK1/2 and PLC-γ1 in GMECs were greatly upregulated in the presence of EGF, and specific inhibitors were capable of blocking the phosphorylation of Akt, ERK1/2 and PLC-γ1. Compared with EGF-treated GMECs, the mRNA levels of FASN, ACC and SCD1 were significantly decreased in GMECs co-treated with PLC-γ1 and Akt inhibitor and EGF (p < 0.05), and TG content was also dropped significantly. These observations implied that EGFR plays an important role in regulating de novo fatty acid synthesis in GMECs, mainly mediated by Akt and PLC-γ1 signaling pathways.

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Section: Plc-γ1 and Pi3k/akt Signaling Is Involved In The Lipid Metabsupporting

confidence: 61%

Epidermal Growth Factor Stimulates Fatty Acid Synthesis Mainly via PLC-γ1/Akt Signaling Pathway in Dairy Goat Mammary Epithelial Cells

Huang

Dai

et al. 2020

Animals

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“…Our data show that Vermentino leaf extract triggered activation of AKT1 via phosphorylation as well as increased FASN mRNA levels in MCF-7 and SKBR-3 cells. Activated AKT1 stimulates FASN expression by gene modulation of sterol regulatory element-binding protein 1c (SREBP1C), which is a transcription factor that activates FASN by binding to its promoter region [45]. Here, we provide evidence that increased AKT1 activation and the related increase in FASN mRNA compensate for Vermentino-induced FASN downregulation.…”

Section: Discussionmentioning

confidence: 84%

SUMOylation Protects FASN Against Proteasomal Degradation in Breast Cancer Cells Treated with Grape Leaf Extract

et al. 2020

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Existing therapeutic strategies for breast cancer are limited by tumor recurrence and drug-resistance. Antioxidant plant-derived compounds such as flavonoids reduce adverse outcomes and have been identified as a potential source of antineoplastic agent with less undesirable side effects. Here, we describe the novel regulation of fatty-acid synthase (FASN), the key enzyme in de novo fatty-acid synthesis, whereby Vitis vinifera L. cv Vermentino leaf hydroalcoholic extract lowers its protein stability that is regulated by small ubiquitin-like modifier (SUMO)ylation. The phenolic compounds characterization was performed by liquid chromatography–mass spectrometry (LC–MS), whereas mass spectrometry (LC–MS/MS), Western blotting/co-immunoprecipitation (Co-IP) and RT-PCR, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clonogenicity assays, and FACS analysis were used to measure the expression of targets and tumorigenicity. Vermentino extract exhibits antitumorigenic effects, and we went on to determine that FASN and ubiquitin-conjugating enzyme 9 (UBC9), the sole E2 enzyme required for SUMOylation, were significantly reduced. Moreover, FASN was found SUMOylated in human breast cancer tissues and cell lines, and lack of SUMOylation caused by SUMO2 silencing reduced FASN protein stability. These results suggest that SUMOylation protects FASN against proteasomal degradation and may exert oncogenic activity through alteration of lipid metabolism, whereas Vermentino extract inhibits these effects which supports the additional validation of the therapeutic value of this compound in breast cancer.

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“…Our data shows that Vermentino leaf extract triggered activation of AKT1 via phosphorylation as well as increased FASN mRNA levels in MCF-7 and SKBR-3 cells. Activated AKT1 stimulates FASN expression by gene modulation of sterol regulatory element-binding protein 1c (SREBP1C), which is a transcription factor that activates FASN by binding to its promoter region (29). Here, we provide evidence that increased AKT1 activation and the related increase in FASN mRNA compensate for Vermentino-induced FASN downregulation.…”

Section: Discussionmentioning

confidence: 84%

SUMOylation protects FASN against proteasomal degradation in breast cancer cells treated with grape leaf extract

Floris

Mazarei

Yang

et al. 2020

Preprint

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Background: Existing therapeutic strategies for breast cancer are limited by tumor recurrence and drug-resistance. Several epidemiological studies indicate that antioxidant plant-derived compounds such as flavonoids reduce adverse outcomes and have been identified as a potential source of antineoplastic agent with less undesirable side effects. Activation of lipid metabolism is an early event in carcinogenesis and a central hallmark in breast cancer. In fact, inhibition of fatty-acid synthesis in breast cancer results in cytotoxicity that triggers apoptosis. Here, we describe the novel regulation of lipid metabolism in breast cancer cells whereby the protein stability and degradation of fatty-acid synthase (FASN), the key enzyme in de novo fatty-acid synthesis, is regulated by SUMOylation. Methods: The phenolic characterization were analyzed by Liquid Chromatography-Mass Spectrometry (LCMS). Profile protein contents was evaluated by Mass Spectrometry (LC-MS/MS). The experiments were performed using MCF7, SKBR-3 human carcinoma cell lines and MCF-12A breast epithelial cell line treated with Vermentino hydroalcoholic extract in dose and time course responses. Protein and mRNA levels were analyzed by western blotting/Co-immunoprecipitation (Co-IP) and RT-PCR, respectively. The number of viable cells and the cell-surviving has been detected by MTT and clonogenicity assays. Apoptotic induction was determined by Flow Cytometric assay using Annexin V-FITC and sorted by A FACSC analysis.Results: We first tested the potential antitumorigenic effects of Vitis vinifera L. cv. Vermentino leaf hydroalcoholic extract in MCF-7 and SKBR-3 breast cancer cell lines and found that this compound demonstrated cytotoxic effects. We went on to determine that FASN and UBC9, the sole E2 enzyme required for SUMOylation, were significantly reduced by treatment with the Vermentino extract.Moreover, we found that FASN was SUMOylated in human breast cancer tissues and cell lines. Finally, lack of SUMOylation caused by SUMO2 silencing reduced FASN protein stability.Conclusion: Altogether, these results suggest that SUMOylation protects FASN against proteasomal degradation and may exert oncogenic activity through alteration of lipid metabolism in breast cancer.Importantly, we found that these effects were significantly inhibited by treatment with Vermentino leaf extract, which supports the additional validation of the therapeutic value of this compound. BackgroundBreast cancer is the most common malignant cancer in females worldwide (1). The existing therapeutic strategies for breast cancer, which include surgery, endocrine therapy, and chemotherapy, are limited by tumor recurrence and drug-resistance (2). Therefore, novel approaches are needed to enhance the efficacy of existing therapeutic agents and to improve current clinical protocols.Adjuvant therapies often attempt to induce cytotoxicity in tumor cells. As tumor cells are known to rely on alternate metabolic processes, such as de novo fatty-acid synthesis, these pathways harbor many pote...

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Ellagic acid ameliorates AKT-driven hepatic steatosis in mice by suppressing de novo lipogenesis via the AKT/SREBP-1/FASN pathway

Abstract: Ellagic acid alleviates hepatic lipid accumulation in mice by suppressing AKT-driven de novo lipogenesis.

Cited by 43 publications

References 42 publications

Epidermal Growth Factor Stimulates Fatty Acid Synthesis Mainly via PLC-γ1/Akt Signaling Pathway in Dairy Goat Mammary Epithelial Cells

Epidermal Growth Factor Stimulates Fatty Acid Synthesis Mainly via PLC-γ1/Akt Signaling Pathway in Dairy Goat Mammary Epithelial Cells

SUMOylation Protects FASN Against Proteasomal Degradation in Breast Cancer Cells Treated with Grape Leaf Extract

SUMOylation protects FASN against proteasomal degradation in breast cancer cells treated with grape leaf extract

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