MicroRNA-451 Negatively Regulates Hepatic Glucose Production and Glucose Homeostasis by Targeting Glycerol Kinase–Mediated Gluconeogenesis

Zhuo, Shu; Yang, Meng; Zhao, Yanan; Chen, Xiaofang; Zhang, Feifei; Li, Na; Yao, Pengle; Zhu, Tengfei; Hong, Mei; Wang, Shanshan; Yu, Lap-Fai; Chen, Shiting; Le, Yingying

doi:10.2337/db16-0166

Cited by 56 publications

(45 citation statements)

References 45 publications

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“…The apparent opposite effects of miR-144/451 (alleviation of I/R-induced heart injury and promotion of HFD-induced cardiac hypertrophy) suggest that 1) miR-144 and miR-451, though produced from the same gene, might function differently; 2) the same miRNA could participate in gene regulation in a compartment-dependent or disease-dependent manner, where the latter is evidenced by our recent finding that miR-451 inhibits the same Cab39/LKB1/AMPK signaling pathway but with opposite cellular effects: protection of red cells against apoptosis [46] vs lipotoxicity in cardiomyocytes [90]. Another metabolism-related study demonstrates that HFD or diabetic condition induces the expression of hepatic miR-451 [91]. Glucose or insulin also upregulates miR-451 in hepatocytes, which leads to the inhibition of hepatic gluconeogenesis and thus low blood glucose levels [91].…”

Section: Function Of Mir-144/451 In Additional Tissuesmentioning

confidence: 99%

“…Another metabolism-related study demonstrates that HFD or diabetic condition induces the expression of hepatic miR-451 [91]. Glucose or insulin also upregulates miR-451 in hepatocytes, which leads to the inhibition of hepatic gluconeogenesis and thus low blood glucose levels [91]. Again, a negative feedback between glucose and miR-451 assures the maintenance of normal levels of blood glucose.…”

Section: Function Of Mir-144/451 In Additional Tissuesmentioning

confidence: 99%

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miR-144/451 in hematopoiesis and beyond

Wang

2019

ExRNA

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MicroRNAs (miRNAs), a class of 18-25 nucleotide (nt) non-coding RNAs, usually inhibit the expression of their target genes. They are transcribed from endogenous genes and are processed for maturation by multiple pathways. miR-144/451, a bicistronic gene locus, encodes miR-144 and miR-451, both of which are highly conserved in evolution. These two miRNAs are on the same primary RNA molecule whose transcription is controlled by multiple nuclear proteins, including GATA1, GATA4, Myc, Oct1, Pax4, FXR, AP1, SMAD3 and SMAD4 depending on tissue types. They are abundant and almost exclusively exist in red blood cells, but low expression of both miR-144 and miR-451 are also detected in non-erythroid lineages. Interestingly, deletion of both miR-144 and miR-451 DNA sequences coding pre-miR-144/451 hairpins in mice leads only mild microcytic anemia but worsen upon a number of stresses including developmental stress, acute blood loss, phenohydrazine-induced hemolysis and precursor depletion by chemotherapeutic drug 5-FU. Such knockout animals older than 15 months also spontaneously develop malignant tumors including B-lymphoma and acute myeloid leukemia, indicating that miR-144/451 is a bona fide tumor-suppressing gene in non-erythroid cells, though its levels are much lower compared to that in red blood cells. Consistent with the findings in animals, disruption of miR-144/451 expression and their abnormal functions are observed in human hematopoietic and non-hematopoietic organs. Moreover, miR-451 is the only miRNA discovered so far whose maturation does not depend on Dicer, an enzyme required by all other miRNAs for maturation. This review focuses on the biogenesis, transcriptional regulation and biological roles of miR-144/451 in erythropoiesis, tumor initiation and other pathological conditions.

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Section: Function Of Mir-144/451 In Additional Tissuesmentioning

confidence: 99%

Section: Function Of Mir-144/451 In Additional Tissuesmentioning

confidence: 99%

miR-144/451 in hematopoiesis and beyond

Wang

2019

ExRNA

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“…Studies have also indicated links between Gyk and the regulation of glucose homeostasis; specifically, it is overexpressed in response to thiazolidinediones, drugs commonly used to treat type 2 diabetes mellitus (7), and this overexpression relieves insulin resistance (8,9). Gyk was recently identified as a target of microRNA-451, which regulates gluconeogenesis through both the glycerol-gluconeogenic axis and the protein kinase B (AKT)-FOXO1-phosphoenolpyruvate carboxykinase/ G6Pase pathway (10). Therefore, mammalian Gyk is a pleiotropic enzyme with a myriad of functions, not all of which have been fully characterized.…”

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confidence: 99%

Glycerol kinase interacts with nuclear receptor NR4A1 and regulates glucose metabolism in the liver

et al. 2019

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Glycerol kinase (Gyk), consisting of 4 isoforms, plays a critical role in metabolism by converting glycerol to glycerol 3‐phosphate in an ATP‐dependent reaction. Only Gyk isoform b is present in whole cells, but its function in the nucleus remains elusive. Previous studies have shown that nuclear orphan receptor subfamily 4 group A member (NR4A)‐1 is an important regulator of hepatic glucose homeostasis and lipid metabolism in adipose tissue. We aimed to elucidate the functional interaction between nuclear Gyk and NR4A1 during hepatic gluconeogenesis in the unfed state and diabetes. We identified nuclear Gyk as a novel corepressor of NR4A1 in the liver; moreover, this recruitment was dependent on the C‐terminal ligand‐binding domain instead of the N‐terminal activation function 1 domain, which interacts with other NR4A1 coregulators. NR4A1 transcriptional activity was inhibited by Gyk via protein‐protein interaction but not enzymatic activity. Moreover, Gyk overexpression suppressed NR4A1 ability to regulate the expression of target genes involved in hepatic gluconeogenesis in vitro and in vivo as well as blood glucose regulation, which was observed in both unfed and diabetic mice. These results highlight the moonlighting function of nuclear Gyk, which was found to act as a coregulator of NR4A1, participating in the regulation of hepatic glucose homeostasis in the unfed state and diabetes.—Miao, L., Yang, Y., Liu, Y., Lai, L., Wang, L., Zhan, Y., Yin, R., Yu, M., Li, C., Yang, X., Ge, C. Glycerol kinase interacts with nuclear receptor NR4A1 and regulates glucose metabolism in the liver. FASEB J. 33, 6736–6747 (2019). http://www.fasebj.org

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“…As Chen et al (29) reported, under metabolic stress, miR-17-92 regulated glucose-stimulated insulin secretion and pancreatic β-cell adaptation. By inhibiting glycerol kinase, miR-451 negatively regulated hepatic gluconeogenesis and blood glucose levels in diabetes (30). Fu et al (31) reported that miR-26a was downregulated in two obese mouse models and regulated insulin signaling and metabolism of glucose.…”

Section: Discussionmentioning

confidence: 99%

Pioglitazone/microRNA‑141/FOXA2: A novel axis in pancreatic β‑cells proliferation and insulin secretion

Zhong

2018

Mol Med Report

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MicroRNAs (miRs) are considered to be effective, post‑transcriptional regulators in the pathophysiology of type 2 diabetes (T2D) and promising treatment targets. However, the function of miR‑141 remains to be elucidated. In the present study, upregulation of miR‑141 was demonstrated in diabetic mice and elderly diabetic patients. Using reverse transcriptase‑quantitative polymerase chain reaction, luciferase reporter assays and western blotting, forkhead box A2 (FOXA2) was identified as a direct target gene of miR‑141. The potential role of miRNA‑141 or FOXA2 was evaluated by overexpressing or silencing miR‑141 or FOXA2, respectively. The increased expression of miR‑141 resulted in impaired glucose‑stimulated insulin secretion (GSIS) and INS‑1 β cell proliferation. In addition, miR‑141 silencing in MIN6 pseudoislets or INS‑1 β cells led to reduced T2D‑associated damage. Furthermore, the expression of miR‑141 may be corrected by treatment with pioglitazone, which is widely used for insulin resistance therapy. The present study also demonstrated the mechanism by which miR‑141 regulated GSIS and proliferation through FOXA2. Overexpression of FOXA2 in MIN6 pseudoislets increased the effect of the miR‑141 inhibitor on GSIS. FOXA2 effectively reversed the effect of miR‑141 overexpression on β cell proliferation. In conclusion, the results of the present study indicate that the pioglitazone/miR‑141/FOXA2 axis may represent a promising target mechanism for T2D treatment.

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MicroRNA-451 Negatively Regulates Hepatic Glucose Production and Glucose Homeostasis by Targeting Glycerol Kinase–Mediated Gluconeogenesis

Cited by 56 publications

References 45 publications

miR-144/451 in hematopoiesis and beyond

miR-144/451 in hematopoiesis and beyond

Glycerol kinase interacts with nuclear receptor NR4A1 and regulates glucose metabolism in the liver

Pioglitazone/microRNA‑141/FOXA2: A novel axis in pancreatic β‑cells proliferation and insulin secretion

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