Micro-RNA-195 and -451 Regulate the LKB1/AMPK Signaling Axis by Targeting MO25

Chen, Hao; Untiveros, Gustavo; McKee, Laurel; Pérez, Jessica; Li, Jing; Antin, Parker B.; Konhilas, John P.

doi:10.1371/journal.pone.0041574

Cited by 59 publications

(46 citation statements)

References 52 publications

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“…35 Also, it is reported that miR-451 levels are significantly increased in the hearts of a hypertrophic cardiomyopathy mouse model and are involved in Cab39 expression in C2C12 cells. 18 However, other unrecognized direct targets of miR-451 may be involved in diabetic cardiomyopathy because growing evidence suggests that miRNAs have large numbers of direct targets.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA-451 Exacerbates Lipotoxicity in Cardiac Myocytes and High-Fat Diet-Induced Cardiac Hypertrophy in Mice Through Suppression of the LKB1/AMPK Pathway

Kuwabara

Horie

Baba

et al. 2015

Circulation Research

183

154

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Editorial, see p 229AMP-activated protein kinase (AMPK) is a major cellular sensor of energy availability. Liver kinase B1 (LKB1) and Ca 2+ /calmodulin-dependent protein kinase kinase β can act as major upstream kinases of AMPK in mammalian cells and phosphorylate AMPK at Thr 172 . 5 LKB1 forms a heterotrimeric complex with ste20-related adaptor and calcium-binding protein 39 (Cab39, also known as MO25α). 6 Although several lines of evidence indicate that AMPK phosphorylation is attenuated in diet-induced obesity (DIO) mouse hearts, 7,8 the mechanisms by which AMPK phosphorylation is decreased are not fully understood.MicroRNAs (miRNAs or miRs) are a large class of small noncoding RNAs. miRNAs suppress the translation of a target mRNA depending on the complementarity between the 5′ side seed sequence of a miRNA and the 3′ untranslated region (3′UTR) of the target mRNA. Although several reports indicate that miRNAs are involved in diabetic cardiomyopathy in a type 1 DM model of streptozotocin-induced diabetic mice, 9-11 miRNA functions in diabetic hearts induced especially by type 2 DM remain to be elucidated.In the present study, we used DIO mice to identify differentially regulated miRNAs in hearts. One of these miRNAs, miR-451, was upregulated in the hearts, and palmitic acid stimulation increased miR-451 levels in neonatal rat cardiac myocytes (NRCMs). miR-451 directly targeted Cab39 in NRCMs, and loss of miR-451 function partly rescued lipotoxicity in vitro. Furthermore, we revealed that high-fat diet (HFD)-induced cardiac hypertrophy was ameliorated in cardiomyocyte-specific miR-451 knockout (miR-451 cKO) mice. Finally, we showed that AMPK phosphorylation was increased and mammalian target of rapamycin (mTOR) phosphorylation was decreased in the HFD-fed miR-451 cKO mice compared with the HFD-fed control mice. These data strongly suggest that cardiac-specific inhibition of miR-451 is a strategy for treating diabetic cardiomyopathy. MethodsDetailed methods are provided in the Online Data Supplement. Results miRNA-451 Expression Is Significantly Increased in DIO Mouse HeartsTo clarify miRNA expression changes in DIO mouse hearts, we used HFD-fed C57BL/6 mice. This is a well-established obesity and type 2 DM model, 12 and the C57BL/6 mice become obese depending on the duration of HFD feeding, as shown in Figure 1A. In line with our and other reports, 8,12,13 liver weights approximately doubled, and fasting blood sugar concentrations increased significantly by 1.5-fold after feeding 45 kcal% fat-containing HFD for 20 weeks ( Figure 1B and 1C). These data suggest that this mouse model had marked insulin resistance and fatty liver and mimicked obesity with type 2 DM in humans.To evaluate miRNA expression changes in the heart, we performed microarray analyses of miRNAs extracted from the hearts of mice fed HFD for 8 and 20 weeks. We focused on miRNAs meeting the following 3 criteria. The miRNA was evidently expressed in the heart (miRNA spot intensity, >100), the expression levels increased depending on the dura...

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Section: Discussionmentioning

confidence: 99%

“…These data were consistent with those in a previous report. 18 Thus, we attempted to investigate miR-451 functions in cardiac myocytes.…”

Section: Mir-451 Expression Is Induced By Palmitic Acid Stimulation mentioning

confidence: 99%

MicroRNA-451 Exacerbates Lipotoxicity in Cardiac Myocytes and High-Fat Diet-Induced Cardiac Hypertrophy in Mice Through Suppression of the LKB1/AMPK Pathway

Kuwabara

Horie

Baba

et al. 2015

Circulation Research

183

154

View full text Add to dashboard Cite

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“…In this study, we first demonstrated the deregulated expression of circulating miR-130a and miR-451 in DLBCL. According to the results of other studies, miR-451 is a significant anti-oncomiRNA in colorectal carcinoma, and promoted PI3k/AKT and LKB1/AMPK activation by repressing the mitogen-activated protein kinase (MAPK) signaling pathway, and caused an decreased in self-renewal, tumorigenicity and vascular endothelial cell proliferation (33,34). In accordance with the above results, we also detected reduced miR-451 expression, which confirmed the function of miR-451 as a oncogene in DLBCL for the first time.…”

Section: Discussionmentioning

confidence: 99%

Circulating microRNA-125b and microRNA-130a expression profiles predict chemoresistance to R-CHOP in diffuse large B-cell lymphoma patients

Yuan

Gui

et al. 2015

Oncology Letters

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Abstract. Numerous studies have reported the aberrant expression profiles of microRNAs (miRNAs) in diffuse large B-cell lymphoma (DLBCL), although very few of these studies were concerned with chemoresistance to R-CHOP in DLBCL patients. This study was designed to assess the correlation between circulating miRNA expression and chemoresistance and prognosis in DLBCL patients. At the start of the study, we demonstrated that miRNA expression levels in serum were significantly associated with those in formalin-fixed, paraffin-embedded tissues, which indicated that circulating miRNAs may be powerful, non-invasive biomarkers reflecting miRNAs levels isolated from tumor tissue. Then from eight potential drug-resistant miRNAs which were deregulated in DLBCL and which had been reported to be associated with drug resistance in other carcinomas, we screened out the circulating miR-125b and miR-130a, which may related to R-CHOP resistance. Dynamic monitoring of the levels of circulating miR-125b and miR-130a further demonstrated that they were involved in recurrence, progression and chemoresistance in DLBCL patients. Finally, we demonstrated that high miR-125b indicated poor prognosis, as patients with higher miR-125b levels had a shorter overall survival. To our knowledge, this is the first study demonstrating that miR-125b and miR-130a are associated with the risk of chemoresistance in DLBCL patients, and that dynamic monitoring of the levels of circulating miR-125b and miR-130a predicts the therapeutic response and disease status of DLBCL patients.

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“…Interestingly, miR-451 promotes glioma cell adaptation to metabolic stress through suppression of the LKB-1-associated protein CAB39 and indirect activation of mTOR signaling [113]. Recently, miR-195 has been found to also target CAB39 and regulate mTOR [114].…”

Section: Amp-activated Protein Kinasementioning

confidence: 99%