Hepatic TET3 contributes to type-2 diabetes by inducing the HNF4α fetal isoform

Li, Da; Cao, Tiefeng; Sun, Xiangrong; Jin, Sung‐Ho; Xie, Di; Huang, Xinmei; Yang, Xiaoyong; Carmichael, Gordon G.; Taylor, Hugh S.; Diano, Sabrina; Huang, Yingqun

doi:10.1038/s41467-019-14185-z

Cited by 29 publications

(16 citation statements)

References 44 publications

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“…However, TLB effectively enhanced the glucose tolerance of KK-Ay mice. Likewise, ITT is implemented to test the body's sensitivity to exogenous insulin (Da et al, 2020). The results showed that KK-Ay mice had a low sensitivity to exogenous insulin, that is why the mice kept a high level of blood glucose after injection of recombinant human insulin, in keeping with the previous studies (Ogiwara et al, 2018).…”

Section: Discussionsupporting

confidence: 66%

Trilobatin, a Natural Food Additive, Exerts Anti-Type 2 Diabetes Effect Mediated by Nrf2/ARE and IRS-1/GLUT2 Signaling Pathways

et al. 2022

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Oxidative stress and aberrant insulin signaling transduction play vital roles in type 2 diabetes mellitus (T2DM). Our previous research has demonstrated that trilobatin (TLB), derived from the leaves of Lithocarpus Polystachyus (Wall.), exhibits a potent antioxidative profile. In the current study, we investigated the anti-T2DM effect of TLB on KK-Ay diabetic mice and further explored the potential mechanisms. Our results showed that TLB significantly reduced the high fasting blood glucose level and insulin resistance and promoted the tolerances to exogenous glucose and insulin in KK-Ay mice. Moreover, TLB reduced the content of reactive oxygen species; enhanced antioxidant enzymes activities, including serum catalase, glutathione peroxidase, and superoxide dismutase; and regulated the abnormal parameters of lipid metabolism, including triglyceride, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and free fatty acid, as evidenced by enzyme-linked immunosorbent assay. Additionally, TLB markedly ameliorated the pancreatic islet morphology near normal and increased the insulin expression of the islet. Whereafter, TLB promoted Nrf2 that was translocated from cytoplasm to nucleus. Moreover, it increased the protein expressions of HO-1, NQO-1, and GLUT-2, and phosphorylation levels of Akt and GSK-3βSer 9 and decreased the protein expressions of keap1 and phosphorylation levels of IRS-1Ser 307 and GSK-3βTyr 216. Taken together, our findings reveal that TLB exhibits an anti-T2DM effect in KK-Ay mice by activating the Nrf2/ARE signaling pathway and regulating insulin signaling transduction pathway, and TLB is promising to be developed into a novel candidate for the treatment of T2DM in clinic due to its favorable druggability.

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Section: Discussionsupporting

confidence: 66%

Trilobatin, a Natural Food Additive, Exerts Anti-Type 2 Diabetes Effect Mediated by Nrf2/ARE and IRS-1/GLUT2 Signaling Pathways

et al. 2022

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“…Interestingly, two new studies in mice showed that increased translation of two proteins in the liver, TET3 and HNF4a, results in increased production of blood glucose and insulin. Specifically, it was shown that abnormal protein signaling of TET3 contributes to the development of fibrosis in the liver [185,186]. Based on these data it has been proposed that targeting the TET3 and HNF4a proteins could reverse type-2 diabetes and liver fibrosis.…”

Section: The Mtorc1 Signaling Pathway In Metabolic and Inflammatory Dmentioning

confidence: 99%

Translation Regulation by eIF2α Phosphorylation and mTORC1 Signaling Pathways in Non-Communicable Diseases (NCDs)

Rios-Fuller

Mahé

Walters

et al. 2020

IJMS

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Non-communicable diseases (NCDs) are medical conditions that, by definition, are non-infectious and non-transmissible among people. Much of current NCDs are generally due to genetic, behavioral, and metabolic risk factors that often include excessive alcohol consumption, smoking, obesity, and untreated elevated blood pressure, and share many common signal transduction pathways. Alterations in cell and physiological signaling and transcriptional control pathways have been well studied in several human NCDs, but these same pathways also regulate expression and function of the protein synthetic machinery and mRNA translation which have been less well investigated. Alterations in expression of specific translation factors, and disruption of canonical mRNA translational regulation, both contribute to the pathology of many NCDs. The two most common pathological alterations that contribute to NCDs discussed in this review will be the regulation of eukaryotic initiation factor 2 (eIF2) by the integrated stress response (ISR) and the mammalian target of rapamycin complex 1 (mTORC1) pathways. Both pathways integrally connect mRNA translation activity to external and internal physiological stimuli. Here, we review the role of ISR control of eIF2 activity and mTORC1 control of cap-mediated mRNA translation in some common NCDs, including Alzheimer’s disease, Parkinson’s disease, stroke, diabetes mellitus, liver cirrhosis, chronic obstructive pulmonary disease (COPD), and cardiac diseases. Our goal is to provide insights that further the understanding as to the important role of translational regulation in the pathogenesis of these diseases.

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“…The evolutionarily conserved transcription factor hepatocyte nuclear factor 4 alpha (HNF4α) plays an important role in promoting hepatic glucose production and regulating energy balance [ 13 ]. In a previous study, Huang and associates reported that the DNA demethylase TET3 binds to and demethylates the P2 promoter of HNF4α, leading to increased transcription of the P2 isoform of HNF4α (known as HNF4α-P2) and a consequently abnormally augmented hepatic glucose production that underlies the chronic hyperglycemia in type 2 diabetes [ 14 ]. More recently, the same group, using mouse models and human primary hepatocytes, demonstrated that metformin, at clinically relevant doses, suppresses hepatic glucose production by activating a conserved regulatory pathway encompassing let-7, TET3, and HNF4α-P2 [ 15 ].…”

Section: Novel Molecular Targets Involved In Glycemic Controlmentioning

confidence: 99%

Molecular mechanisms of action of metformin: latest advances and therapeutic implications

Zhu

Jia

et al. 2023

Clin Exp Med

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Metformin is among the most widely used antidiabetic drugs. Studies over the past few years have identified multiple novel molecular targets and pathways that metformin acts on to exert its beneficial effects in treating type 2 diabetes as well as other disorders involving dysregulated inflammation and redox homeostasis. In this mini-review, we discuss the latest cuttingedge research discoveries on novel molecular targets of metformin in glycemic control, cardiovascular protection, cancer intervention, anti-inflammation, antiaging, and weight control. Identification of these novel targets and pathways not only deepens our understanding of the molecular mechanisms by which metformin exerts diverse beneficial biological effects, but also provides opportunities for developing new mechanistically based drugs for human diseases.

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Hepatic TET3 contributes to type-2 diabetes by inducing the HNF4α fetal isoform

Cited by 29 publications

References 44 publications

Trilobatin, a Natural Food Additive, Exerts Anti-Type 2 Diabetes Effect Mediated by Nrf2/ARE and IRS-1/GLUT2 Signaling Pathways

Trilobatin, a Natural Food Additive, Exerts Anti-Type 2 Diabetes Effect Mediated by Nrf2/ARE and IRS-1/GLUT2 Signaling Pathways

Translation Regulation by eIF2α Phosphorylation and mTORC1 Signaling Pathways in Non-Communicable Diseases (NCDs)

Molecular mechanisms of action of metformin: latest advances and therapeutic implications

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