NFE2 Induces miR-423-5p to Promote Gluconeogenesis and Hyperglycemia by Repressing the Hepatic FAM3A-ATP-Akt Pathway

Yang, Weili; Wang, Junpei; Chen, Zhenzhen; Chen, Ji; Meng, Yuhuan; Chen, Liming; Chang, Yongsheng; Geng, Bin; Sun, Libo; Dou, Lin; Li, Jian; Guan, Youfei; Cui, Qinghua; Yang, Jichun

doi:10.2337/db16-1172

Cited by 75 publications

(87 citation statements)

References 48 publications

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“…The sequences for the primers used for real time PCR are provided in supplemental Table 1. For the detection of the expression level of miR‐423‐5p, Bulge‐Loop real‐time RT‐PCR was performed as described previously …”

Section: Methodsmentioning

confidence: 99%

“…FAM3A is a new mitochondrial protein that enhances ATP production, while other members of FAM3 gene family are secretory proteins . FAM3A suppresses hepatic gluconeogenesis and lipogenesis by activating protein kinase B (Akt) and adenosine 5′‐monophosphate (AMP)‐activated protein kinase (AMPK) pathways, and a decrease in hepatic FAM3A expression causes fasting hyperglycemia and hepatic lipid deposition . FAM3A is a target gene of peroxisome proliferator‐activated receptor gamma (PPARγ), and it mediates the beneficial effects of PPARγ’s activation on liver ischemia/reperfusion injury .…”

Section: Introductionmentioning

confidence: 99%

“…11,14 FAM3A suppresses hepatic gluconeogenesis and lipogenesis by activating protein kinase B (Akt) and adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) pathways, and a decrease in hepatic FAM3A expression causes fasting hyperglycemia and hepatic lipid deposition. 12,13 FAM3A is a target gene of peroxisome proliferator-activated receptor gamma (PPARγ), and it mediates the beneficial effects of PPARγ's activation on liver ischemia/reperfusion injury. 15,16 Beyond liver, FAM3A also regulates the functions of vascular smooth muscular cells (VSMCs) and adipocytes by modulating ATP-Akt pathways.…”

Section: Introductionmentioning

confidence: 99%

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FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

et al. 2020

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So far, the mechanism that links mitochondrial dysfunction to PDX1 inhibition in the pathogenesis of pancreatic β cell dysfunction under diabetic condition remains largely unclear. This study determined the role of mitochondrial protein FAM3A in regulating PDX1 expression in pancreatic β cells using gain‐ and loss‐of function methods in vitro and in vivo. Within pancreas, FAM3A is highly expressed in β, α, δ, and pp cells of islets. Islet FAM3A expression was correlated with insulin expression under physiological and diabetic conditions. Mice with specific knockout of FAM3A in islet β cells exhibited markedly blunted insulin secretion and glucose intolerance. FAM3A‐deficient islets showed significant decrease in PDX1 expression, and insulin expression and secretion. FAM3A overexpression upregulated PDX1 and insulin expressions, and augmented insulin secretion in cultured islets and β cells. Mechanistically, FAM3A enhanced ATP production to elevate cellular Ca2+ level and promote insulin secretion. Furthermore, FAM3A‐induced ATP release activated CaM to function as a co‐activator of FOXA2, stimulating PDX1 gene transcription. In conclusion, FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic β cells. Inhibition of FAM3A will trigger mitochondrial dysfunction to repress PDX1 and insulin expressions.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

et al. 2020

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“…It inhibits tumour growth by inducing cell cycle arrest and apoptosis in the early stage of tumour formation. 7,8 It has been reported that Akt activation plays a critical role in TGFβ-promoted development of breast cancer. 3,4 Protein kinase B (Akt) is an important intracellular molecule that stimulates cell proliferation and inhibits apoptosis 5,6 beyond its roles in regulating glucose and lipid metabolism as the key molecule of insulin signalling transduction.…”

Section: Introductionmentioning

confidence: 99%

FAM3C‐YY1 axis is essential for TGFβ‐promoted proliferation and migration of human breast cancer MDA‐MB‐231 cells via the activation of HSF1

Yang

Feng

Meng

et al. 2019

J Cellular Molecular Medi

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Family with sequence similarity three member C (FAM3C) (interleukin‐like EMT inducer [ILEI]), heat shock factor 1 (HSF1) and Ying‐Yang 1 (YY1) have been independently reported to be involved in the pathogenesis of various cancers. However, whether they are coordinated to trigger the development of cancer remains unknown. This study determined the role and mechanism of YY1 and HSF1 in FAM3C‐induced proliferation and migration of breast cancer cells. In human MDA‐MB‐231 breast cancer cell line, transforming growth factor‐β (TGFβ) up‐regulated FAM3C, HSF1 and YY1 expressions. FAM3C overexpression promoted the proliferation and migration of MDA‐MB‐231 cells with YY1 and HSF1 up‐regulation, whereas FAM3C silencing exerted the opposite effects. FAM3C inhibition repressed TGFβ‐induced HSF1 activation, and proliferation and migration of breast cancer cells. YY1 was shown to directly activate HSF1 transcription to promote the proliferation and migration of breast cancer cells. YY1 silencing blunted FAM3C‐ and TGFβ‐triggered activation of HSF1‐Akt‐Cyclin D1 pathway, and proliferation and migration of breast cancer cells. Inhibition of HSF1 blocked TGFβ‐, FAM3C‐ and YY1‐induced proliferation and migration of breast cancer cells. YY1 and HSF1 had little effect on FAM3C expression. Similarly, inhibition of HSF1 also blunted FAM3C‐ and TGFβ‐promoted proliferation and migration of human breast cancer BT‐549 cells. In human breast cancer tissues, FAM3C, YY1 and HSF1 protein expressions were increased. In conclusion, FAM3C activated YY1‐HSF1 signalling axis to promote the proliferation and migration of breast cancer cells. Furthermore, novel FAM3C‐YY1‐HSF1 pathway plays an important role in TGFβ‐triggered proliferation and migration of human breast cancer MDA‐MB‐231 cells.

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“…Eight‐week‐old male C57BL/6 mice and 8‐ to 12‐week‐old male db/db and db/m (C57BKS background Jackson Laboratory, USA) were used in this study. 8‐10 week old male C57BL/6 mice were fed on 45% high fat diet (HFD) or normal diet (ND) for 12 weeks to induce diabetic and steatotic phenotype as detailed previously . 12‐ to 16‐ week old male db/db mice and db/m mice on BKS ground were also used in this study.…”

Section: Methodsmentioning

confidence: 99%

FAM3B (PANDER) functions as a co‐activator of FOXO1 to promote gluconeogenesis in hepatocytes

Chi

Meng

Wang

et al. 2018

J Cellular Molecular Medi

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FAM3B, also known as PANcreatic DERived factor (PANDER), promotes gluconeogenesis and lipogenesis in hepatocytes. However, the underlying mechanism(s) still remains largely unclear. This study determined the mechanism of PANDER‐induced FOXO1 activation in hepatocytes. In mouse livers and cultured hepatocytes, PANDER protein is located in both the cytoplasm and nucleus. Nuclear PANDER distribution was increased in the livers of obese mice. In cultured mouse and human hepatocytes, PANDER was co‐localized with FOXO1 in the nucleus. PANDER directly interacted with FOXO1 in mouse and human hepatocytes. PANDER overexpression enhanced PANDER‐FOXO1 interaction, and detained FOXO1 in the nucleus upon insulin stimulation in hepatocytes. With the increase in PANDER‐FOXO1 interaction, PANDER overexpression upregulated the expression of gluconeogenic genes and promoted gluconeogenesis in both human and mouse hepatocytes. Luciferase reporter assays further revealed that PANDER augmented the transcriptional activity of FOXO1 on gluconeogenic genes. Moreover, PANDER overexpression also interfered the binding of AS1842856, a specific FOXO1 inhibitor, with FOXO1, and impaired its inhibitory effects on gluconeogenic gene expression and gluconeogenesis in hepatocytes. siRNA mediated‐silencing of FOXO1 inhibited PANDER‐promoted gluconeogenic gene expression and glucose production in hepatocytes. In conclusion, PANDER protein is abundantly present in the nucleus, where it functions as a new co‐activator of FOXO1 to induce gluconeogenic gene expression in hepatocytes.

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NFE2 Induces miR-423-5p to Promote Gluconeogenesis and Hyperglycemia by Repressing the Hepatic FAM3A-ATP-Akt Pathway

Cited by 75 publications

References 48 publications

FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

FAM3C‐YY1 axis is essential for TGFβ‐promoted proliferation and migration of human breast cancer MDA‐MB‐231 cells via the activation of HSF1

FAM3B (PANDER) functions as a co‐activator of FOXO1 to promote gluconeogenesis in hepatocytes

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