Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver

Yamada, Hiroya; Suzuki, Kôji; Ichino, Naohiro; Ando, Yoshitaka; Sawada, Akira; Osakabe, Keisuke; Sugimoto, Keiko; Ohashi, Koji; Teradaira, Ryouji; Inoue, Takashi; Hamajima, Nobuyuki; Hashimoto, Shuji

doi:10.1016/j.cca.2013.05.021

Cited by 286 publications

(257 citation statements)

References 38 publications

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“…miR-106-25 is associated with TGF␤ tumor suppressor signaling pathway in the liver (37), and miR-122 is associated with hepatitis-C (27) and nonalcoholic steatohepatitis (5), which is one of the risk factors for hepatocellular carcinoma (1). Furthermore, plasma levels of miR-122 and miR-34a were higher in patients with nonalcoholic fatty liver disease (55). These findings suggest that exposure to maternal undernutrition in early prenatal life may have an impact on hepatic growth and physiology beyond programming of the insulin-signaling and gluconeogenic pathways.…”

Section: Impact Of Pcun and Piun On Mirsmentioning

confidence: 81%

Impact of embryo number and maternal undernutrition around the time of conception on insulin signaling and gluconeogenic factors and microRNAs in the liver of fetal sheep

Lie

Morrison

Williams-Wyss

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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-This study aimed to determine whether exposure of the oocyte and/or embryo to maternal undernutrition results in the later programming of insulin action in the liver and factors regulating gluconeogenesis. To do this, we collect livers from singleton and twin fetal sheep that were exposed to periconceptional (PCUN; Ϫ60 to 7 days) or preimplantation (PIUN; 0 -7 days) undernutrition at 136 -138 days of gestation (term ϭ 150 days). The mRNA and protein abundance of insulin signaling and gluconeogenic factors were then quantified using qRT-PCR and Western blotting, respectively, and global microRNA expression was quantified using deep sequencing methodology. We found that hepatic PEPCK-C mRNA (P Ͻ 0.01) and protein abundance and the protein abundance of IRS-1 (P Ͻ 0.01), p110␤ (P Ͻ 0.05), PTEN (P Ͻ 0.05), CREB (P Ͻ 0.01), and pCREB (Ser 133 ; P Ͻ 0.05) were decreased in the PCUN and PIUN singletons. In contrast, hepatic protein abundance of IRS-1 (P Ͻ 0.01), p85 (P Ͻ 0.01), p110␤ (P Ͻ 0.001), PTEN (P Ͻ 0.01), Akt2 (P Ͻ 0.01), p-Akt (Ser 473 ; P Ͻ 0.01), and p-FOXO-1 (Thr24) (P Ͻ 0.01) was increased in twins. There was a decrease in PEPCK-C mRNA (P Ͻ 0.01) but, paradoxically, an increase in PEPCK-C protein (P Ͻ 0.001) in twins. Both PCUN and PIUN altered the hepatic expression of 23 specific microRNAs. We propose that the differential impact of maternal undernutrition in the presence of one or two embryos on mRNAs and proteins involved in the insulin signaling and gluconeogenesis is explained by changes in the expression of a suite of specific candidate microRNAs.pregnancy; nutrition; fetus; epigenetic IT HAS BEEN DEMONSTRATED in a range of epidemiological and experimental studies that exposure of the oocyte, embryo, or fetus to a range of environmental stressors, including poor maternal nutrition, results in poor metabolic and cardiovascular outcomes in postnatal life (8,9,13,22,25,41,42,53,56). In sheep, maternal undernutrition from 60 days before to 30 days after conception resulted in an impairment of the insulin and glucose responses to a glucose tolerance test at 10 mo after birth (49). The effects of exposure to maternal undernutrition during early gestation were also more pronounced in singleton than in twin offspring. However, it is not known whether exposure to maternal undernutrition limited to around the time of conception alone is sufficient to program changes in the insulin-signaling pathway in tissues of metabolic importance such as the liver or whether there is a differential impact of maternal undernutrition in the periconceptional period in singletons and twins.Insulin acts through the insulin receptor (IR), which is stabilized by caveolin-1 (Cav-1), resulting in a series of activations by phosphorylation of the insulin receptor substrate-1 (IRS-1) or -2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), and conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). Conversion of PIP2 to PIP3 is negatively regulated by phosphatase and tensin homolog (...

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Section: Impact Of Pcun and Piun On Mirsmentioning

confidence: 81%

Impact of embryo number and maternal undernutrition around the time of conception on insulin signaling and gluconeogenic factors and microRNAs in the liver of fetal sheep

Lie

Morrison

Williams-Wyss

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Although miR-33 antagonism remarkably increases HDL and lowers very lowdensity lipoprotein (VLDL), one recent study reported that long-term inhibition of miR-33 may increase CEs and triglycerides (TGs), leading to hepatic steatosis in mice fed a highfat diet [24] . Hepatic miR-122 is decreased in the livers of NASH patients, while it is increased in the blood [19,25,26] . The silencing of miR-122 caused an accumulation of both cholesterol and TGs in mouse livers [27,28] .…”

Section: Introductionmentioning

confidence: 97%

Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse non-alcoholic steatohepatitis

et al. 2017

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Dicer1 is an enzyme essential for microRNA (miRNA) maturation. The loss of miRNAs resulted from Dicer1 deficiency greatly contributes to the progression of many diseases, including lipid dysregulation, but its role in hepatic accumulation of free cholesterol (FC) that is critical in the development of non-alcoholic steatohepatitis (NASH) remains elusive. In this study, we used the liver-specific Dicer1-knockout mice to identify the miRNAs involved in hepatic FC accumulation. In a widely used dietary NASH model, mice were fed a methionine-choline-deficient (MCD) diet for 3 weeks, which resulted in significant increase in hepatic FC levels as well as decrease of Dicer1 mRNA levels in livers. The liver-specific Dicer1-knockout induced hepatic FC accumulation at 5-6 weeks, accompanied by increased mRNA and protein levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a rate-limiting enzyme of cholesterol synthesis in livers. Eleven predicted miRNAs were screened, revealing that miR-29a/b/c significantly suppressed HMGCR expression by targeting the HMGCR mRNA 3'-UTR. Overexpression of miR-29a in SMMC-7721 cells, a steatosis hepatic cell model, significantly decreased HMGCR expression and the FC level. Furthermore, the expression levels of miR-29a were inversely correlated with HMGCR expression levels in the MCD diet mouse model in vivo and in 2 steatosis hepatic cell models (SMMC-7721 and HL-7702 cells) in vitro. Our results show that Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse NASH, and miR-29 may serve as an important regulator of hepatic cholesterol homeostasis. Thus, miR-29a could be utilized as a potential therapeutic target for the treatment of non-alcoholic fatty liver disease as well as for other liver diseases associated with FC accumulation.

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“…40,44,45 Serum/plasma levels of miR-122 correlate with hepatic necro-inflammation, liver damage, cell death and increased aminotransferase levels in acute and chronic liver diseases. 44,[46][47][48][49] Interestingly, hepatic and circulating miR-122 levels do not correlate in NAFLD 14,39,[50][51][52][53][54][55] or viral hepatitis 41,47,49,56 although both have been statistically associated with various measures of disease severity in these studies. Together these studies show that miR-122 may play a role in most liver diseases.…”

Section: Microrna-122mentioning

confidence: 62%

“…14 Together these studies suggest that differentially expressed miRs in humans and animal models of NASH regulate genes with diverse functions involved in the pathogenesis of NAFLD, including metabolism of lipid and glucose, regulation of the unfolded protein response, endoplasmic reticulum stress, oxidative stress, cellular differentiation, inflammation and apoptosis. 14,36 Notably, miR-34a has been shown to be up-regulated in both human serum 50,51 and liver in humans and animal models of NAFLD. 14,55,121,122 Two recent studies suggest two differing mechanisms for the involvement of miR-34a in NASH pathogenesis through down-regulation of SIRT-1; a) leading to AMP kinase dephosphorylation and subsequent decreased phosphorylation of HMGCoA, ultimately leading to cholesterol accumulation 121 ; b) increased acetylation of p53 causing activation of apoptosis.…”

Section: Non-alcoholic Fatty Liver Disease (Nafld)mentioning

confidence: 99%

MicroRNAs in Liver Disease: Bench to Bedside

Shah

Nelson

Kowdley

2013

Journal of Clinical and Experimental Hepatology

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MicroRNAs (miRs) are small non-coding RNAs that negatively regulate gene expression by pairing with partially complementary target sequences in the 3 0 UTRs of mRNAs to promote degradation and/or block translation. Aberrant miR expression is associated with development of multiple diseases including hepatic diseases. The role of miRs in the regulation of gene expression and rapid progress in the field of microRNA research are resulting in momentum toward development of diagnostic markers and novel therapeutic strategies for human liver diseases. Recent studies provide clear evidence that miRs are abundant in the liver and modulate a diverse spectrum of biological functions, thereby supporting an association between alterations of miR homeostasis and pathological liver diseases. Here we review the role of miRs in liver as their physiological and pathological importance has been demonstrated in metabolism, immunity, viral hepatitis, oncogenesis, fatty liver diseases (alcoholic and non-alcoholic), drug-induced liver injury, fibrosis as well as acute liver failure. ( J CLIN EXP HEPATOL 2013;3:231-242)

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Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver

Cited by 286 publications

References 38 publications

Impact of embryo number and maternal undernutrition around the time of conception on insulin signaling and gluconeogenic factors and microRNAs in the liver of fetal sheep

Impact of embryo number and maternal undernutrition around the time of conception on insulin signaling and gluconeogenic factors and microRNAs in the liver of fetal sheep

Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse non-alcoholic steatohepatitis

MicroRNAs in Liver Disease: Bench to Bedside

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