Tiny RNA with great effects: miR-155 in alcoholic liver disease
2016; Elsevier BV; Volume: 64; Issue: 6 Linguagem: Inglês
10.1016/j.jhep.2016.02.039
ISSN1600-0641
AutoresPhillipp Hartmann, Frank Tacke,
Tópico(s)Cancer-related molecular mechanisms research
ResumoThe pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitisJournal of HepatologyVol. 64Issue 6PreviewAlcoholic liver disease (ALD) is one of the most common causes of liver diseases in the world [1]. The clinical manifestations of ALD range from simple fatty liver to more severe forms of liver injury, including alcoholic hepatitis, cirrhosis, and hepatocellular carcinoma. Alcoholic hepatitis has high mortality and morbidity with limited treatment options. The pathomechanism of ALD involves complex interactions between the effects of alcohol and its toxic metabolites on various cell types in the liver and gut, induction of reactive oxygen species, and upregulation of the inflammatory cascade [2–5]. Full-Text PDF MicroRNAs (miRNAs) comprise a class of small RNA molecules of ∼18–25 nucleotides in length that do not contain protein-encoding information but regulate gene expression. Often, one miRNA can affect the expression of several genes, which makes miRNA an important epigenetic regulatory mechanism for many physiological and pathophysiological processes throughout the body, including in the healthy liver as well as in liver disease [1Wang B. Majumder S. Nuovo G. Kutay H. Volinia S. Patel T. et al.Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice.Hepatology. 2009; 50: 1152-1161Crossref PubMed Scopus (265) Google Scholar, 2Roderburg C. Urban G.W. Bettermann K. Vucur M. Zimmermann H. Schmidt S. et al.Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis.Hepatology. 2011; 53: 209-218Crossref PubMed Scopus (659) Google Scholar, 3Zhang Y. Wei W. Cheng N. Wang K. Li B. Jiang X. et al.Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling.Hepatology. 2012; 56: 1631-1640Crossref PubMed Scopus (238) Google Scholar, 4Miller A.M. Gilchrist D.S. Nijjar J. Araldi E. Ramirez C.M. Lavery C.A. et al.MiR-155 has a protective role in the development of non-alcoholic hepatosteatosis in mice.PLoS One. 2013; 8e72324Crossref PubMed Scopus (97) Google Scholar]. miRNAs modulate gene expression by several mechanisms, such as targeting mRNA cleavage, or post-translational repression or activation. Thereby, in the liver they affect inflammation, fibrosis, and lipid and glucose metabolism [[5]Szabo G. Bala S. MicroRNAs in liver disease.Nat Rev Gastroenterol Hepatol. 2013; 10: 542-552Crossref PubMed Scopus (456) Google Scholar]. A multitude of different miRNAs with their diverse functions offer numerous targets for novel treatment options. MicroRNA-155 (miR-155) appears to be one of the biologically most relevant miRNAs in several liver diseases [1Wang B. Majumder S. Nuovo G. Kutay H. Volinia S. Patel T. et al.Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice.Hepatology. 2009; 50: 1152-1161Crossref PubMed Scopus (265) Google Scholar, 3Zhang Y. Wei W. Cheng N. Wang K. Li B. Jiang X. et al.Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling.Hepatology. 2012; 56: 1631-1640Crossref PubMed Scopus (238) Google Scholar, 4Miller A.M. Gilchrist D.S. Nijjar J. Araldi E. Ramirez C.M. Lavery C.A. et al.MiR-155 has a protective role in the development of non-alcoholic hepatosteatosis in mice.PLoS One. 2013; 8e72324Crossref PubMed Scopus (97) Google Scholar, 6Sarkar N. Panigrahi R. Pal A. Biswas A. Singh S.P. Kar S.K. et al.Expression of microRNA-155 correlates positively with the expression of Toll-like receptor 7 and modulates hepatitis B virus via C/EBP-beta in hepatocytes.J Viral Hepat. 2015; 22: 817-827Crossref PubMed Scopus (36) Google Scholar, 7Lin X. Jia J. Du T. Li W. Wang X. Wei J. et al.Overexpression of miR-155 in the liver of transgenic mice alters the expression profiling of hepatic genes associated with lipid metabolism.PLoS One. 2015; 10e0118417Google Scholar, 8Longchamps R.J. Abey S.K. Martino A.C. Henderson W.A. Letter: gender-associated cell-free microRNA profiles in non-alcoholic fatty liver disease.Aliment Pharmacol Ther. 2014; 39: 997-998Crossref PubMed Scopus (6) Google Scholar, 9Bala S. Marcos M. Kodys K. Csak T. Catalano D. Mandrekar P. et al.Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor alpha (TNF{alpha}) production via increased mRNA half-life in alcoholic liver disease.J Biol Chem. 2011; 286: 1436-1444Crossref PubMed Scopus (327) Google Scholar, 10Bala S. Szabo G. MicroRNA Signature in Alcoholic Liver Disease.Int J Hepatol. 2012; 2012: 498232Crossref PubMed Google Scholar, 11Chen W. Han C. Zhang J. Song K. Wang Y. Wu T. Deletion of Mir155 prevents Fas-induced liver injury through up-regulation of Mcl-1.Am J Pathol. 2015; 185: 1033-1044Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. It has been described that miR-155 controls functional networks in the liver related to injury responses, steatosis, inflammation, fibrosis, and carcinogenesis. However, miR-155 seems to exert pleiotropic functions depending on the etiology and disease context. During Hepatitis B virus (HBV) infection, miR-155 is suppressed; and the ectopic expression of miRNA-155 in vitro decreases HBV load by inhibiting CCAAT/enhancer-binding protein-β (C/EBPβ) [[6]Sarkar N. Panigrahi R. Pal A. Biswas A. Singh S.P. Kar S.K. et al.Expression of microRNA-155 correlates positively with the expression of Toll-like receptor 7 and modulates hepatitis B virus via C/EBP-beta in hepatocytes.J Viral Hepat. 2015; 22: 817-827Crossref PubMed Scopus (36) Google Scholar]. On the contrary, it is found at elevated levels in livers of patients infected with Hepatitis C virus (HCV); and HCV-induced miR-155 expression fosters hepatocyte proliferation and tumorigenesis via increased WNT signaling [[3]Zhang Y. Wei W. Cheng N. Wang K. Li B. Jiang X. et al.Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling.Hepatology. 2012; 56: 1631-1640Crossref PubMed Scopus (238) Google Scholar]. Additionally, patients with chronic HCV infection who responded to antiviral treatment do not show augmented miR-155 in peripheral monocytes in contrast to non-responders [[12]Bala S. Tilahun Y. Taha O. Alao H. Kodys K. Catalano D. et al.Increased microRNA-155 expression in the serum and peripheral monocytes in chronic HCV infection.J Transl Med. 2012; 10: 151Crossref PubMed Scopus (124) Google Scholar]. Similarly ambiguous and diverse roles are found in non-viral liver diseases: miR-155 knockout (KO) mice are protected from Fas-induced liver injury by activation of the anti-apoptotic protein myeloid cell leukemia-1 (MCL-1) [[11]Chen W. Han C. Zhang J. Song K. Wang Y. Wu T. Deletion of Mir155 prevents Fas-induced liver injury through up-regulation of Mcl-1.Am J Pathol. 2015; 185: 1033-1044Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. Mice fed a high-fat diet (HFD) over 24 weeks display an upregulated hepatic expression of miR-155 [[4]Miller A.M. Gilchrist D.S. Nijjar J. Araldi E. Ramirez C.M. Lavery C.A. et al.MiR-155 has a protective role in the development of non-alcoholic hepatosteatosis in mice.PLoS One. 2013; 8e72324Crossref PubMed Scopus (97) Google Scholar]. Mice deficient in miR-155 display an aggravated liver phenotype after HFD feeding relative to wild-type mice with increased hepatic expression of genes important in glucose regulation (PCK1, CEBPA), fatty acid uptake (CD36) and lipid metabolism (FASN, FABP4, LPL, ABCD2, PLA2G7) [[4]Miller A.M. Gilchrist D.S. Nijjar J. Araldi E. Ramirez C.M. Lavery C.A. et al.MiR-155 has a protective role in the development of non-alcoholic hepatosteatosis in mice.PLoS One. 2013; 8e72324Crossref PubMed Scopus (97) Google Scholar]. As a responsible mediator for this phenotype, the miR-155 target gene NR1H3 (LXRα) has been postulated [[4]Miller A.M. Gilchrist D.S. Nijjar J. Araldi E. Ramirez C.M. Lavery C.A. et al.MiR-155 has a protective role in the development of non-alcoholic hepatosteatosis in mice.PLoS One. 2013; 8e72324Crossref PubMed Scopus (97) Google Scholar]. Correspondingly, mice with hepatic overexpression of miR-155 are protected from HFD-induced liver disease; it has been proposed that the miR-155 target and regulator of lipid metabolism carboxylesterase 3/triacylglycerol hydrolase (CES3/TGH) largely mediated this protection [[7]Lin X. Jia J. Du T. Li W. Wang X. Wei J. et al.Overexpression of miR-155 in the liver of transgenic mice alters the expression profiling of hepatic genes associated with lipid metabolism.PLoS One. 2015; 10e0118417Google Scholar]. Interestingly, in non-alcoholic fatty liver disease (NAFLD), gender-specific differences in miRNA profiles appear to exist with male NAFLD patients possessing higher hsa-miR-155-5p serum levels relative to female NAFLD patients [[8]Longchamps R.J. Abey S.K. Martino A.C. Henderson W.A. Letter: gender-associated cell-free microRNA profiles in non-alcoholic fatty liver disease.Aliment Pharmacol Ther. 2014; 39: 997-998Crossref PubMed Scopus (6) Google Scholar], supporting the potential use of circulating miR-155 levels for individualized risk assessment in liver disease. Experimental non-alcoholic steatohepatitis (NASH) brought about either by choline-deficient and amino acid-defined (CDAA) diet or by methionine-choline-deficient (MCD) diet induces miR-155 expression in the murine liver [1Wang B. Majumder S. Nuovo G. Kutay H. Volinia S. Patel T. et al.Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice.Hepatology. 2009; 50: 1152-1161Crossref PubMed Scopus (265) Google Scholar, 13Csak T. Bala S. Lippai D. Kodys K. Catalano D. Iracheta-Vellve A. et al.MicroRNA-155 deficiency attenuates liver steatosis and fibrosis without reducing inflammation in a mouse model of steatohepatitis.PLoS One. 2015; 10e0129251Crossref Scopus (72) Google Scholar]. In contrast to animal studies using HFD feeding, deficiency of miR-155 attenuates steatosis and fibrosis in MCD-induced NASH by downregulation of lipid metabolism genes (ADRP, DGAT2, CPT1A, FABP4) and by alteration of fibrosis-related genes (decreased SMAD3, and PDGF; increased nuclear binding of C/EBPβ), respectively; but not hepatic injury and inflammation [[13]Csak T. Bala S. Lippai D. Kodys K. Catalano D. Iracheta-Vellve A. et al.MicroRNA-155 deficiency attenuates liver steatosis and fibrosis without reducing inflammation in a mouse model of steatohepatitis.PLoS One. 2015; 10e0129251Crossref Scopus (72) Google Scholar]. miR-155 also promotes the development of hepatocellular carcinoma (HCC) in chronic HCV infection and in CDAA-induced NASH [1Wang B. Majumder S. Nuovo G. Kutay H. Volinia S. Patel T. et al.Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice.Hepatology. 2009; 50: 1152-1161Crossref PubMed Scopus (265) Google Scholar, 3Zhang Y. Wei W. Cheng N. Wang K. Li B. Jiang X. et al.Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling.Hepatology. 2012; 56: 1631-1640Crossref PubMed Scopus (238) Google Scholar]. The group around Dr. Szabo has investigated the role of miR-155 in the past, focusing on its involvement in the pathogenesis of alcoholic liver disease (ALD). It evidenced that miR-155 is highly expressed in alcohol-exposed RAW 264.7 macrophages, as well as in isolated hepatocytes and Kupffer cells (KCs) of alcohol fed mice [9Bala S. Marcos M. Kodys K. Csak T. Catalano D. Mandrekar P. et al.Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor alpha (TNF{alpha}) production via increased mRNA half-life in alcoholic liver disease.J Biol Chem. 2011; 286: 1436-1444Crossref PubMed Scopus (327) Google Scholar, 10Bala S. Szabo G. MicroRNA Signature in Alcoholic Liver Disease.Int J Hepatol. 2012; 2012: 498232Crossref PubMed Google Scholar]; and its high level in macrophages amplifies the production of the important mediator of hepatic steatosis, inflammation and liver cell death in ALD, tumor necrosis factor alpha (TNF-α) [[9]Bala S. Marcos M. Kodys K. Csak T. Catalano D. Mandrekar P. et al.Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor alpha (TNF{alpha}) production via increased mRNA half-life in alcoholic liver disease.J Biol Chem. 2011; 286: 1436-1444Crossref PubMed Scopus (327) Google Scholar]. In this issue of Journal of Hepatology, Bala et al. [[14]Bala S. Csak T. Saha B. Zatsiorsky J. Kodys K. Catalano D. et al.The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis.J Hepatol. 2016; 64: 1378-1387Abstract Full Text Full Text PDF Scopus (178) Google Scholar] demonstrate in their excellent work that miR-155 worsens alcohol-induced steatohepatitis and liver fibrosis in vivo (Fig. 1). To study the specific role of miR-155 in the aforementioned liver diseases, wild-type (WT) mice and miR-155 KO mice as well as Toll-like receptor (TLR)4 KO mice were treated with Lieber-DeCarli alcohol diet over five weeks, or with intraperitoneal injections of carbon tetrachloride (CCl4) over two or nine weeks, two established models to induce experimental ALD and liver fibrosis, respectively [[14]Bala S. Csak T. Saha B. Zatsiorsky J. Kodys K. Catalano D. et al.The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis.J Hepatol. 2016; 64: 1378-1387Abstract Full Text Full Text PDF Scopus (178) Google Scholar]. miR-155 KO mice were protected from consequences of chronic alcohol feeding as evidenced by significantly lower hepatic triglycerides, alanine aminotransferase (ALT) levels (marker of liver injury), and thiobarbituric acid reactive substances (TBARS, measure of lipid peroxidation) compared with WT mice after alcohol feeding. The miR-155 target, peroxisome proliferator-activated receptor alpha (PPARα) [[15]Zhou S. Wang Y. Meng Y. Xiao C. Liu Z. Brohawn P. et al.In vivo therapeutic success of MicroRNA-155 (miR-155) antagomir in a mouse model of lupus alveolar hemorrhage.Arthritis Rheumatol. 2015; ([in press])Google Scholar] as a modulator of lipid metabolism, oxidative stress, inflammatory response and fibrogenesis has been found to be decreased in ALD [[16]Nakajima T. Kamijo Y. Tanaka N. Sugiyama E. Tanaka E. Kiyosawa K. et al.Peroxisome proliferator-activated receptor alpha protects against alcohol-induced liver damage.Hepatology. 2004; 40: 972-980Crossref PubMed Scopus (192) Google Scholar]. The authors hence chose to measure PPARα gene expression, which confirmed lower mRNA levels in WT mice after ethanol feeding relative to isocaloric WT mice, and they were also lower in miR-155 KO mice after alcohol feeding [[14]Bala S. Csak T. Saha B. Zatsiorsky J. Kodys K. Catalano D. et al.The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis.J Hepatol. 2016; 64: 1378-1387Abstract Full Text Full Text PDF Scopus (178) Google Scholar]. Bala et al. then assessed the binding of peroxisome proliferator-activated receptor response element (PPRE) and PPARα using an electrophoretic mobility shift assay (EMSA), and found reduced binding of PPRE and a trend toward reduction in binding of PPARα in WT mice after alcohol feeding, which was not evidenced in their KO counterparts. To further support the role of miR-155 in steatosis by modulating PPRE binding, a decrease of PPRE binding in isolated hepatocytes from WT mice after induction of steatosis by MCP-1 treatment in vitro was demonstrated, which was not observed in treated hepatocytes from miR-155 KO mice (Fig. 1). PPARγ, a member of the same family as PPARα, is regulated by miR-155 as well, since naïve and alcohol-treated RAW 264.7 macrophages both showed higher PPARγ gene expression after treatment with a miR-155 inhibitor in vitro. Interestingly, PPARγ and PPARα target genes important for lipid metabolism and fatty acid uptake, such as FABP4, LXRα, ACC1, LDL receptor, and HMGCR were found to be upregulated in alcohol fed WT mice but not in alcohol fed miR-155 KO mice [[14]Bala S. Csak T. Saha B. Zatsiorsky J. Kodys K. Catalano D. et al.The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis.J Hepatol. 2016; 64: 1378-1387Abstract Full Text Full Text PDF Scopus (178) Google Scholar]. A blood lipid profile of the mouse groups would have been interesting besides the above-mentioned changes in gene expression, as miR-155 KO mice display an altered profile already at baseline [[4]Miller A.M. Gilchrist D.S. Nijjar J. Araldi E. Ramirez C.M. Lavery C.A. et al.MiR-155 has a protective role in the development of non-alcoholic hepatosteatosis in mice.PLoS One. 2013; 8e72324Crossref PubMed Scopus (97) Google Scholar]. As the cytokine MCP-1 triggers liver steatosis [[17]Baeck C. Wehr A. Karlmark K.R. Heymann F. Vucur M. Gassler N. et al.Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury.Gut. 2012; 61: 416-426Crossref PubMed Scopus (386) Google Scholar] and the recruitment of macrophages to injured livers [[18]Marra F. Tacke F. Roles for chemokines in liver disease.Gastroenterology. 2014; 147e571Abstract Full Text Full Text PDF PubMed Scopus (532) Google Scholar], Bala et al. measured MCP-1 levels in liver and plasma in the respective mouse groups with and without LPS. They found significantly induced MCP-1 concentrations in WT mice following alcohol feeding in particular after LPS challenge, which were significantly higher than in their KO counterparts. As miR-155 modulates inflammation [[9]Bala S. Marcos M. Kodys K. Csak T. Catalano D. Mandrekar P. et al.Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor alpha (TNF{alpha}) production via increased mRNA half-life in alcoholic liver disease.J Biol Chem. 2011; 286: 1436-1444Crossref PubMed Scopus (327) Google Scholar], the authors then assessed inflammatory markers and found increased TNF-α and interleukin-1β (IL-1β) concentrations in liver and plasma of WT mice compared with miR-155 KO mice following ethanol administration and LPS challenge [[14]Bala S. Csak T. Saha B. Zatsiorsky J. Kodys K. Catalano D. et al.The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis.J Hepatol. 2016; 64: 1378-1387Abstract Full Text Full Text PDF Scopus (178) Google Scholar]. Similarly, macrophage activation markers (CD68 and MIP2) as well as the pro-fibrotic F4/80+ CD163+ CD206+ macrophages were detected at significantly augmented levels in WT mice after alcohol feeding relative to isocaloric fed mice and also higher than in alcohol fed KO mice, while isocaloric KO mice showed an increased percentage of M2 macrophages. Importantly, the M2 macrophage phenotype had previously been associated with protective roles against steatosis and liver injury in mouse models of ALD [[19]Wan J. Benkdane M. Teixeira-Clerc F. Bonnafous S. Louvet A. Lafdil F. et al.M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease.Hepatology. 2014; 59: 130-142Crossref PubMed Scopus (368) Google Scholar] and NAFLD [[20]Bartneck M. Fech V. Ehling J. Govaere O. Theresa Warzecha K. Hittatiya K. et al.Histidine-rich glycoprotein promotes macrophage activation and inflammation in chronic liver disease.Hepatology. 2015; (in press)PubMed Google Scholar]. Bala et al. conducted additional in vitro studies, and determined that isolated KCs from isocaloric fed miR-155 deficient mice exhibited a predominance of the M2 phenotype when treated with M1 polarizing stimuli, as KCs from miR-155 KO mice showed elevated gene expression of the M2 marker arginase 1 and M2 transcriptional regulators C/EBPβ and STAT3 after stimulation with LPS or IFNγ vs. WT-KCs. However, miR-155 might also play a role in M1 macrophage polarization, as LPS or IFNγ treatment of KO-KCs induced expression of the M1 marker iNOS and M1 transcriptional regulator HIF1α more strongly than in WT-KCs [[14]Bala S. Csak T. Saha B. Zatsiorsky J. Kodys K. Catalano D. et al.The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis.J Hepatol. 2016; 64: 1378-1387Abstract Full Text Full Text PDF Scopus (178) Google Scholar], which was unexpected and to some extent in contrast to other reports [[21]Cai X. Yin Y. Li N. Zhu D. Zhang J. Zhang C.Y. et al.Re-polarization of tumor-associated macrophages to pro-inflammatory M1 macrophages by microRNA-155.J Mol Cell Biol. 2012; 4: 341-343Crossref PubMed Scopus (196) Google Scholar]. As fibrosis is a common consequence of chronic injury and inflammation, pro-fibrotic genes such as TGFβ, procollagen 1α and vimentin were found reduced in miR-155 KO compared with WT mice after ethanol treatment. To better evaluate the role of miR-155 in liver fibrosis, the more potent CCl4-induced liver fibrosis model was employed [17Baeck C. Wehr A. Karlmark K.R. Heymann F. Vucur M. Gassler N. et al.Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury.Gut. 2012; 61: 416-426Crossref PubMed Scopus (386) Google Scholar, 22Seki E. Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut.J Physiol. 2012; 590: 447-458Crossref PubMed Scopus (306) Google Scholar, 23Seki E. De Minicis S. Osterreicher C.H. Kluwe J. Osawa Y. Brenner D.A. et al.TLR4 enhances TGF-beta signaling and hepatic fibrosis.Nat Med. 2007; 13: 1324-1332Crossref PubMed Scopus (1484) Google Scholar]. Analogous to the above-mentioned results, miR-155 KO mice were protected from inflammation and fibrosis after CCl4 injections [[14]Bala S. Csak T. Saha B. Zatsiorsky J. Kodys K. Catalano D. et al.The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis.J Hepatol. 2016; 64: 1378-1387Abstract Full Text Full Text PDF Scopus (178) Google Scholar]. WT mice experienced a significant induction of fibrosis after CCl4 injections, and an increase of miR-155 in the liver in relation to control mice. The authors could reproduce the miR-155 induction in cirrhotic livers of alcoholic patients. Both ALD and CCl4-induced liver fibrosis depend on elevated plasma LPS levels [22Seki E. Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut.J Physiol. 2012; 590: 447-458Crossref PubMed Scopus (306) Google Scholar, 23Seki E. De Minicis S. Osterreicher C.H. Kluwe J. Osawa Y. Brenner D.A. et al.TLR4 enhances TGF-beta signaling and hepatic fibrosis.Nat Med. 2007; 13: 1324-1332Crossref PubMed Scopus (1484) Google Scholar]. Bala et al. thus determined plasma LPS, and found a spike of its levels in alcohol fed WT mice which was not observed in ethanol fed miR-155 KO mice [[14]Bala S. Csak T. Saha B. Zatsiorsky J. Kodys K. Catalano D. et al.The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis.J Hepatol. 2016; 64: 1378-1387Abstract Full Text Full Text PDF Scopus (178) Google Scholar]. Hepatic miR-155 appears to depend on LPS, as LPS injections induced miR-155 expression in WT mice the source of which were liver mononuclear cells (MNCs) as opposed to hepatocytes. Furthermore, as the authors show, this induction is dependent on TLR4, a critical LPS receptor in liver disease [22Seki E. Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut.J Physiol. 2012; 590: 447-458Crossref PubMed Scopus (306) Google Scholar, 23Seki E. De Minicis S. Osterreicher C.H. Kluwe J. Osawa Y. Brenner D.A. et al.TLR4 enhances TGF-beta signaling and hepatic fibrosis.Nat Med. 2007; 13: 1324-1332Crossref PubMed Scopus (1484) Google Scholar], since ethanol fed TLR4 KO mice did not exhibit elevated hepatic miR-155 levels [[14]Bala S. Csak T. Saha B. Zatsiorsky J. Kodys K. Catalano D. et al.The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis.J Hepatol. 2016; 64: 1378-1387Abstract Full Text Full Text PDF Scopus (178) Google Scholar]. Combining the available experimental evidence from different models, miR-155 appears to play a hepatoprotective role in HFD-induced liver disease [4Miller A.M. Gilchrist D.S. Nijjar J. Araldi E. Ramirez C.M. Lavery C.A. et al.MiR-155 has a protective role in the development of non-alcoholic hepatosteatosis in mice.PLoS One. 2013; 8e72324Crossref PubMed Scopus (97) Google Scholar, 7Lin X. Jia J. Du T. Li W. Wang X. Wei J. et al.Overexpression of miR-155 in the liver of transgenic mice alters the expression profiling of hepatic genes associated with lipid metabolism.PLoS One. 2015; 10e0118417Google Scholar] and HBV [[6]Sarkar N. Panigrahi R. Pal A. Biswas A. Singh S.P. Kar S.K. et al.Expression of microRNA-155 correlates positively with the expression of Toll-like receptor 7 and modulates hepatitis B virus via C/EBP-beta in hepatocytes.J Viral Hepat. 2015; 22: 817-827Crossref PubMed Scopus (36) Google Scholar], and an exacerbating role in HCV [[3]Zhang Y. Wei W. Cheng N. Wang K. Li B. Jiang X. et al.Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling.Hepatology. 2012; 56: 1631-1640Crossref PubMed Scopus (238) Google Scholar], Fas-induced liver injury [[11]Chen W. Han C. Zhang J. Song K. Wang Y. Wu T. Deletion of Mir155 prevents Fas-induced liver injury through up-regulation of Mcl-1.Am J Pathol. 2015; 185: 1033-1044Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar], NASH induced by CDAA diet [[1]Wang B. Majumder S. Nuovo G. Kutay H. Volinia S. Patel T. et al.Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice.Hepatology. 2009; 50: 1152-1161Crossref PubMed Scopus (265) Google Scholar] and MCD diet [[13]Csak T. Bala S. Lippai D. Kodys K. Catalano D. Iracheta-Vellve A. et al.MicroRNA-155 deficiency attenuates liver steatosis and fibrosis without reducing inflammation in a mouse model of steatohepatitis.PLoS One. 2015; 10e0129251Crossref Scopus (72) Google Scholar], and finally ALD [[14]Bala S. Csak T. Saha B. Zatsiorsky J. Kodys K. Catalano D. et al.The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis.J Hepatol. 2016; 64: 1378-1387Abstract Full Text Full Text PDF Scopus (178) Google Scholar]. Bala et al. show in an exceptional work [[14]Bala S. Csak T. Saha B. Zatsiorsky J. Kodys K. Catalano D. et al.The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis.J Hepatol. 2016; 64: 1378-1387Abstract Full Text Full Text PDF Scopus (178) Google Scholar] how miR-155, or the lack thereof, modulates many signaling pathways affecting steatosis and lipid metabolism, inflammation, fibrosis, oxidative stress and macrophage polarization in ALD (Fig. 1). While this study is certainly both extensive and comprehensive, it at the same time exposes new questions for future research. For instance, while endotoxemia and subsequent TLR signaling convincingly explains miR-155 upregulation in macrophages in ALD, it remains to be determined which pathways induce miR-155 in hepatocytes. Moreover, although a large proportion of the steatogenic and inflammatory processes could be explained by the effects of miR-155 on PPAR signaling, it would be interesting to see how much of the impact of miR-155 in ALD is independent of PPAR signaling, possibly by creating a double-KO mouse for miR-155 and a gene involved in PPAR signaling. Also, model-dependent differences in steatosis and fibrosis development upon HFD, MCD diet or alcohol feeding require further comparative analyses, alongside in-depth analysis of human samples from different stages of NAFLD and ALD. Finally, from a translational perspective, it would be intriguing to investigate the therapeutic effect of a specific miR-155 inhibitor in ALD or NAFLD in vivo, such as a miR-155 antagomir to silence miR-155 expression [[15]Zhou S. Wang Y. Meng Y. Xiao C. Liu Z. Brohawn P. et al.In vivo therapeutic success of MicroRNA-155 (miR-155) antagomir in a mouse model of lupus alveolar hemorrhage.Arthritis Rheumatol. 2015; ([in press])Google Scholar]. In conclusion, miR-155 appears to be a key miRNA that regulates important pathways in the initiation and progression of ALD, leading from exogenous stress to hepatic inflammation and fibrosis, implying that targeting dysregulated miR-155 might have therapeutic potential in ALD. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The manuscript was supported in part by the Deutsche Forschungsgemeinschaft (DFG) grants 7336/1-1 (to PH), Ta434/5-1 (to FT) and SFB/TRR57 (to FT).
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