IGF1 suppresses cholesterol accumulation in the liver of growth hormone-deficient mice via the activation of ABCA1

Fukunaga, Kohji; Imachi, Hitomi; Lyu, Jingya; Dong, Tao; Sato, Seisuke; Ibata, Tomohiro; Kobayashi, Toshihiro; Yoshimoto, Takuo; Yonezaki, Kazuko; Matsunaga, Toru; Murao, Koji

doi:10.1152/ajpendo.00134.2018

Cited by 20 publications

(20 citation statements)

References 48 publications

(62 reference statements)

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“…Thus, ABCA1 has a beneficial effect to protect the liver from cholesterol accumulation. This is also confirmed by our recent study that the upregulation of hepatic ABCA1 expression by insulin-like growth factor-1 (IGF-1) or glucagon-like peptide-1 (GLP-1) reduced hepatic cholesterol accumulation in mice [19,20]. In this study, hepatic ABCA1 expression was elevated by 2-ME 2 , which contributed to the reduction of the lipid content in hepatocytes.…”

Section: Discussionsupporting

confidence: 87%

“…As a cholesterol exporter, ABCA1 exports intracellular cholesterol to HDL in the presence of ApoA-I. Our previous study showed that the upregulation of hepatic ABCA1 induced by insulin-like growth factor-1 (IGF-1) or glucagon-like peptide-1 (GLP-1) decreased the lipid content in HepG2 cells [19,20]. In this study, we demonstrated that 2-ME 2 significantly reduced the cholesterol content to 78 ± 6% of that in the control group.…”

Section: -Me 2 Reduces Lipid Content Via the Pi3k Pathway In Hepg2 Cellsmentioning

confidence: 99%

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Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells

et al. 2022

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ATP-binding cassette transporter A1 (ABCA1) is a key regulator of lipid efflux, and the absence of ABCA1 induces hepatic lipid accumulation, which is one of the major causes of fatty liver. 2-Methoxyestradiol (2-ME2) has been demonstrated to protect against fatty liver. In this study, we investigated the effects of 2-ME2 on the hepatic lipid content and ABCA1 expression. We found that 2-ME2 dose-dependently increased ABCA1 expression, and therefore, the lipid content was significantly decreased in HepG2 cells. 2-ME2 enhanced the ABCA1 promoter activity; however, this effect was reduced after the inhibition of the PI3K pathway. The overexpression of Akt or p110 induced ABCA1 promoter activity, while dominant-negative Akt diminished the ability of 2-ME2 on ABCA1 promoter activity. Further, 2-ME2 stimulated the rapid phosphorylation of Akt and FoxO1 and reduced the nuclear accumulation of FoxO1. Chromatin immunoprecipitation confirmed that FoxO1 bonded to the ABCA1 promoter region. The binding was reduced by 2-ME2, which facilitated ABCA1 gene transcription. Furthermore, mutating FoxO1-binding sites in the ABCA1 promoter region or treatment with FoxO1-specific siRNA disrupted the effect of 2-ME2 on ABCA1 expression. All of our results demonstrated that 2-ME2 might upregulate ABCA1 expression via the PI3K/Akt/FoxO1 pathway, which thus reduces the lipid content in hepatocytes.

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Section: Discussionsupporting

confidence: 87%

Section: -Me 2 Reduces Lipid Content Via the Pi3k Pathway In Hepg2 Cellsmentioning

confidence: 99%

Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells

et al. 2022

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“…Another study reports that the cAMP-specific inhibitor PDE4 can increase cholesterol efflux by activating ABCA1 expression in human THP-1 and mouse J774.A1 macrophages [ 48 ]. Constitutively active AKT can enhance the promoter activity of ABCA1, and the specific inhibitor PI3K LY294002 has been reported to down-regulate the expression of ABCA1 in mice [ 49 ]. In MC3T3-E1 cells, Liraglutide, an agonist of GLP-1R, has been shown to promote cell proliferation and inhibit cell apoptosis by activating the expression of PI3K/AKT and cAMP/PKA signaling pathways [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Geniposide Ameliorated Dexamethasone-Induced Cholesterol Accumulation in Osteoblasts by Mediating the GLP-1R/ABCA1 Axis

Zheng

Xiao

Zhang

et al. 2021

Cells

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Background: Overexposure to glucocorticoid (GC) produces various clinical complications, including osteoporosis (OP), dyslipidemia, and hypercholesterolemia. Geniposide (GEN) is a natural iridoid compound isolated from Eucommia ulmoides. Our previous study found that GEN could alleviate dexamethasone (DEX)-induced differentiation inhibition of MC3T3-E1 cells. However, whether GEN protected against Dex-induced cholesterol accumulation in osteoblasts was still unclear. Methods: DEX was used to induce rat OP. Micro-CT data was obtained. The ALP activity and mineralization were determined by the staining assays, and the total intracellular cholesterol was determined by the ELISA kits. The protein expression was detected by western blot. Results: GEN ameliorated Dex-induced micro-structure damages and cell differentiation inhibition in the bone trabecula in rats. In MC3T3-E1 cells, Dex enhanced the total intracellular cholesterol, which reduced the activity of cell proliferation and differentiation. Effectively, GEN decreased DEX-induced cholesterol accumulation, enhanced cell differentiation, and upregulated the expression of the GLP-1R/ABCA1 axis. In addition, inhibition of ABAC1 expression reversed the actions of GEN. Treatment with Exendin9-39, a GLP-1R inhibitor, could abrogate the protective activity of GEN. Conclusions: GEN ameliorated Dex-induced accumulation of cholesterol and inhibition of cell differentiation by mediating the GLP-1R/ABCA1 axis in MC3T3-E1 cells.

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“…Purified pABCA1-LUC was transfected into INS-1 by reagent Lipofectamine2000 (Life Technologies, Gaithersburg, MD, USA). After transfection, cells were maintained in a medium containing HDL or OxLDL for 24 h with or without pre-treatment with LY294002 (10 μM), PD98095 (10 μM), SP600125 (10 μM), or SB203580 (1 μM) to separately inhibit the phosphatidylinositol 3 kinase (PI3K), mitogen-activated protein kinase (MEK), c-Jun N-terminal kinase (JNK), or p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway for 30 min [ 24 ]. Then these cells were lysed by buffer, and the ABCA1 promoter activity was measured according to the manufacturer’s instructions (ToyoInk; Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

Oxidized LDL Downregulates ABCA1 Expression via MEK/ERK/LXR Pathway in INS-1 Cells

et al. 2021

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Impaired insulin secretion is one of the main causes of type 2 diabetes. Cholesterol accumulation-induced lipotoxicity contributes to impaired insulin secretion in pancreatic beta cells. However, the detailed mechanism in this process remains unclear. In this study, we proved that oxidized low-density lipoprotein (OxLDL) reduced insulin content, decreased PDX-1 expression, and impaired glucose-stimulated insulin secretion (GSIS) in INS-1 cells, which were rescued by addition of high-density lipoprotein (HDL). OxLDL receptors and cholesterol content were increased by OxLDL. Consistently, OxLDL suppressed cholesterol transporter ABCA1 expression and transcription in a dose-dependent and time-dependent manner. Inhibition of MEK by its specific inhibitor, PD98059, altered the effect of OxLDL on ABCA1 transcription and activation of ERK. Next, chromatin immunoprecipitation assay demonstrated that liver X receptor (LXR) could directly bind to ABCA1 promoter and this binding was inhibited by OxLDL. Furthermore, OxLDL decreased the nuclear LXR expression, which was prevented by HDL. LXR-enhanced ABCA1 transcription was suppressed by OxLDL, and the effect was cancelled by mutation of the LXR-binding sites. In summary, our study shows that OxLDL down-regulates ABCA1 expression by MEK/ERK/LXR pathway, leading to cholesterol accumulation in INS-1 cells, which may result in impaired insulin synthesis and GSIS.

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IGF1 suppresses cholesterol accumulation in the liver of growth hormone-deficient mice via the activation of ABCA1

Cited by 20 publications

References 48 publications

Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells

Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells

Geniposide Ameliorated Dexamethasone-Induced Cholesterol Accumulation in Osteoblasts by Mediating the GLP-1R/ABCA1 Axis

Oxidized LDL Downregulates ABCA1 Expression via MEK/ERK/LXR Pathway in INS-1 Cells

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