Differential expression of microRNAs in mouse liver under aberrant energy metabolic status

Li, Shengjie; Chen, Xi; Zhang, Hongjie; Liang, Xiangying; Xiang, Yang; Yu, Chaohui; Zen, Ke; Li, Youming; Zhang, Chenyu

doi:10.1194/jlr.m800509-jlr200

Cited by 175 publications

(139 citation statements)

References 57 publications

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“…For example, the expression of miR-122 may be either downregulated in humans and mice, or upregulated in rats. [26][27][28] All these findings confirm a connection between definite miRNA signatures and pathogenesis of NAFLD, but also suggest that further investigations are required.…”

supporting

confidence: 56%

“…In keeping with a previous published study, we confirmed the downregulation of miR-122. 26 In liver, miR-122 regulates several targets affecting lipid homeostasis, including fatty acid synthase, 3-hydroxy-3-methyl-glutarylcoenzyme A reductase and their transcriptional activators, the sterolresponse-element binding protein-1c and 2. Therefore, miR-122 downregulation may have a significant role in the pathogenesis of the disease.…”

Section: Discussionmentioning

confidence: 99%

“…25 Four recent reports analyzed miRNA profiles in animal models and human NAFLD. [26][27][28][29] Li et al 26 found that miR-34a, miR-31, miR-103, miR-107, miR-194, miR-335-5p, miR-221 and miR-200a were upregulated, whereas miR-29c, miR-451 and miR-21 were downregulated in liver of mice with diet-induced NASH. However, the expression levels of specific hepatic miRNAs during NAFLD pathogenesis are still controversial.…”

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confidence: 99%

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Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease

Alisi

Sacco

Bruscalupi

et al. 2011

Laboratory Investigation

178

116

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Nonalcoholic fatty liver disease (NAFLD) is an emerging disease with a broad spectrum of liver conditions. The complex molecular pathogenesis of NAFLD is still unclear. In this study, we conducted an analysis of microRNA (miRNA) expression profiles in liver of rats made NAFLD by different diets. To this aim, Sprague-Dawley rats were fed ad libitum for 3 months with different diets: standard diet (SD), diet enriched in fats and low in carbohydrates (HFD), SD with high fructose (SD-HF) and diet with high levels of fats and fructose (HFD-HF). Our results demonstrated that the treatment with different dietetic regimens caused a significant increase of the body weight and the alteration of some metabolic parameters compared with control animals, as well as various liver injuries. The miRNAs analysis showed the significant downregulation of three miRNAs (miR-122, miR-451 and miR-27) and the upregulation of miR-200a, miR-200b and miR-429 in HFD, SD-HF and HFD-HF rats. Besides, miR-21 expression was significantly decreased only in fructose-enriched diets. These miRNAs target molecules involved in the control of lipid and carbohydrate metabolism, signal transduction, cytokine and chemokine-mediated signaling pathway and apoptosis. Western blot analysis of PKCd, LITAF, ALDOLASE-A, p38MAPK, PTEN, LIPIN1, EPHRIN-A1, EPHA2 and FLT1 showed a diet-induced deregulation of all these proteins. Interestingly, the expression pattern of LITAF, PTEN, LIPIN1, EPHRIN-A1, EPHA2 and FLT1 might be well explained by the trend of their specific mRNAs, by potentially regulatory miRNAs, or both. In conclusion, we highlight for the first time the potential involvement of novel determinants (miRNAs and proteins) in the molecular pathogenesis of diet-induced NAFLD.

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supporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease

Alisi

Sacco

Bruscalupi

et al. 2011

Laboratory Investigation

178

116

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“…Indeed, miR-200a is decreased in the kidney of non-obese diabetic apoE KO mice (Wang et al 2011) and in the liver of spontaneous diabetic non-obese GK rats (Herrera et al 2010). Interestingly, miR-200a is increased in liver of obese diabetic ob/ob mice (Li et al 2009) as well as in liver and pancreatic islets of obese diabetes-resistant B6-ob mice (Zhao et al 2009). These findings indicate that the expression of miR-200a is decreased with diabetes but is increased in cases of obesity or when diabetes is associated with obesity.…”

Section: Figurementioning

confidence: 99%

Early leptin blockade predisposes fat-fed rats to overweight and modifies hypothalamic microRNAs

Benoît¹,

Ould-Hamouda²,

Crépin³

et al. 2013

Journal of Endocrinology

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Perinatal leptin impairment has long-term consequences on energy homeostasis leading to body weight gain. The underlying mechanisms are still not clearly established. We aimed to analyze the long-term effects of early leptin blockade. In this study, newborn rats received daily injection of a pegylated rat leptin antagonist (pRLA) or saline from day 2 (d2) to d13 and then body weight gain, insulin/leptin sensitivity, and expression profile of microRNAs (miRNAs) at the hypothalamic level were determined at d28, d90, or d153 (following 1 month of high-fat diet (HFD) challenge). We show that pRLA treatment predisposes rats to overweight and promotes leptin/insulin resistance in both hypothalamus and liver at adulthood. pRLA treatment also modifies the hypothalamic miRNA expression profile at d28 leading to the upregulation of 34 miRNAs and the downregulation of four miRNAs. For quantitative RT-PCR confirmation, we show the upregulation of rno-miR-10a at d28 and rno-miR-200a, rno-miR-409-5p, and rno-miR-125a-3p following HFD challenge. Finally, pRLA treatment modifies the expression of genes involved in energy homeostasis control such as UCPs and AdipoRs. In pRLA rat muscle, Ucp2/3 and Adipor1/r2 are upregulated at d90. In liver, pRLA treatment upregulates Adipor1/r2 following HFD challenge. These genes are known to be involved in insulin resistance and type 2 diabetes. In conclusion, we demonstrate that the impairment of leptin action in early life promotes insulin/leptin resistance and modifies the hypothalamic miRNA expression pattern in adulthood, and finally, this study highlights the potential link between hypothalamic miRNA expression pattern and insulin/leptin responsiveness.

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“…miR-122, the most abundant miRNA in the liver, has been reported to mainly affect lipid metabolism by regulating the expression of SREBP-1c, Fas and HMG-CoA (34)(35)(36). Indeed, downregulation of miR-122 was observed in the livers of ob/ob mice, a well-established hyperglycemic model of NAFLD, and in human NASH patients (20,37). Thus, miR-122, a key regulator of cholesterol and fatty-acid metabolism, may be an attractive therapeutic target for metabolic diseases, including NASH.…”

mentioning

confidence: 99%

Upregulated microRNA-199a-5p inhibits nuclear receptor corepressor 1 translation in mice with non-alcoholic steatohepatitis

Zhang

Wang

et al. 2014

Molecular Medicine Reports

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Abstract. Mounting evidence indicates that dysregulated microRNAs (miRNAs) are important in the etiology and pathogenesis of steatohepatitis. However, the functions of miRNAs in the pathophysiological process of non-alcoholic steatohepatitis (NASH) are poorly understood. In this study, C57BL/6J mice were fed a methionine-choline-deficient (MCD) diet for eight weeks in order to induce hepatic steatohepatitis. Using reverse transcription polymerase chain reaction, the hepatic expression levels of miR-199a-5p, miR-122 and miR-221 in the mice were examined. Bioinformatic analysis of dysregulated miR-199a-5p was performed to predict the potential role of miR-199a-5p in NASH. The MCD diet was found to significantly reduce miR-122 expression levels and significantly increase miR-199a-5p expression levels in mouse livers, compared with those of mice fed a control diet. In the bioinformatic analysis, miR-199a-5p was identified to be predominantly involved in transcription, protein serine/threonine kinase activity, insulin signaling, and the Wnt and mitogen-activated protein kinase signaling pathways. The regulation of nuclear receptor corepressor 1 (NCOR1) by miR-199a-5p was also examined by silencing and overexpressing this miRNA in LX-2 cells. The data revealed that NCOR1 protein levels were significantly reduced and enhanced by miR-199a-5p mimic and inhibitor, respectively. These findings suggest a key role for miR-199a-5p in the progression of NASH through inhibition of NCOR1 translation, and provide novel insights into NASH pathogenesis.

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Differential expression of microRNAs in mouse liver under aberrant energy metabolic status

Abstract: Abbreviations: FDR, false discovery rate; miRNA, microRNA; NAFLD, nonalcoholic fatty liver disease; qRT-PCR, quantitative reverse transcription polymerase chain reaction; SAM, signifi cance analysis of microarray; STZ, streptozotocin.

Cited by 175 publications

References 57 publications

Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease

Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease

Early leptin blockade predisposes fat-fed rats to overweight and modifies hypothalamic microRNAs

Upregulated microRNA-199a-5p inhibits nuclear receptor corepressor 1 translation in mice with non-alcoholic steatohepatitis

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