Src-mediated Tyr353 phosphorylation of IP3R1 promotes its stability and causes apoptosis in palmitic acid-treated hepatocytes

Yu, Ting; Zheng, Enze; Li, Yanping; Li, Yuqi; Xia, Jun; Ding, Qiuying; Hou, Zhengping; Ruan, Xiong Z.; Zhao, Lei; Chen, Yaxi

doi:10.1016/j.yexcr.2020.112438

Cited by 11 publications

(7 citation statements)

References 36 publications

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“…Certain lipids, such as saturated FFAs, have toxic effects on hepatocytes. PA, a kind of saturated FFA, is often used to simulate the pathogenesis of NAFLD and induce liver cell damage for in vitro experiments in many studies [19,20]. Thus, here, we treated the cells with PA to induce liver cell damage to mimic the pathogenesis of NAFLD.…”

Section: Discussionmentioning

confidence: 99%

Exosomes secreted by palmitic acid-treated hepatocytes promote LX-2 cell activation by transferring miRNA-107

Wang

Lai

et al. 2021

Cell Death Discov.

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Activation of hepatic stellate cells (HSCs) is a key inducer of liver fibrogenesis in nonalcoholic fatty liver disease (NAFLD). Exosomes play an important role between hepatocytes and HSCs. This study aims to explore the role of exosomes derived from palmitic acid (PA)-treated hepatocytes in regulating HSCs (LX-2 cell) proliferation and activation and the underlying mechanisms. Exosomes were isolated from PA-treated human normal hepatocytes and incubated with LX-2 cells. Cell Counting Kit-8 (CCK-8) was performed to determine LX-2 cell proliferation, and the expression of fibrosis markers α-smooth muscle actin (α-SMA) and collagen type 1 α1 (CoL1A1) were examined to evaluateLX-2 cell activation. PA induced hepatocytes to release more exosomes enriched in miR-107. Mechanically, on the one hand, exosomes from PA-treated hepatocytes shuttled miR-107 to LX-2 cells, where miR-107 activated Wnt signaling by targeting DKK1 and thereby induced LX-2 cell activation; on the other hand, PA-treated hepatocytes derived exosomes also delivered miR-107 to CD4 + T lymphocytes, where miR-107 elevated IL-9 expression by targeting Foxp1, which bound to the IL-9 promoter in CD4 + T cells and suppressed Th9 cell differentiation and reduced IL-9 expression, and thus promoted LX-2 cell activation by activating Raf/MEK/ERK signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Exosomes secreted by palmitic acid-treated hepatocytes promote LX-2 cell activation by transferring miRNA-107

Wang

Lai

et al. 2021

Cell Death Discov.

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“…Therefore, Ca 2+ channels may be used as a potential target for the diagnosis, prevention and treatment of NAFLD. The following is a summary of the mechanism of action and/or treatment strategies of several types of Ca 2+ channels in NAFLD (Table II) (43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62).…”

Section: Ca 2+ Channels In the Development And Progression Of Nafld A...mentioning

confidence: 99%

“…IP3R1 is mainly distributed in the ER, which controls mitochondrial ca 2+ signaling and lipid metabolism via connecting with VDAC on the outer membrane of the mitochondria. IP3R2 is concentrated near the apical membrane and regulates the bile solute secretion of liver cells (50). Therefore, IP3R1 and IP3R2 serve different roles in the progression of NAFLD.…”

Section: 45-trisphosphate Receptor (Ip3r)1 Deletion Inhibits the Deve...mentioning

confidence: 99%

“…This may have been due to the increased phosphorylation of Tyr353 in IP3R1 via the tyrosine kinase signaling pathway that led to the increased stability of the IP3R1 protein. Therefore, mitochondrial ca 2+ overload may induce mitochondrial dysfunction in hepatocytes (50). In summary, the specific inhibition of IP3R1 channels to reduce mitochondrial dysfunction in hepatocytes may be a potential novel clinical strategy for the treatment of NAFLD and the prevention of its further development.…”

Section: 45-trisphosphate Receptor (Ip3r)1 Deletion Inhibits the Deve...mentioning

confidence: 99%

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Role of Ca²⁺ channels in non-alcoholic fatty liver disease and their implications for therapeutic strategies (Review)

et al. 2022

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Non-alcoholic fatty liver disease (NAFLd) is a clinically progressive illness that can advance from simple fatty liver to non-alcoholic hepatitis and liver fibrosis. Cirrhosis and hepatocellular carcinoma are two of the most common diseases caused by NAFLD. As there are no early disease biomarkers and no US Food and drug Administration-approved medications, treatment for NAFLd is still focused on altering lifestyle and dietary habits, which makes it difficult to treat effectively. As a result, a novel treatment is urgently needed to prevent NAFLD progression. Calcium (Ca 2+ ) channels regulate intracellular ca 2+ homeostasis via the mediation of ca 2+ flow. Previous studies have reported that Ca 2+ channel expression varies throughout the development and progression of NAFLd, which results in the dysregulation of intracellular ca 2+ homeostasis, endoplasmic reticulum stress, mitochondrial dysfunction and autophagy suppression, all of which contribute to NAFLD progression. Several types of ca 2+ channels (including two-pore segment channel 2, transient receptor potential, inositol triphosphate receptor, voltage-dependent anion channel 1, store-operated ca 2+ entry, purinergic receptor X7 and potassium ca 2+ -activated channel subfamily N member 4) have been identified as potential targets for preventing NAFLd development and controlling intracellular ca 2+ homeostasis. To achieve this, these channels can be blocked or activated, which exerts anti-steatotic, anti-inflammatory, anti-fibrotic and other effects, which ultimately prevents the development of NAFLD. In the present review NAFLd therapeutics and the treatments that target ca 2+ channels that are currently being developed were examined. Contents 1. Introduction 2. Physiological role of Ca 2+ in the liver 3. Dysregulation of Ca 2+ channel expression and the disturbance of Ca 2+ homeostasis in NAFLd 4. Ca 2+ channels in the development and progression of NAFLd and as an NAFLd therapeutic target 5. Conclusion and future perspectives

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“…This is in concert with observations in hepatocyte cellular models in which InsP3R1 was upregulated upon palmitate treatment. The upregulation is due to enhanced protein stability through the Src-dependent tyrosine phosphorylation of InsP3R1 [ 47 ]. However, the InsP3R1 levels remained unaltered in a high-fat diet and ob/ob mouse models, suggesting differences in the regulatory mechanisms between species [ 48 ].…”

Section: Alterations In Ca 2+ Homeostasis and Organelle Dysfunction In Development Of Nafldmentioning

confidence: 99%

Emerging Roles of Calcium Signaling in the Development of Non-Alcoholic Fatty Liver Disease

Chen

Hsu

Chen

et al. 2021

IJMS

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The liver plays a central role in energy metabolism. Dysregulated hepatic lipid metabolism is a major cause of non-alcoholic fatty liver disease (NAFLD), a chronic liver disorder closely linked to obesity and insulin resistance. NAFLD is rapidly emerging as a global health problem with currently no approved therapy. While early stages of NAFLD are often considered benign, the disease can progress to an advanced stage that involves chronic inflammation, with increased risk for developing end-stage disease including fibrosis and liver cancer. Hence, there is an urgent need to identify potential pharmacological targets. Ca2+ is an essential signaling molecule involved in a myriad of cellular processes. Intracellular Ca2+ is intricately compartmentalized, and the Ca2+ flow is tightly controlled by a network of Ca2+ transport and buffering proteins. Impaired Ca2+ signaling is strongly associated with endoplasmic reticulum stress, mitochondrial dysfunction and autophagic defects, all of which are etiological factors of NAFLD. In this review, we describe the recent advances that underscore the critical role of dysregulated Ca2+ homeostasis in lipid metabolic abnormalities and discuss the feasibility of targeting Ca2+ signaling as a potential therapeutic approach.

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Src-mediated Tyr353 phosphorylation of IP3R1 promotes its stability and causes apoptosis in palmitic acid-treated hepatocytes

Cited by 11 publications

References 36 publications

Exosomes secreted by palmitic acid-treated hepatocytes promote LX-2 cell activation by transferring miRNA-107

Exosomes secreted by palmitic acid-treated hepatocytes promote LX-2 cell activation by transferring miRNA-107

Role of Ca²⁺ channels in non-alcoholic fatty liver disease and their implications for therapeutic strategies (Review)

Emerging Roles of Calcium Signaling in the Development of Non-Alcoholic Fatty Liver Disease

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Src-mediated Tyr353 phosphorylation of IP3R1 promotes its stability and causes apoptosis in palmitic acid-treated hepatocytes

Cited by 11 publications

References 36 publications

Exosomes secreted by palmitic acid-treated hepatocytes promote LX-2 cell activation by transferring miRNA-107

Exosomes secreted by palmitic acid-treated hepatocytes promote LX-2 cell activation by transferring miRNA-107

Role of Ca2+ channels in non-alcoholic fatty liver disease and their implications for therapeutic strategies (Review)

Emerging Roles of Calcium Signaling in the Development of Non-Alcoholic Fatty Liver Disease

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Product

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Role of Ca²⁺ channels in non-alcoholic fatty liver disease and their implications for therapeutic strategies (Review)