Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states

Kang, Hye Suk; Cho, Ho Chan; Lee, Jae Ho; Oh, Goo Taeg; Koo, Seung Hoi; Park, Byung Hyun; Lee, In Kyu; Choi, Hueng Sik; Song, Dong Hyun; Im, Seung Soon

doi:10.1038/srep23665

Cited by 39 publications

(37 citation statements)

References 42 publications

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“…Mouse primary hepatocytes were isolated from WT and Pparα -null mice as described previously 24 . Briefly, isolated primary hepatocytes were cultured in Dulbecco’s modified Eagle’s medium (DMEM; Invitrogen, Carlsbad, CA, USA) containing 10% heat-inactivated FBS, 100 units/ml penicillin G, 100 μg/ml streptomycin, 10 μM dexamethasone, 100 nM insulin, and 25 mM glucose.…”

Section: Methodsmentioning

confidence: 99%

PPARα-dependent Insig2a overexpression inhibits SREBP-1c processing during fasting

Lee

Kang

Park

et al. 2017

Sci Rep

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Peroxisome-proliferator-activated receptor alpha (PPARα) and sterol regulatory element-binding protein (SREBP) play a role in regulating cellular fatty acid and cholesterol homeostasis via fatty acid oxidation and lipogenesis. The control of SREBP processing is regulated by the insulin induced gene (INSIG)2a protein, which binds SREBP to prevent SREBP translocation to the Golgi apparatus during nutrient starvation in the liver. However, the regulation of SREBP-1c processing by INSIGs during fasting and the regulatory mechanisms of the mouse Insig2a gene expression have not been clearly addressed. In the present study, we found that Insig2a was upregulated by PPARα in mouse livers and primary hepatocytes during fasting, whereas Insig2a mRNA expression was decreased in the livers of refed mice. A PPAR-responsive element between −126 bp and −114 bp in the Insig2a promoter was identified by a transient transfection assay and a chromatin immunoprecipitation assay; its role in regulation by PPARα was characterised using Pparα-null mice. These results suggest that PPARα is a trans-acting factor that enhances Insig2a gene expression, thereby suppressing SREBP-1c processing during fasting.

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Section: Methodsmentioning

confidence: 99%

PPARα-dependent Insig2a overexpression inhibits SREBP-1c processing during fasting

Lee

Kang

Park

et al. 2017

Sci Rep

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“…The PPARα response element (PPRE) was identified on a mouse IGFBP-2 promoter, indicating that IGFBP-2 is a direct target of PPARα. Moreover, mRNA expression of the IGFBP-2 gene is activated by metformin, which is an antidiabetic drug for patients with diabetes and obesity, and the serum level of IGFBP-2 is stimulated in metformin-challenged diabetic patients [10]. A recent study in humans suggested that the circulating concentration of IGFBP-2 is associated with metabolic syndrome, including insulin resistance and obesity [1112].…”

Section: Transcriptional Regulation Of Igfbp-2mentioning

confidence: 99%

“…Production of IGFBP-2 is decreased in obese people compared with nonobese individuals, and concentrations of serum IGFBP-2 decrease with increasing body mass index [13]. Several reports have demonstrated that circulating IGFBP-2 concentrations are lower in patients with type 2 diabetes mellitus or obesity [1031]. Because overexpression of IGFBP-2 leads to recovered blood glucose levels in diabetic animal models, and because the antidiabetic drug, metformin, can recover serum IGFBP-2 levels in diabetic patients [10], decreased IGFBP-2 levels may lead to the development of diabetes in humans.…”

Section: Clinical Relevance Of Igfbp-2 Levels In Human Serummentioning

confidence: 99%

“…Several reports have demonstrated that circulating IGFBP-2 concentrations are lower in patients with type 2 diabetes mellitus or obesity [1031]. Because overexpression of IGFBP-2 leads to recovered blood glucose levels in diabetic animal models, and because the antidiabetic drug, metformin, can recover serum IGFBP-2 levels in diabetic patients [10], decreased IGFBP-2 levels may lead to the development of diabetes in humans. Thus, IGFBP-2 may be useful as a biomarker of metabolic disease.…”

Section: Clinical Relevance Of Igfbp-2 Levels In Human Serummentioning

confidence: 99%

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Recent Insights into Insulin-Like Growth Factor Binding Protein 2 Transcriptional Regulation

et al. 2017

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Insulin-like growth factor binding proteins (IGFBPs) are major regulators of insulin-like growth factor bioavailability and activity in metabolic signaling. Seven IGFBP family isoforms have been identified. Recent studies have shown that IGFBPs play a pivotal role in metabolic signaling and disease, including the pathogenesis of obesity, diabetes, and cancer. Although many studies have documented the various roles played by IGFBPs, transcriptional regulation of IGFBPs is not well understood. In this review, we focus on the regulatory mechanisms of IGFBP gene expression, and we summarize the findings of transcription factor activity in the IGFBP promoter region.

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“…PPARα, a molecular target of resveratrol [39], participates in the promotion of adipocyte differentiation, the modulation of nutritional metabolism, and the inhibition of in ammatory response [40,41]. Previous study showed that resveratrol increased the levels of sirtuin-1 (SIRT1) and PPARα to mediate its protective effect on hypertension under maternal high-fat diet in the kidneys of male progeny [42].…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Attenuates High-Fat Diet Induced Hepatic Lipid Homeostasis Disorder and Decreases m6A RNA Methylation

et al. 2020

Preprint

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Purpose: N 6 -methyladenosine (m6A) mRNA methylation is affected by dietary factors and associated with lipid metabolism, however, whether the regulatory role of resveratrol in lipid metabolism is involved in m6A mRNA methylation remain unknown. Here, the objective of this study was to investigate the effect of resveratrol on hepatic lipid metabolism and m6A RNA methylation in the liver of mice.Methods: A total of 24 male mice were randomly allocated to LFD (low-fat diet), LFDR (low-fat diet + resveratrol), HFD (high-fat diet), and HFDR (high-fat diet + resveratrol) groups for 12 weeks (n = 6/group).Results: Compared to the HFD group, dietary resveratrol supplementation reduced the body weight, relative abdominal, epididymal, and perirhemtric fat weight, however, significantly increased average daily feed intake in mice given high-fat diet. The amounts of serum low density lipoprotein cholesterol (LDL), liver total cholesterol (TC), triacylglycerol (TAG) were significantly decreased by resveratrol supplementation. In addition, Resveratrol significantly enhanced the levels of peroxisome proliferator-activated receptor alpha (PPARα), peroxisome proliferator-activated receptor beta/delta (PPARβ/δ), cytochrome P450 family 4 subfamily a polypeptide 10/14 (CYP4A10/14), acyl-CoA oxidase 1 (ACOX1), and fatty acid-binding protein 4 (FABP4) mRNA, and inhibited acyl-CoA carboxylase (ACC) mRNA levels in the liver. Furthermore, the resveratrol in high-fat diet increased the transcript levels of methyltransferase like 3 (METTL3), alkB homolog 5 (ALKBH5), fat mass and obesity associated protein (FTO), and YTH domain family 2 (YTHDF2), whereas decreased the level of YTH domain family 3 (YTHDF3) and m6A abundance in mice liver.Conclusion: The beneficial effect of resveratrol on lipid metabolism disorder under high-fat diet may be due to decrease of m6A RNA methylation and increase of PPARα mRNA, providing mechanistic insights into the function of resveratrol in alleviating the disturbance of lipid metabolism in mice.

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Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states

Cited by 39 publications

References 42 publications

PPARα-dependent Insig2a overexpression inhibits SREBP-1c processing during fasting

PPARα-dependent Insig2a overexpression inhibits SREBP-1c processing during fasting

Recent Insights into Insulin-Like Growth Factor Binding Protein 2 Transcriptional Regulation

Resveratrol Attenuates High-Fat Diet Induced Hepatic Lipid Homeostasis Disorder and Decreases m6A RNA Methylation

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