Enhanced glucose tolerance in pancreatic derived factor (PANDER) knockout C57BL/6 mice

Moak, Shari L.; Dougan, Grace C.; MarElia, Catherine B.; Danse, Whitney A.; Fernandez, Aurora; Kuehl, Melanie N.; Athanason, Mark G.; Burkhardt, Brant R.

doi:10.1242/dmm.016402

Cited by 17 publications

(15 citation statements)

References 34 publications

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“…FAM3A plays important roles in regulation of hepatic and glucose metabolism via ATP-P2 receptor-mediated activation of Akt pathways independent of insulin (7). FAM3B (PANDER) exerts deleterious effects on pancreatic b-cell function (9,10) and hepatic insulin signaling (11)(12)(13)(14). To date, FAM3C, also known as interleukin-like epithelial-mesenchymal transition (EMT) inducer (ILEI), has been reported to be important in embryonic development, EMT, and the progression of some cancers (15)(16)(17).…”

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confidence: 99%

Hepatic Activation of the FAM3C-HSF1-CaM Pathway Attenuates Hyperglycemia of Obese Diabetic Mice

et al. 2017

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FAM3C is a member of the family with sequence similarity 3 (FAM3) gene family, and this study determined its role and mechanism in regulation of hepatic glucose/lipid metabolism. In obese diabetic mice, FAM3C expression was reduced in the liver, and hepatic FAM3C restoration improved insulin resistance, hyperglycemia, and fatty liver. FAM3C overexpression increased the expression of heat shock factor 1 (HSF1), calmodulin (CaM), and phosphorylated protein kinase B (Akt) and reduced that of gluconeogenic and lipogenic genes in diabetic mouse livers with the suppression of gluconeogenesis and lipid deposition. In cultured hepatocytes, FAM3C overexpression upregulated HSF1 expression, which elevated CaM protein level by inducing CALM1 transcription to activate Akt in a Ca- and insulin-independent manner. Furthermore, FAM3C overexpression promoted nuclear exclusion of FOXO1 and repressed gluconeogenic gene expression and gluconeogenesis in a CaM-dependent manner in hepatocytes. Hepatic HSF1 overexpression activated the CaM-Akt pathway to repress gluconeogenic and lipogenic gene expression and improve hyperglycemia and fatty liver in obese diabetic mice. In conclusion, the FAM3C-HSF1-CaM-Akt pathway plays important roles in regulating glucose and lipid metabolism in hepatocytes independent of insulin and calcium. Restoring hepatic FAM3C expression is beneficial for the management of type 2 diabetes and fatty liver.

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confidence: 99%

Hepatic Activation of the FAM3C-HSF1-CaM Pathway Attenuates Hyperglycemia of Obese Diabetic Mice

et al. 2017

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“…PANDER-deficient mouse livers exhibited lower hepatic TG content than wild type mice. Moreover, PANDER-deficient mice also had higher hepatic pAkt and pAMPK levels than wild type mice [114]. Inhibition of PANDER expression has been proposed to mediate the beneficial effects of aerobic swimming training on steatosis in obese mice [115].…”

Section: Liver-derived Pander In Glucose and Lipid Metabolismmentioning

confidence: 99%

“…It is likely that insulin resistance, inhibition of AMPK activity and upregulation of PPARγ also contribute to PANDER-induced lipid deposition in the liver [111,112,114]. Wilson et al reported a secretory form of PANDER in the medium of cultured hepatocytes with PANDER overexpression [112].…”

Section: Liver-derived Pander In Glucose and Lipid Metabolismmentioning

confidence: 99%

FAM3 gene family: A promising therapeutical target for NAFLD and type 2 diabetes

et al. 2018

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Non-alcoholic fatty liver disease (NAFLD) and diabetes are severe public health issues worldwide. The Family with sequence similarity 3 (FAM3) gene family consists of four members designated as FAM3A, FAM3B, FAM3C and FAM3D, respectively. Recently, there had been increasing evidence that FAM3A, FAM3B and FAM3C are important regulators of glucose and lipid metabolism. FAM3A expression is reduced in the livers of diabetic rodents and NAFLD patients. Hepatic FAM3A restoration activates ATP-P2 receptor-Akt and AMPK pathways to attenuate steatosis and hyperglycemia in obese diabetic mice. FAM3C expression is also reduced in the liver under diabetic condition. FAM3C is a new hepatokine that activates HSF1-CaM-Akt pathway and represses mTOR-SREBP1-FAS pathway to suppress hepatic gluconeogenesis and lipogenesis. In contrast, hepatic expression of FAM3B, also called PANDER, is increased under obese state. FAM3B promotes hepatic lipogenesis and gluconeogenesis by repressing Akt and AMPK activities, and activating lipogenic pathway. Under obese state, the imbalance among hepatic FAM3A, FAM3B and FAM3C signaling networks plays important roles in the pathogenesis of NAFLD and type 2 diabetes. This review briefly discussed the latest research progress on the roles and mechanisms of FAM3A, FAM3B and FAM3C in the regulation of hepatic glucose and lipid metabolism.

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“…Hepatic PANDER overexpression promotes gluconeogenesis and lipogenesis, whereas hepatic PANDER silencing ameliorated fatty liver and hyperglycemia in obese mice . PANDER knockout (PANKO) mice exhibit increased hepatic insulin sensitivity . In humans, increased circulating PANDER levels have been reported to be associated with pancreatic β cell dysfunction, hyperglycemia and insulin resistance in various races .…”

Section: Introductionmentioning

confidence: 99%

“…13,14 PANDER knockout (PANKO) mice exhibit increased hepatic insulin sensitivity. 15,16 In humans, increased circulating PANDER levels have been reported to be associated with pancreatic β cell dysfunction, hyperglycemia and insulin resistance in various races. [17][18][19] Overall, these clinical and experimental studies had established that PANDER plays important roles in the regulation of glucose and lipid metabolism.…”

Section: Introductionmentioning

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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Enhanced glucose tolerance in pancreatic derived factor (PANDER) knockout C57BL/6 mice

Cited by 17 publications

References 34 publications

Hepatic Activation of the FAM3C-HSF1-CaM Pathway Attenuates Hyperglycemia of Obese Diabetic Mice

Hepatic Activation of the FAM3C-HSF1-CaM Pathway Attenuates Hyperglycemia of Obese Diabetic Mice

FAM3 gene family: A promising therapeutical target for NAFLD and type 2 diabetes

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

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