A Pathway Involving Farnesoid X Receptor and Small Heterodimer Partner Positively Regulates Hepatic Sirtuin 1 Levels via MicroRNA-34a Inhibition

Lee, Ji-Young; Padhye, Amruta; Sharma, Abhilasha; Song, Guisheng; Miao, Ji; Mo, Yin Yuan; Wang, Li; Kemper, Jongsook Kim

doi:10.1074/jbc.m109.094524

Cited by 233 publications

(224 citation statements)

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“…3A). Similar feedback loops have been described for a number of miRNAs in a host of different biological systems (4,16,29,30,32,34,45,46,48,52,57) and recently was described for miR-24 and menin in the parathyroid (32). miR-24 is produced from two separate chromosomal locations in both the human and mouse genomes (Fig.…”

Section: Mir-24 Impacts Cell Viability and Proliferation In Vitromentioning

confidence: 96%

miR-24 regulates menin in the endocrine pancreas

Vijayaraghavan

Maggi

Crabtree

2014

American Journal of Physiology-Endocrinology and Metabolism

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Vijayaraghavan J, Maggi EC, Crabtree JS. miR-24 regulates menin in the endocrine pancreas. Am J Physiol Endocrinol Metab 307: E84 -E92, 2014. First published May 13, 2014; doi:10.1152/ajpendo.00542.2013.-Menin, the product of the MEN1 gene, functions as a tumor suppressor and was first identified in 1997 due to its causative role in the endocrine tumor disorder multiple endocrine neoplasia, type 1 (MEN1). More recently, menin has been identified as a key player in pancreatic islet biology with the observation of an inverse relationship between menin levels and pancreatic islet proliferation. However, the factors regulating menin and the MEN1 gene in the pancreas are poorly understood. Here, we describe the regulation of menin by miR-24 and demonstrate that miR-24 directly decreases menin levels and impacts downstream cell cycle inhibitors in MIN6 insulinoma cells and in ␤lox5 immortalized ␤-cells. This regulation of menin impacts cell viability and proliferation in ␤lox5 cells. Furthermore, our data show a feedback regulation between miR-24 and menin that is present in the pancreas, suggesting that miR-24 regulates menin levels in the pancreatic islet. menin; MEN1; pancreatic islet; miR-24; miRNA THE ENDOCRINE PANCREAS is responsible for maintaining normal glucose homeostasis through the tightly controlled, regulated release of insulin from the pancreatic islet. Pancreatic islets have the unique ability to dynamically and reversibly expand to adapt to changes in insulin demand through careful balance of cell growth and renewal (including ␤-cell replication, neogenesis, transdifferentiation, and hypertrophy), and cell death (apoptosis, atrophy, and autophagy). When this process becomes compromised, it leads to the clinical manifestation of gestational diabetes or type 2 diabetes (T2D). However, detailed knowledge of the mechanisms underlying this process is lacking.MicroRNAs (miRNAs), an evolutionarily conserved class of posttranscriptional regulators, are short ϳ22-nucleotide noncoding RNA sequences that regulate the expression of mRNA targets by binding to the 3=-UTR and inhibiting translation and/or targeting the mRNA for degradation. There is growing evidence that miRNAs regulate key biological processes in the pancreatic islet (13,14,17,27,33,49). For example, miR-375, the first miRNA identified in ␤-cell function, regulates insulin secretion and is essential for normal glucose homeostasis and turnover of ␣-and ␤-cells (40, 41). Other recent studies indicate a role for miR-338-3p and miR-181a in ␤-cell differentiation and insulin sensitivity, respectively (7, 23). p38 (MAPK) is downregulated by miR-24 through the insulinresponsive glucose transporter 4 (GLUT4) to affect peripheral insulin resistance (21). miR-24 also regulates insulin production by targeting the insulin transcriptional repressors Sox6 and Bhlhe22 (35).

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Section: Mir-24 Impacts Cell Viability and Proliferation In Vitromentioning

confidence: 96%

miR-24 regulates menin in the endocrine pancreas

Vijayaraghavan

Maggi

Crabtree

2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Consistent with their critical biological functions, miRs are aberrantly expressed in human diseases, such as metabolic disease and cancer (10,12). We have shown that miR-34a, which targets SIRT1 deacetylase, is aberrantly elevated in fatty livers of high-fat (HF) diet-induced obese mice and leptin-deficient ob/ob mice and that miR-34a is the most highly elevated hepatic miR in metabolic disease-prone FXR-null mice (13,14). Consistent with these findings, a recent study has shown that miR34a was the most highly elevated hepatic miR in dietary and genetic obese mice (15).…”

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confidence: 87%

“…S1). Down-regulation of miR-34a by antisense miR-34a in mouse Hepa1c1c7 cells resulted in a dose-dependent increase in expression of βKL, as well as a known miR-34a target, SIRT1 (14,20) (Fig. 1 A-D and SI Appendix, Fig.…”

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confidence: 99%

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Aberrantly elevated microRNA-34a in obesity attenuates hepatic responses to FGF19 by targeting a membrane coreceptor β-Klotho

Choi

Kim

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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MicroRNA-34a (miR-34a) is the most highly elevated hepatic miR in obese mice and is also substantially elevated in patients who have steatosis, but its role in obesity and metabolic dysfunction remains unclear. After a meal, FGF19 is secreted from the ileum; binds to a hepatic membrane receptor complex, FGF19 receptor 4 and coreceptor β-Klotho (βKL); and mediates postprandial responses under physiological conditions, but hepatic responses to FGF19 signaling were shown to be impaired in patients with steatosis. Here, we show an unexpected functional link between aberrantly elevated miR-34a and impaired βKL/FGF19 signaling in obesity. In vitro studies show that miR-34a down-regulates βKL by binding to the 3′ UTR of βKL mRNA. Adenoviral-mediated overexpression of miR-34a in mice decreased hepatic βKL levels, impaired FGF19-activated ERK and glycogen synthase kinase signaling, and altered expression of FGF19 metabolic target genes. Consistent with these results, βKL levels were decreased and hepatic responses to FGF19 were severely impaired in dietary obese mice that have elevated miR-34a. Remarkably, in vivo antisense inhibition of miR-34a in obese mice partially restored βKL levels and improved FGF19 target gene expression and metabolic outcomes, including decreased liver fat. Further, antimiR-34a treatment in primary hepatocytes of obese mice restored FGF19-activated ERK and glycogen synthase kinase signaling in a βKL-dependent manner. These results indicate that aberrantly elevated miR-34a in obesity attenuates hepatic FGF19 signaling by directly targeting βKL. The miR-34a/βKL/FGF19 axis may present unique therapeutic targets for FGF19-related human diseases, including metabolic disorders and cancer.etabolic disorders, such as fatty liver, obesity, and type II diabetes, due to abnormally regulated lipid and glucose levels are serious medical problems worldwide (1). The roles of pancreatic insulin in the regulation of fed-state metabolism and development of such metabolic disorders are well known, but recently discovered and relatively less understood is the role of an intestinal hormone, FGF19 (or mouse FGF15) (2). FGF19 constitutes a unique endocrine metabolic regulatory axis. After a meal, expression of FGF19 is induced by the bile acid-activated nuclear receptor, farnesoid X receptor (FXR), in the small intestine (2). Secreted FGF19 binds to a hepatic membrane receptor complex, FGF19 receptor 4 (FGFR4), and its coreceptor β-Klotho (βKL) (3-6), and it then triggers the activation of cellular kinases, including ERK and glycogen synthase kinase (GSK), to mediate postprandial metabolic responses (7,8). Interestingly, a recent study showed that the hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease (NAFLD) and insulin resistance (9). Despite the functional importance of βKL in transmitting FGF19 signaling, little is known about how the expression of βKL is regulated and why FGF19 signaling is impaired in patients who have fatty liver.MicroRNAs (miRs) are small, noncoding RNAs a...

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“…miR-103/ 107 and let-7 mainly regulate insulin signalling in peripheral tissues such as adipose tissue and skeletal muscle by targeting caveolin-1 and IR/IRS2, respectively 15,16 . miR-143 and miR-34a affect hepatic insulin signalling by targeting oxysterol-bindingprotein-related protein 8 (ORP8) and Sirtuin 1 (SIRT1), respectively 17,18 . miR-33 affects hepatic insulin action by targeting multiple metabolic regulators, including Sirtuin 6 (SIRT6), a1 subunit of AMP-activated protein kinase (AMPKa1) and IRS2.…”

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Hepatic miR-378 targets p110α and controls glucose and lipid homeostasis by modulating hepatic insulin signalling

et al. 2014

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Understanding the regulation of insulin signalling in tissues provides insights into carbohydrate and lipid metabolism in physiology and disease. Here we show that hepatic miR-378/378* expression changes in response to fasting and refeeding in mice. Mice overexpressing hepatic miR-378/378* exhibit pure hepatic insulin resistance. miR-378 inhibits hepatic insulin signalling through targeting p110a, a subunit of PI3K and hence a critical component of insulin signalling. Knockdown of hepatic p110a mimics the effect of miR-378, while restoration of p110a expression abolishes the action of miR-378 on insulin signalling as well as its systemic effects on glucose and lipid homeostasis. miR-378/378* knockout mice display hypoglycemia and increased hepatic triglyceride level with enhanced insulin sensitivity. Inhibition of hepatic p110a in miR-378/378* knockout mice corrects the abnormal glucose tolerance. Finally, we show that overexpression of hepatic miR-378/378* ameliorates hepatic steatosis in ob/ob mice without exacerbating hyperglycemia. Our findings establish fasting-responsive miR-378 as a critical regulator of hepatic insulin signalling.

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A Pathway Involving Farnesoid X Receptor and Small Heterodimer Partner Positively Regulates Hepatic Sirtuin 1 Levels via MicroRNA-34a Inhibition

Cited by 233 publications

References 40 publications

miR-24 regulates menin in the endocrine pancreas

miR-24 regulates menin in the endocrine pancreas

Aberrantly elevated microRNA-34a in obesity attenuates hepatic responses to FGF19 by targeting a membrane coreceptor β-Klotho

Hepatic miR-378 targets p110α and controls glucose and lipid homeostasis by modulating hepatic insulin signalling

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