Atorvastatin induces MicroRNA-145 expression in HEPG2 cells via regulation of the PI3K/AKT signalling pathway

Docrat, Taskeen; Nagiah, Savania; Anand, Krishnan; Naidoo, Dhaneshree Bestinee; Chuturgoon, Anil A.

doi:10.1016/j.cbi.2018.04.005

Cited by 26 publications

(16 citation statements)

References 63 publications

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“…Hinoi et al (58) found that the PI3K/Akt pathway could indirectly promote the nuclear translocation of PGC1α, which serves crucial roles in FA oxidation. Consistent with a previous study (59), the livers of HFD-fed hamsters in the present study exhibited a significant reduction in AMPK phosphorylation levels compared with the control group. Akt phosphorylation, as well as PPARα and PGC1α protein expression levels were also reduced in the model group compared with the control.…”

Section: Discussionsupporting

confidence: 93%

Atorvastatin promotes AMPK signaling to protect against high fat diet‑induced non‑alcoholic fatty liver in golden hamsters

Zhang

et al. 2020

Exp Ther Med

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Non-alcoholic fatty liver disease (NAFLD) is characterized by diffuse fatty acid degeneration and excess fat accumulation in the liver. Notably, the currently available medications used to treat NAFLD remain limited. The aim of the present study was to investigate the protective role of atorvastatin (Ato) against NAFLD in golden hamsters fed a high fat diet (HFD) and in HepG2 cells treated with palmitate, and identify the underlying molecular mechanism. Ato (3 mg/kg) was administered orally every day for 8 weeks to the hamsters during HFD administration. Hamsters in the model group developed hepatic steatosis with high serum levels of triglyceride, cholesterol, insulin and C-reactive protein, which were effectively reduced by treatment with Ato. Additionally, the relative liver weight of hamsters treated with Ato was markedly lower compared with that of the model group. Hematoxylin and eosin, and oil red O staining indicated that the livers of the animals in the model group exhibited large and numerous lipid droplets, which were markedly decreased after Ato treatment. Western blot analysis indicated that Ato inhibited fat accumulation in the liver through the AMP-activated protein kinase (AMPK)-dependent activation of peroxisome proliferator activated receptor α (PPARα), peroxisome proliferator-activated receptor-γ coactivator 1 α and their target genes. Furthermore, in vitro, Ato inhibited PA-induced lipid accumulation in HepG2 cells. This inhibitory effect was attenuated following Compound C treatment, indicating that AMPK may be a potential target of Ato. In conclusion, the increase in AMPK-mediated PPARα and its target genes may represent a novel molecular mechanism by which Ato prevents NAFLD.

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Section: Discussionsupporting

confidence: 93%

Atorvastatin promotes AMPK signaling to protect against high fat diet‑induced non‑alcoholic fatty liver in golden hamsters

Zhang

et al. 2020

Exp Ther Med

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“…[ 20 ] MiR-145 is correlated with the progression of various cancers by regulating the expression of multiple target genes, especially a number of genes that regulate angiogenesis and proliferation. [ 21 – 23 ] Our previous work showed that the expression of miR-145 was significantly lower in UM tissues than normal uveal samples. Overexpression of miR-145 suppressed cell proliferation by blocking cells in G1 phase from entering S phase and promoted cell apoptosis in UM cells.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-145 suppresses uveal melanoma angiogenesis and growth by targeting neuroblastoma RAS viral oncogene homolog and vascular endothelial growth factor

Yang

Wang

et al. 2020

Chinese Medical Journal

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Background Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. It has been demonstrated that microRNA-145 (miR-145) is correlated with the progression of various cancers by regulating the expression of multiple target genes, especially a number of genes that regulate angiogenesis and proliferation. However, the underlying mechanisms of miR-145 in tumor angiogenesis of UM are still not well illustrated. Thus, we aimed to explore the potential target genes or pathways regulated by miR-145 in UM and the effect of miR-145 on invasion and angiogenesis. Methods Totally, 24 choroid samples were collected in our study, including 12 UM samples and 12 normal uveal tissues. The expression of neuroblastoma RAS viral oncogene homolog (N-RAS), phosphorylated protein kinase B (p-AKT), and vascular endothelial growth factor (VEGF) in UM tissues and normal uveal tissues was analyzed using Western blotting analysis. Lentivirus expression system was used to construct MUM-2B and OCM-1 cell lines with stable overexpression of miR-145. Transwell and endothelial cell tube formation assay were used to measure the effects of miR-145 on the invasion and angiogenesis of UM in vitro . The downstream target genes of miR-145 were predicted by bioinformatics and confirmed using a luciferase assay. BALB/c nude mice models were established to investigate the mechanisms of miR-145 on tumor growth and angiogenesis in vivo . Group data comparisons were performed using analysis of Student's t test. A two-tailed P < 0.05 was considered as statistically significant. Results The results of Western blotting analysis indicated that the expressions of N-RAS (1.10 ± 0.35 vs. 0.41 ± 0.36, t = 3.997, P = 0.012), p-AKT (1.16 ± 0.22 vs. 0.57 ± 0.03, t = 7.05, P = 0.001), and VEGF (0.97 ± 0.32 vs. 0.45 ± 0.21, t = 3.314, P = 0.008) in UM tumor tissues were significantly higher than those in normal uveal tissue. Luciferase assay demonstrated N-RAS and VEGF as downstream targets of miR-145. Moreover, tube formation assay revealed that miR-145-transfected human microvascular endothelial cell line formed shorter tube length (36.10 ± 1.51 mm vs. 42.91 ± 0.94 mm, t = 6.603, P = 0.003) and less branch points (350.00 ± 19.97 vs. 406.67 ± 17.62, t = 3.685, P = 0.021) as compared with controls. In addition, the numbers of invaded MUM-2B and OCM-1 cells with miR-145 overexpression were significantly lower than the controls (35.7 ± 3.3 ...

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“…It has been described that expression levels of IRS1 are modulated by miR-145 in hepatocytes [158] whereas in mice, upregulation of miR-145 in the liver leads to insulin resistance [159]. Atorvastatin treatment has also been shown to differentially upregulate miR-145 and modulates PI3K/Akt signaling pathway [160].…”

Section: Modulation Of the Insulin Signaling Pathwaymentioning

confidence: 99%

Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights

Galicia-García

Jebari

Larrea-Sebal

et al. 2020

IJMS

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Statins are the gold-standard treatment for the prevention of primary and secondary cardiovascular disease, which is the leading cause of mortality worldwide. Despite the safety and relative tolerability of statins, observational studies, clinical trials and meta-analyses indicate an increased risk of developing new-onset type 2 diabetes mellitus (T2DM) after long-term statin treatment. It has been shown that statins can impair insulin sensitivity and secretion by pancreatic β-cells and increase insulin resistance in peripheral tissues. The mechanisms involved in these processes include, among others, impaired Ca2+ signaling in pancreatic β-cells, down-regulation of GLUT-4 in adipocytes and compromised insulin signaling. In addition, it has also been described that statins’ impact on epigenetics may also contribute to statin-induced T2DM via differential expression of microRNAs. This review focuses on the evidence and mechanisms by which statin therapy is associated with the development of T2DM. This review describes the multifactorial combination of effects that most likely contributes to the diabetogenic effects of statins. Clinically, these findings should encourage clinicians to consider diabetes monitoring in patients receiving statin therapy in order to ensure early diagnosis and appropriate management.

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Atorvastatin induces MicroRNA-145 expression in HEPG2 cells via regulation of the PI3K/AKT signalling pathway

Cited by 26 publications

References 63 publications

Atorvastatin promotes AMPK signaling to protect against high fat diet‑induced non‑alcoholic fatty liver in golden hamsters

Atorvastatin promotes AMPK signaling to protect against high fat diet‑induced non‑alcoholic fatty liver in golden hamsters

MicroRNA-145 suppresses uveal melanoma angiogenesis and growth by targeting neuroblastoma RAS viral oncogene homolog and vascular endothelial growth factor

Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights

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