ApoC2 deficiency elicits severe hypertriglyceridemia and spontaneous atherosclerosis: A rodent model rescued from neonatal death

Gao, Mingming; Yang, C. Y.; Wang, Xiaowei; Guo, Mengmeng; Liu, Yang; Gao, Shanshan; Zhang, Xin; Ruan, Guiyun; Li, Xiangping; Tian, Wenhong; Lu, Guotao; Dong, X.L.; Ma, Sisi; Li, Weiqin; Wang, Yuhui; Zhu, Haibo; He, Juan; Yang, Hongyuan; Liu, George; Xia, Xian

doi:10.1016/j.metabol.2020.154296

Cited by 22 publications

(19 citation statements)

References 40 publications

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“…APOC2 is also highly expressed in acute myeloid leukemia and is associated with poor clinical outcomes. In addition, APOC2 promotes the growth of leukemia through the CD36-ERK signaling pathway (18). These studies indicated that APOC2 plays an important role in cancer cells; however, we lack a detailed explanation of its mechanism in these diseases.…”

Section: Discussionmentioning

confidence: 98%

“…APOC2 plays an important role in TRL metabolism because it can guide lipoproteins to active LPL sites and act as a physiological activator of LPL, which is the main enzyme that hydrolyzes plasma triglycerides (TG) on TRLs (15)(16)(17). Therefore, APOC2 can provide energy transport and storage for cells by regulating lipid metabolism (18). APOC2 de ciency can cause severe hypertriglyceridemia and lead to cardiovascular disease (19,20).…”

Section: Introductionmentioning

confidence: 99%

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Apolipoprotein C-II induces EMT to Promote Gastric Cancer Peritoneal Metastasis via PI3K/AKT/mTOR Pathway

Wang

Yang

et al. 2021

Preprint

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Background: Peritoneal metastasis (PM) occurs frequently in patients with gastric cancer (GC) and confers poor survival. Lipid metabolism and epithelial-mesenchymal transition (EMT) play an important role in GC metastasis. As Apolipoprotein C-II (APOC2) is a key protein in lipid metabolism, few studies have investigated the role of APOC2 in PM. This study aims to elucidate the potential molecular mechanism of APOC2 in the PM of GC.Methods: The Tandem Mass Tagging (TMT) method followed by liquid chromatography-tandem mass spectrometry-based proteomics analysis was used to compare the levels of differentially expressed proteins between human PM and GC tissues. APOC2 expression was evaluated by immunoblotting, and immunohistochemistry analysis (n = 111). APOC2 over-expression and knock-down expression cell models were developed and tested in vitro. RNA sequencing analysis evaluated the changes in gene expression after APOC2 knockdown in GC cells. The Agilent Seahorse XF platform and lipid staining assay were used to evaluate the role of APOC2 in lipid metabolism of GC cells. Spheroid cell invasion assay, apoptosis assay, colony formation assay, wound-healing assays, and transwell assays were performed and peritoneal implants into nude mice were done to assess the biological effects of APOC2. The underlying mechanisms were investigated using Western blot, inhibitor or activator treatment assays.Results: APOC2 was highly abundant in GC cells and PM tissues. And high APOC2 levels in GC tissues correlated with poor patient prognosis. Knockdown of APOC2 inhibited the malignant phenotype of cancer cells and EMT significantly. Massive gene expression alterations after APOC2 knockdown, which were associated with various signaling pathways, especially the PI3K/AKT signaling pathway and lipid metabolism. Furthermore, the regulatory effects of APOC2 on the EMT were partially attributed to the PI3K/AKT/mTOR signaling pathway. The results in vivo also showed that APOC2 modulated GC PM.Conclusions: We verified that knockdown of APOC2 suppressed GC cell Lipid metabolism, proliferation, migration, invasion, and EMT, accompanied by inactivation of PI3K/AKT/mTOR signaling pathway. APOC2 overexpression had the opposite effects GC cell phenotypes and mechanisms. Collectively, our results identified APOC2 in PM as a potential therapeutic target.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Apolipoprotein C-II induces EMT to Promote Gastric Cancer Peritoneal Metastasis via PI3K/AKT/mTOR Pathway

Wang

Yang

et al. 2021

Preprint

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“…ApoC2 −/− hamsters were created in our laboratory as described previously, 18 which showed the characteristics of sHTG and death during the lactation period. Because all neonatal ApoC2 −/− hamsters died within 10 days after birth, daily administration of normal hamster serum via the orbital vein was needed for rescue until weaning on day 21.…”

Section: Methodsmentioning

confidence: 99%

“…infusion of wild-type (WT) hamster serum and then survival to adulthood with sHTG, thus providing an ideal animal model for the study of sHTG caused by ApoC2 deficiency. 18 …”

Section: Introductionmentioning

confidence: 99%

“…infusion of wild-type (WT) hamster serum and then survival to adulthood with sHTG, thus providing an ideal animal model for the study of sHTG caused by ApoC2 deficiency. 18 To our knowledge, clinical treatment for patients with ApoC2 deficiency has not yet been systemically reported, and conventional lipid-lowering drugs are largely ineffective. Transfusion of normal plasma containing ApoC2 may only be applied to save lives during the onset of severe pancreatitis.…”

Section: Introductionmentioning

confidence: 99%

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AAV-Mediated ApoC2 Gene Therapy: Reversal of Severe Hypertriglyceridemia and Rescue of Neonatal Death in ApoC2-Deficient Hamsters

Yang

Tian²,

Ma³

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Apolipoprotein C2 (ApoC2) is a key activator of lipoprotein lipase for plasma triglyceride metabolism. ApoC2-deficient patients present with severe hypertriglyceridemia and recurrent acute pancreatitis, for whom the only effective treatment is the infusion of normal plasma containing ApoC2. However, since ApoC2 has a fast catabolic rate, a repeated infusion is required, which limits its clinical use. To explore a safe and efficient approach for ApoC2 deficiency, we herein established an adeno-associated virus expressing human ApoC2 (AAV-hApoC2) to evaluate the efficacy and safety of gene therapy in ApoC2-deficient hypertriglyceridemic hamsters. Administration of AAV-hApoC2 via jugular or orbital vein in adult and neonatal ApoC2-deficient hamsters, respectively, could prevent the neonatal death and effectively improve severe hypertriglyceridemia of ApoC2-deficient hamsters without side effects in a long-term manner. Our novel findings in the present study demonstrate that AAV-hApoC2-mediated gene therapy will be a promising therapeutic approach for clinical patients with severe hypertriglyceridemia caused by ApoC2 deficiency.

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CRISPR/Cas9 Genome Editing for Tissue‐Specific In Vivo Targeting: Nanomaterials and Translational Perspective

et al. 2023

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Clustered randomly interspaced short palindromic repeats (CRISPRs) and its associated endonuclease protein, i.e., Cas9, have been discovered as an immune system in bacteria and archaea; nevertheless, they are now being adopted as mainstream biotechnological/molecular scissors that can modulate ample genetic and nongenetic diseases via insertion/deletion, epigenome editing, messenger RNA editing, CRISPR interference, etc. Many Food and Drug Administration‐approved and ongoing clinical trials on CRISPR adopt ex vivo strategies, wherein the gene editing is performed ex vivo, followed by reimplantation to the patients. However, the in vivo delivery of the CRISPR components is still under preclinical surveillance. This review has summarized the nonviral nanodelivery strategies for gene editing using CRISPR/Cas9 and its recent advancements, strategic points of view, challenges, and future aspects for tissue‐specific in vivo delivery of CRISPR/Cas9 components using nanomaterials.

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ApoC2 deficiency elicits severe hypertriglyceridemia and spontaneous atherosclerosis: A rodent model rescued from neonatal death

Cited by 22 publications

References 40 publications

Apolipoprotein C-II induces EMT to Promote Gastric Cancer Peritoneal Metastasis via PI3K/AKT/mTOR Pathway

Apolipoprotein C-II induces EMT to Promote Gastric Cancer Peritoneal Metastasis via PI3K/AKT/mTOR Pathway

AAV-Mediated ApoC2 Gene Therapy: Reversal of Severe Hypertriglyceridemia and Rescue of Neonatal Death in ApoC2-Deficient Hamsters

CRISPR/Cas9 Genome Editing for Tissue‐Specific In Vivo Targeting: Nanomaterials and Translational Perspective

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