Stress-activated<i>miR-21/miR-21*</i>in hepatocytes promotes lipid and glucose metabolic disorders associated with high-fat diet consumption

Calo, Nicolas; Ramadori, Pierluigi; Sobolewski, Cyril; Romero, Yannick; Maeder, Christine; Fournier, Margot; Rantakari, Pia; Zhang, Fuping; Poutanen, Matti; Dufour, Jean–François; Humar, Bostjan; Nef, Serge; Foti, Michelangelo

doi:10.1136/gutjnl-2015-310822

Cited by 107 publications

(99 citation statements)

References 70 publications

(58 reference statements)

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“…3, 4 miR-21 is greatly increased in the liver of NASH patients 5 and in animal models of NASH. 6, 7, 8, 9 In hepatocytes, miR-21 is induced by unsaturated fatty acids in a mTOR/NF- κ B-dependent manner. 10 It was recently demonstrated that liver miR-21 has an active role in NASH pathogenesis through inhibition of nuclear receptor peroxisome proliferator-activated receptor α (PPAR α ).…”

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confidence: 99%

miR-21 ablation and obeticholic acid ameliorate nonalcoholic steatohepatitis in mice

et al. 2017

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microRNAs were recently suggested to contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a disease lacking specific pharmacological treatments. In that regard, nuclear receptors are arising as key molecular targets for the treatment of nonalcoholic steatohepatitis (NASH). Here we show that, in a typical model of NASH-associated liver damage, microRNA-21 (miR-21) ablation results in a progressive decrease in steatosis, inflammation and lipoapoptosis, with impairment of fibrosis. In a complementary fast food (FF) diet NASH model, mimicking features of the metabolic syndrome, miR-21 levels increase in both liver and muscle, concomitantly with decreased expression of peroxisome proliferator-activated receptor α (PPARα), a key miR-21 target. Strikingly, miR-21 knockout mice fed the FF diet supplemented with farnesoid X receptor (FXR) agonist obeticholic acid (OCA) display minimal steatosis, inflammation, oxidative stress and cholesterol accumulation. In addition, lipoprotein metabolism was restored, including decreased fatty acid uptake and polyunsaturation, and liver and muscle insulin sensitivity fully reinstated. Finally, the miR-21/PPARα axis was found amplified in liver and muscle biopsies, and in serum, of NAFLD patients, co-substantiating its role in the development of the metabolic syndrome. By unveiling that miR-21 abrogation, together with FXR activation by OCA, significantly improves whole body metabolic parameters in NASH, our results highlight the therapeutic potential of nuclear receptor multi-targeting therapies for NAFLD.

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confidence: 99%

miR-21 ablation and obeticholic acid ameliorate nonalcoholic steatohepatitis in mice

et al. 2017

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“…Unexpectedly, levels of nucleotides as well as methionine and its derivative S-adenosylmethionine were not decreased upon knockdown of MTHFD1L (Supplemental Figure 5, A and B). NADPH is required for lipid synthesis, which supports HCC development (30)(31)(32). We performed Oil Red O staining to quantitate the levels of triglycerides and lipids in the MTHFD1L-knockdown HCC cells and in HCC tumors treated with antifolate drug (methotrexate, MTX); however, no significant difference in lipid metabolism could be detected (Supplemental Figure 5, C and D).…”

Section: Discussionmentioning

confidence: 99%

Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma

Lee¹,

Xu²,

Chiu³

et al. 2017

Journal of Clinical Investigation

115

106

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“…Deletion of murine miRNA-21 specifically in hepatocytes indicated a crucial role for hepatic miRNA-21 in metabolic disorders associated with diet-induced obesity. Deletion of miRNA-21 in hepatocytes increased insulin sensitivity and modulated the expression of multiple key metabolic transcription factors involved in fatty acid uptake, de novo-lipogenesis, gluconeogenesis and glucose output [311]. Furthermore, long-term inhibition of miRNA-21 reduced body weight and adipocyte size in db/db mice [312].…”

Section: Milk-mediated Epigenetic Signaling and Diseases Of Civilmentioning

confidence: 99%

Milk’s Role as an Epigenetic Regulator in Health and Disease

2017

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Abstract:It is the intention of this review to characterize milk's role as an epigenetic regulator in health and disease. Based on translational research, we identify milk as a major epigenetic modulator of gene expression of the milk recipient. Milk is presented as an epigenetic "doping system" of mammalian development. Milk exosome-derived micro-ribonucleic acids (miRNAs) that target DNA methyltransferases are implicated to play the key role in the upregulation of developmental genes such as FTO, INS, and IGF1. In contrast to miRNA-deficient infant formula, breastfeeding via physiological miRNA transfer provides the appropriate signals for adequate epigenetic programming of the newborn infant. Whereas breastfeeding is restricted to the lactation period, continued consumption of cow's milk results in persistent epigenetic upregulation of genes critically involved in the development of diseases of civilization such as diabesity, neurodegeneration, and cancer. We hypothesize that the same miRNAs that epigenetically increase lactation, upregulate gene expression of the milk recipient via milk-derived miRNAs. It is of critical concern that persistent consumption of pasteurized cow's milk contaminates the human food chain with bovine miRNAs, that are identical to their human analogs. Commercial interest to enhance dairy lactation performance may further increase the epigenetic miRNA burden for the milk consumer.

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Stress-activatedmiR-21/miR-21*in hepatocytes promotes lipid and glucose metabolic disorders associated with high-fat diet consumption

Cited by 107 publications

References 70 publications

miR-21 ablation and obeticholic acid ameliorate nonalcoholic steatohepatitis in mice

miR-21 ablation and obeticholic acid ameliorate nonalcoholic steatohepatitis in mice

Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma

Milk’s Role as an Epigenetic Regulator in Health and Disease

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