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

Despite years of effort, exact pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains obscure. To gain an insight into the regulatory roles of microRNAs (miRNAs) in aberrant energy metabolic status and pathogenesis of NAFLD, we analyzed the expression of miRNAs in livers of ob/ob mice, streptozotocin (STZ)-induced type 1 diabetic mice, and normal C57BL/6 mice by miRNA microarray. Compared with normal C57BL/6 mice, ob/ob mice showed upregulation of eight miRNAs and downregulation of four miRNAs in fatty livers. Upregulation of miR-34a and downregulation of miR-122 was found in livers of STZ-induced diabetic mice. These results demonstrate that distinct miRNAs are strongly dysregulated in NAFLD and hyperglycemia. Comparison between miRNA expressions in livers of ob/ob mice and STZ-administered mice further revealed upregulation of four miRNAs and downregulation of two miRNAs in livers of ob/ob mice, indicating that these miRNAs may represent a molecular signature of NAFLD. A distinctive miRNA expression pattern was identified in ob/ob mouse liver, and hierarchical clustering of this pattern could clearly discriminate ob/ob mice from either normal C57BL/6 mice or STZ-administered mice. These findings suggest an important role of miRNAs in hepatic energy metabolism and implicate the participation of miRNAs in the pathophysiological processes of NAFLD. Despite years of effort, exact pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains obscure. To gain an insight into the regulatory roles of microRNAs (miRNAs) in aberrant energy metabolic status and pathogenesis of NAFLD, we analyzed the expression of miRNAs in livers of ob/ob mice, streptozotocin (STZ)-induced type 1 diabetic mice, and normal C57BL/6 mice by miRNA microarray. Compared with normal C57BL/6 mice, ob/ob mice showed upregulation of eight miRNAs and downregulation of four miRNAs in fatty livers. Upregulation of miR-34a and downregulation of miR-122 was found in livers of STZ-induced diabetic mice. These results demonstrate that distinct miRNAs are strongly dysregulated in NAFLD and hyperglycemia. Comparison between miRNA expressions in livers of ob/ob mice and STZ-administered mice further revealed upregulation of four miRNAs and downregulation of two miRNAs in livers of ob/ob mice, indicating that these miRNAs may represent a molecular signature of NAFLD. A distinctive miRNA expression pattern was identified in ob/ob mouse liver, and hierarchical clustering of this pattern could clearly discriminate ob/ob mice from either normal C57BL/6 mice or STZ-administered mice. These findings suggest an important role of miRNAs in hepatic energy metabolism and implicate the participation of miRNAs in the pathophysiological processes of NAFLD. Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide and is becoming a major public health concern in modern society (1Clark J.M. Brancati F.L. Diehl A.M. Nonalcoholic fatty liver disease.Gastroenterology. 2002; 122: 1649-1657Abstract Full Text Full Text PDF PubMed Scopus (762) Google Scholar, 2Browning J.D. Szczepaniak L.S. Dobbins R. Nuremberg P. Horton J.D. Cohen J.C. Grundy S.M. Hobbs H.H. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.Hepatology. 2004; 40: 1387-1395Crossref PubMed Scopus (2907) Google Scholar, 3Amarapurkar D.N. Hashimoto E. Lesmana L.A. Sollano J.D. Chen P.J. Goh K.L. How common is non-alcoholic fatty liver disease in the Asia-Pacific region and are there local differences?.J. Gastroenterol. Hepatol. 2007; 22: 788-793Crossref PubMed Scopus (315) Google Scholar). 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Recently, a new class of RNA regulatory genes known as microRNAs (miRNAs) has been found to introduce a whole new layer of gene regulation in eukaryotes. miRNAs are endogenous noncoding RNAs of 19–24 nucleotides in length that play an important role in the negative regulation of gene expression by base-pairing to complementary sites on the target mRNAs, causing a block of translation or degradation of the target mRNA (9Bartel D.P. MicroRNAs: genomics, biogenesis, mechanism, and function.Cell. 2004; 116: 281-297Abstract Full Text Full Text PDF PubMed Scopus (29238) Google Scholar). In addition to the fundamental roles in diverse biological and pathological processes, including developmental timing, apoptosis, proliferation, differentiation, organ development, carcinogenesis, and immune response (10Ambros V. MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing.Cell. 2003; 113: 673-676Abstract Full Text Full Text PDF PubMed Scopus (1086) Google Scholar, 11Esquela-Kerscher A. Slack F.J. Oncomirs - microRNAs with a role in cancer.Nat. Rev. Cancer. 2006; 6: 259-269Crossref PubMed Scopus (6161) Google Scholar, 12Hoefig K.P. Heissmeyer V. MicroRNAs grow up in the immune system.Curr. Opin. Immunol. 2008; 20: 281-287Crossref PubMed Scopus (56) Google Scholar), miRNAs are also reported to play important roles in energy metabolism, both in invertebrates and vertebrate animals. The role of miRNAs in energy metabolism was first indicated by a study in the fruit fly Drosophlia melanogaster, suggesting an important role of miR-14 in energy metabolism on the whole-animal level (13Xu P. Vernooy S.Y. Guo M. Hay B.A. The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism.Curr. 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McKay R. et al.miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting.Cell Metab. 2006; 3: 87-98Abstract Full Text Full Text PDF PubMed Scopus Google Scholar) an miR-122 into mice and found that this could hepatic fatty and hepatic fatty and et al. Chen Yu J. MicroRNA expression pattern in of nonalcoholic fatty liver 2008; Full Text Full Text PDF PubMed Scopus Google Scholar) also reported that miR-122 level was in NAFLD these findings a between miRNAs and energy miRNAs play a role in the pathophysiological processes of NAFLD remains to To this we miRNA to miRNAs in livers of ob/ob mice of NAFLD with A. Diehl A.M. of Gastroenterol. 2002; PubMed Scopus Google Scholar, A.M. from of 2005; PubMed Scopus Google and streptozotocin (STZ)-induced type 1 diabetic mice glucose fatty to the roles of miRNAs in livers NAFLD and C57BL/6 mice and four and normal C57BL/6 mice four and four were from of For STZ-induced type 1 diabetic C57BL/6 mice a of in were glucose were from the and were The mice with glucose were mice were in a with a and to and a fat, and on a were and glucose and The liver were and in and for insulin of these were by the was the and were in with the for for and of and by the of liver were and and RNA were to the RNA and on miRNA were as C.G. B. N. C. M. M. S. M. et for microRNA profiling in and mouse 2004; PubMed Scopus Google Scholar, J.M. J. S.M. A for analysis of microRNA gene 2004; PubMed Scopus Google Scholar). of RNA was the miRNA to RNA RNA was with and was on the miRNA in to and mouse miRNA RNA from mouse was analyzed on were and were These of were to The miRNA been into and in a to the miRNAs were as A.J. M. et of microRNAs by 2005; PubMed Scopus Google Scholar, P. MicroRNA expression profiling of whole 2006; PubMed Scopus Google Scholar) The and were as A.J. M. et of microRNAs by 2005; PubMed Scopus Google Scholar). 1 of RNA was the for for and for The 1 and 1 The for the were as for by of for and for 1 an were in The is as the which the the The miRNA expression were to The expression was the and the were as of gene expression and the PubMed Scopus Google Scholar). miRNAs were identified the analysis of R. G. analysis of to the PubMed Scopus Google Scholar) with a and were to the The genes and were and hierarchical were were in were as and the with were a The analysis of miRNA was the D.P. of microRNA 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) A. M.N. R. L. P. M. et microRNA target 2005; PubMed Scopus Google Scholar) and B. A.J. A. Tuschl T. C. MicroRNA Biol. 2004; PubMed Scopus Google Scholar) To the involvement of miRNAs in NAFLD and we a analysis of miRNAs in livers of ob/ob mice and eight C57BL/6 mice as in the glucose insulin and liver of the ob/ob mice were with of the C57BL/6 mice, suggesting the aberrant energy metabolic status of ob/ob mice. RNAs were from liver of ob/ob mice and C57BL/6 mice and in miRNA The of miRNA expression in livers of ob/ob mice and C57BL/6 mice was clearly revealed by a hierarchical clustering analysis of the miRNA in the by hierarchical analysis showed two major in mice C57BL/6 indicating a miRNA expression pattern in the fatty livers of ob/ob mice the normal livers of C57BL/6 of of of glucose and insulin the mice were glucose and insulin the mice were as of glucose insulin liver liver glucose and insulin the mice were in a new as of glucose insulin liver liver To further a R. G. analysis of to the PubMed Scopus Google Scholar) was is an that a for gene and genes that are with an such as the type of analyzed analysis the miRNA expression in livers of ob/ob mice were with of C57BL/6 mice. In this an was The expressions of miRNAs were two 2 or on these analysis a of miRNAs that were in livers of ob/ob mice these eight miRNAs and were and miRNAs and were in ob/ob mice liver these demonstrate that distinct miRNAs are in NAFLD with the roles of miRNAs as functional in the pathophysiological processes of these miRNAs in livers of ob/ob mice and STZ-induced diabetic mice with of C57BL/6 the of genes identified by mice C57BL/6 miRNAs were as by to to by diabetic mice C57BL/6 miRNAs were as by to to by the of genes identified by These miRNAs were as by to to by in a new causing and of pancreatic A. L. R. of the of Biol. Med. PubMed Scopus Google Scholar), STZ-induced type 1 diabetic mice an of glucose fatty diabetic mouse was to study the between hepatic miRNA expression and hyperglycemia. of glucose of the mice were and in the the of these mice the the glucose level of STZ-administered mice was that of C57BL/6 mice. the of STZ-administered mice was with that of C57BL/6 mice this mice were and liver were for RNA and miRNA analysis of miRNA a and showed that miR-34a was in liver of STZ-induced diabetic mice with of C57BL/6 mice hierarchical clustering of miRNA expression from liver of STZ-induced diabetic mice and C57BL/6 mice is in in showed between and C57BL/6 indicating that miRNA expression in mice livers was for To the miRNAs that may in the pathophysiological processes of NAFLD, we the miRNA expression pattern in livers of ob/ob mice with that of STZ-induced diabetic mice. ob/ob mice as an both NAFLD and STZ-induced diabetic mice as a a simple status of hyperglycemia. in hierarchical clustering of liver miRNA expression of ob/ob mice and STZ-induced diabetic mice a with two major in clearly these two of a miRNA expression pattern in nonalcoholic fatty the of on the hepatic miRNA and identified four miRNAs and and two miRNAs and in ob/ob with indicating that these miRNAs may represent a molecular signature of miRNAs in livers of ob/ob mice with of STZ-induced diabetic the of genes identified by the of genes identified by in a new In this both and mice and four normal C57BL/6 and four ob/ob and eight STZ-induced diabetic were To further liver miRNAs in these of we the liver miRNA expression in of and in and analysis of miRNA a and dysregulated miRNAs in livers of ob/ob mice normal C57BL/6 mice, dysregulated miRNAs in livers of ob/ob mice C57BL/6 mice, four dysregulated miRNAs in livers of STZ-induced diabetic mice C57BL/6 mice, and dysregulated miRNAs in livers of ob/ob mice STZ-induced diabetic mice. hierarchical clustering of miRNA expression in liver by of ob/ob mouse from normal C57BL/6 mouse and of ob/ob mouse from STZ-induced diabetic mouse been identified and which is to the results of These results suggest that the expressions of the distinct miRNA expression these mouse are by To the of the miRNA we A.J. 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In this we found that miRNAs in liver of ob/ob mice were dysregulated with of C57BL/6 mice. eight miRNAs and were and miRNAs and were A distinctive miRNA expression pattern was identified in ob/ob mouse liver, and hierarchical clustering of this pattern could clearly discriminate ob/ob mice from normal C57BL/6 mice and STZ-administered mice, indicating the participation of miRNAs in the pathophysiological processes of NAFLD with hyperglycemia. mice, of type 2 diabetes with also NAFLD. analysis of miRNA expression in livers of mice are required in the to the of on liver miRNA ob/ob mice and insulin are also as of type 2 diabetes with glucose has been to regulate of genes and also in cell E. S. H. of gene expression by Opin. Metab. 2007; PubMed Scopus Google Scholar). remains glucose an impact on the miRNA an from and of Google Scholar), is widely to of type 1 diabetes and of A. L. R. of the of Biol. Med. PubMed Scopus Google Scholar). STZ-induced type 1 diabetic mice with fatty In this we the STZ-administered mice as a of fatty To the of glucose on the liver miRNA we the miRNA expressions in livers of STZ-induced type 1 diabetic mice with of C57BL/6 mice. showed an expression analysis also to the STZ-induced diabetic mice from the normal C57BL/6 mice, indicating that glucose liver miRNA expression miRNA expression in the miRNAs these two miR-34a is and miR-122 is in both ob/ob mice and STZ-induced diabetic mice, suggesting that miR-34a and miR-122 may related to the regulation of glucose To the miRNAs in NAFLD the of we further liver miRNA expression of ob/ob mice with that of STZ-induced diabetic mice. The miRNAs with that these miRNAs are to in lipid metabolism and to the of NAFLD. A of reported the miR-34a expressions in of M. G. M. M. et of miR-34a by gene expression and 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, H. N. M. 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McKay R. et al.miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting.Cell Metab. 2006; 3: 87-98Abstract Full Text Full Text PDF PubMed Scopus Google Scholar, J. Rajewsky N. R. Tuschl T. M. M. of microRNAs in vivo with 2005; PubMed Scopus Google Scholar, M.J. miR-122 with and 2008; PubMed Scopus Google Scholar, J. M. S. M. A. S. M. M. et microRNA in 2008; PubMed Scopus Google Scholar). the of miR-122 in liver and the role in energy metabolism, we expression in the of miR-122 was in found that miR-122 was in livers of both ob/ob mice and STZ-induced diabetic mice. to with the reported regulatory of miR-122 in energy metabolism, and we that the of miR-122 in NAFLD and diabetic livers may of a of liver cells lipid or glucose the major for the biological of miRNAs is target genes the has been a in target and of and two related miRNAs that a Z. J. S. A. B. L. J. M. G. a class of Dev. 2002; PubMed Scopus Google Scholar), were by to mRNA in pathways that and lipid B.R. miRNA a of the role of miRNAs in lipid metabolism, with a that regulates metabolic Metab. 2007; PubMed Scopus Google Scholar). In with this we found that and were in ob/ob mice with normal C57BL/6 mice and STZ-administered mice. These results strongly suggest the role of and in the pathogenesis of NAFLD and the of in miRNA major for miRNA target and we analyzed the target genes of the miRNAs identified in livers of ob/ob mice and STZ-induced diabetic mice. The target genes of the dysregulated miRNAs genes that are related to glucose or lipid metabolism in liver and may play important roles in NAFLD. The of miRNAs and target genes may to in mRNA degradation J. R. of translation and mRNA degradation by miRNAs and Dev. 2006; 20: PubMed Scopus Google Scholar). we the with liver mRNA expression of C57BL/6 mice C.P. profiling in energy metabolism, and and with by in ob/ob mouse Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. T. of and on hepatic gene expression in PubMed Scopus Google Scholar). mRNA expression of was found dysregulated in ob/ob mice, and the of genes were in with the of suggesting these genes to that may by miRNAs mRNA target genes that were dysregulated in ob/ob mice on mRNA may by miRNAs on a that the of from and was by the major to a target gene of miR-122 was to in livers of ob/ob mice in we to in ob/ob mice. In with this a study reported that was in livers of ob/ob mice with that of the hepatic and in and J. PubMed Scopus Google Scholar), indicating the between miR-122 and are required to these target genes of the miRNAs and the regulatory of miRNAs in NAFLD and hyperglycemia. In this study for the first an analysis of miRNA expression in livers of ob/ob mice, STZ-induced diabetic mice, and normal C57BL/6 mice. The study has identified a distinctive miRNA expression pattern in fatty livers of ob/ob mice, which could clearly ob/ob mice from either normal C57BL/6 mice or STZ-induced diabetic mice. The findings of this study demonstrate a in pathophysiological processes of NAFLD and for clinical for in analysis and and for with microRNA nonalcoholic fatty liver disease analysis of streptozotocin