Genetic and Epigenetic Regulation in Nonalcoholic Fatty Liver Disease (NAFLD)
Abstract
1. Introduction
2. Genetics in NAFLD
3. Epigenetics in NAFLD
3.1. Histone Modifications
3.2. DNA Methylation
3.3. MicroRNAs
4. Concluding Remarks
Acknowledgments
Author Contributions
Conflicts of Interest
References
- Ludwig, J.; Viggiano, T.R.; McGill, D.B.; Oh, B.J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin. Proc. 1980, 55, 434–438. [Google Scholar] [PubMed]
- Italian Association for the Study of the Liver (AISF). AISF position paper on nonalcoholic fatty liver disease (NAFLD): Updates and future directions. Dig. Liver Dis. 2017, 49, 471–483. [Google Scholar]
- Chalasani, N.; Younossi, Z.; Lavine, J.E.; Diehl, A.M.; Brunt, E.M.; Cusi, K.; Charlton, M.; Sanyal, A.J. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012, 55, 2005–2023. [Google Scholar] [CrossRef] [PubMed]
- Musso, G.; Gambino, R.; Cassader, M.; Pagano, G. Meta-analysis: Natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann. Med. 2011, 43, 617–649. [Google Scholar] [CrossRef] [PubMed]
- Piscaglia, F.; Svegliati-Baroni, G.; Barchetti, A.; Pecorelli, A.; Marinelli, S.; Tiribelli, C.; Bellentani, S. HCC-NAFLD Italian Study Group. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study. Hepatology 2016, 63, 827–838. [Google Scholar]
- Farrell, G.C.; van Rooyen, D.; Gan, L.; Chitturi, S. NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications. Gut Liver 2012, 6, 149–171. [Google Scholar] [CrossRef] [PubMed]
- Targher, G.; Byrne, C.D.; Lonardo, A.; Zoppini, G.; Barbui, C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis. J. Hepatol. 2016, 65, 589–600. [Google Scholar] [CrossRef] [PubMed]
- Kim, J.; Lee, D.Y.; Park, S.E.; Park, C.-Y.; Lee, W.-Y.; Oh, K.-W.; Park, S.-W.; Rhee, E.-J. Increased risk for development of coronary artery calcification in subjects with non-alcoholic fatty liver disease and systemic inflammation. PLoS ONE 2017, 12, e0180118. [Google Scholar] [CrossRef] [PubMed]
- Sinn, D.H.; Kang, D.; Chang, Y.; Ryu, S.; Gu, S.; Kim, H.; Seong, D.; Cho, S.J.; Yi, B.-K.; Park, H.-D.; et al. Non-alcoholic fatty liver disease and progression of coronary artery calcium score: A retrospective cohort study. Gut 2017, 66, 323–329. [Google Scholar] [CrossRef] [PubMed]
- Vernon, G.; Baranova, A.; Younossi, Z.M. Systematic review: The epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment. Pharmacol. Ther. 2011, 34, 274–285. [Google Scholar] [CrossRef] [PubMed]
- Non-alcoholic Fatty Liver Disease Study Group; Lonardo, A.; Bellentani, S.; Argo, C.K.; Ballestri, S.; Byrne, C.D.; Caldwell, S.H.; Cortez-Pinto, H.; Grieco, A.; Machado, M.V.; et al. Epidemiological modifiers of non-alcoholic fatty liver disease: Focus on high-risk groups. Dig. Liver Dis. 2015, 47, 997–1006. [Google Scholar]
- Cordero, P.; Campion, J.; Milagro, F.I.; Martinez, J.A. Transcriptomic and epigenetic changes in early liver steatosis associated to obesity: Effect of dietary methyl donor supplementation. Mol. Genet. Metab. 2013, 110, 388–395. [Google Scholar] [CrossRef] [PubMed]
- Targher, G.; Lonardo, A.; Byrne, C.D. Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus. Nat. Rev. Endocrinol. 2018, 14, 99–114. [Google Scholar] [PubMed]
- Colak, Y.; Yesil, A.; Mutlu, H.H.; Caklili, O.T.; Ulasoglu, C.; Senates, E.; Takir, M.; Kostek, O.; Yilmaz, Y.; Yilmaz Enc, F.; et al. A potential treatment of non-alcoholic fatty liver disease with SIRT1 activators. J. Gastrointestin. Liver Dis. 2014, 23, 311–319. [Google Scholar] [PubMed]
- Rinella, M.E. Nonalcoholic fatty liver disease: A systematic review. JAMA 2015, 313, 2263–2273. [Google Scholar] [CrossRef] [PubMed]
- Wong, V.W.-S.; Chitturi, S.; Wong, G.L.-H.; Yu, J.; Chan, H.L.-Y.; Farrell, G.C. Pathogenesis and novel treatment options for non-alcoholic steatohepatitis. Lancet Gastroenterol. Hepatol. 2016, 1, 56–67. [Google Scholar] [CrossRef]
- Piccinino, F.; Sagnelli, E.; Pasquale, G.; Giusti, G. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J. Hepatol. 1986, 2, 165–173. [Google Scholar] [CrossRef]
- Romero-Gómez, M.; Zelber-Sagi, S.; Trenell, M. Treatment of NAFLD with diet, physical activity and exercise. J. Hepatol. 2017, 67, 829–846. [Google Scholar]
- Townsend, S.A.; Newsome, P.N. Review article: New treatments in non-alcoholic fatty liver disease. Aliment. Pharmacol. Ther. 2017, 46, 494–507. [Google Scholar] [CrossRef] [PubMed]
- Romeo, S.; Kozlitina, J.; Xing, C.; Pertsemlidis, A.; Cox, D.; Pennacchio, L.A.; Boerwinkle, E.; Cohen, J.C.; Hobbs, H.H. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 2008, 40, 1461–1465. [Google Scholar] [CrossRef] [PubMed]
- Anstee, Q.M.; Day, C.P. The genetics of NAFLD. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 645–655. [Google Scholar] [CrossRef] [PubMed]
- Sookoian, S.; Castaño, G.O.; Burgueño, A.L.; Gianotti, T.F.; Rosselli, M.S.; Pirola, C.J. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J. Lipid Res. 2009, 50, 2111–2116. [Google Scholar] [CrossRef] [PubMed]
- Xu, J.; Xin, Y.; Lü, W.; Lin, Z.; Zhang, D.; Zhang, M.; Dong, Q.; Jiang, X.; Xuan, S. Polymorphism rs738409 in PNPLA3 is associated with inherited susceptibility to non-alcoholic fatty liver disease. Zhonghua Gan Zang Bing Za Zhi 2013, 21, 619–623. [Google Scholar] [PubMed]
- Zhang, L.; You, W.; Zhang, H.; Peng, R.; Zhu, Q.; Yao, A.; Li, X.; Zhou, Y.; Wang, X.; Pu, L.; et al. PNPLA3 polymorphisms (rs738409) and non-alcoholic fatty liver disease risk and related phenotypes: A meta-analysis. J. Gastroenterol. Hepatol. 2015, 30, 821–829. [Google Scholar] [CrossRef]
- Liu, Y.-L.; Patman, G.L.; Leathart, J.B.S.; Piguet, A.-C.; Burt, A.D.; Dufour, J.-F.; Day, C.P.; Daly, A.K.; Reeves, H.L.; Anstee, Q.M. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J. Hepatol. 2014, 61, 75–81. [Google Scholar] [CrossRef] [PubMed]
- Valenti, L.; Motta, B.M.; Soardo, G.; Iavarone, M.; Donati, B.; Sangiovanni, A.; Carnelutti, A.; Dongiovanni, P.; Rametta, R.; Bertelli, C.; et al. PNPLA3 I148M Polymorphism, Clinical Presentation, and Survival in Patients with Hepatocellular Carcinoma. PLoS ONE 2013, 8, e75982. [Google Scholar] [CrossRef] [PubMed]
- Hyysalo, J.; Stojkovic, I.; Kotronen, A.; Hakkarainen, A.; Sevastianova, K.; Makkonen, J.; Lundbom, N.; Rissanen, A.; Krauss, R.M.; Melander, O.; et al. Genetic variation in PNPLA3 but not APOC3 influences liver fat in non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 2012, 27, 951–956. [Google Scholar] [CrossRef] [PubMed]
- Pirazzi, C.; Adiels, M.; Burza, M.A.; Mancina, R.M.; Levin, M.; Ståhlman, M.; Taskinen, M.-R.; Orho-Melander, M.; Perman, J.; Pujia, A.; et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J. Hepatol. 2012, 57, 1276–1282. [Google Scholar] [CrossRef] [PubMed]
- He, S.; McPhaul, C.; Li, J.Z.; Garuti, R.; Kinch, L.; Grishin, N.V.; Cohen, J.C.; Hobbs, H.H. A Sequence Variation (I148M) in PNPLA3 Associated with Nonalcoholic Fatty Liver Disease Disrupts Triglyceride Hydrolysis. J. Biol. Chem. 2010, 285, 6706–6715. [Google Scholar] [CrossRef] [PubMed]
- Winberg, M.E.; Khalaj Motlagh, M.; Stenkula, K.G.; Holm, C.; Jones, H.A. Adiponutrin: A multimeric plasma protein. Biochem. Biophys. Res. Commun. 2014, 446, 1114–1119. [Google Scholar] [CrossRef] [PubMed]
- BasuRay, S.; Smagris, E.; Cohen, J.C.; Hobbs, H.H. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 2017, 66, 1111–1124. [Google Scholar] [CrossRef] [PubMed]
- Chamorro, A.-J.; Torres, J.-L.; Mirón-Canelo, J.-A.; González-Sarmiento, R.; Laso, F.-J.; Marcos, M. Systematic review with meta-analysis: The I148M variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3 ) is significantly associated with alcoholic liver cirrhosis. Aliment. Pharmacol. Ther. 2014, 40, 571–581. [Google Scholar] [CrossRef] [PubMed]
- Sagnelli, C.; Merli, M.; Uberti-Foppa, C.; Hasson, H.; Cirillo, G.; Grandone, A.; Salpietro, S.; Minichini, C.; Del Giudice, E.M.; Lazzarin, A.; et al. Impact of PNPLA3 variants on liver histology of 168 patients with HIV infection and chronic hepatitis C. Clin. Microbiol. Infect. 2016, 22, 372–378. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Shen, J.; Wong, G.L.-H.; Chan, H.L.-Y.; Chan, R.S.-M.; Chan, H.-Y.; Chu, W.C.-W.; Cheung, B.H.-K.; Yeung, D.K.-W.; Li, L.S.; Sea, M.M.-M.; et al. PNPLA3 gene polymorphism and response to lifestyle modification in patients with nonalcoholic fatty liver disease. J. Gastroenterol. Hepatol. 2015, 30, 139–146. [Google Scholar] [CrossRef] [PubMed]
- Mancina, R.M.; Dongiovanni, P.; Petta, S.; Pingitore, P.; Meroni, M.; Rametta, R.; Borén, J.; Montalcini, T.; Pujia, A.; Wiklund, O.; et al. The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent. Gastroenterology 2016, 150, 1219–1230. [Google Scholar] [CrossRef] [PubMed]
- Donati, B.; Dongiovanni, P.; Romeo, S.; Meroni, M.; McCain, M.; Miele, L.; Petta, S.; Maier, S.; Rosso, C.; De Luca, L.; et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci. Rep. 2017, 7, 4492. [Google Scholar] [CrossRef] [PubMed]
- Kozlitina, J.; Smagris, E.; Stender, S.; Nordestgaard, B.G.; Zhou, H.H.; Tybjærg-Hansen, A.; Vogt, T.F.; Hobbs, H.H.; Cohen, J.C. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 2014, 46, 352–356. [Google Scholar] [CrossRef] [PubMed]
- Mahdessian, H.; Taxiarchis, A.; Popov, S.; Silveira, A.; Franco-Cereceda, A.; Hamsten, A.; riksson, P.; van’t Hooft, F. TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content. Proc. Natl. Acad. Sci. USA 2014, 111, 8913–8918. [Google Scholar] [CrossRef] [PubMed]
- Dongiovanni, P.; Petta, S.; Maglio, C.; Fracanzani, A.L.; Pipitone, R.; Mozzi, E.; Motta, B.M.; Kaminska, D.; Rametta, R.; Grimaudo, S.; et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 2015, 61, 506–514. [Google Scholar] [CrossRef] [PubMed]
- Petta, S.; Miele, L.; Bugianesi, E.; Cammà, C.; Rosso, C.; Boccia, S.; Cabibi, D.; Di Marco, V.; Grimaudo, S.; Grieco, A.; et al. Glucokinase Regulatory Protein Gene Polymorphism Affects Liver Fibrosis in Non-Alcoholic Fatty Liver Disease. PLoS ONE 2014, 9, e87523. [Google Scholar] [CrossRef] [PubMed]
- Eslam, M.; Hashem, A.M.; Leung, R.; Romero-Gomez, M.; Berg, T.; Dore, G.J.; Chan, H.L.K.; Irving, W.L.; Sheridan, D.; Abate, M.L.; et al. International Hepatitis C Genetics Consortium (IHCGC) Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease. Nat. Commun. 2015, 6, 6422. [Google Scholar] [CrossRef] [PubMed]
- Petta, S.; Valenti, L.; Tuttolomondo, A.; Dongiovanni, P.; Pipitone, R.M.; Cammà, C.; Cabibi, D.; Di Marco, V.; Fracanzani, A.L.; Badiali, S.; Nobili, V.; et al. Interferon lambda 4 rs368234815 TT>δG variant is associated with liver damage in patients with nonalcoholic fatty liver disease. Hepatology 2017, 66, 1885–1893. [Google Scholar] [CrossRef] [PubMed]
- Portela, A.; Esteller, M. Epigenetic modifications and human disease. Nat. Biotechnol. 2010, 28, 1057–1068. [Google Scholar] [CrossRef] [PubMed]
- Ling, C.; Groop, L. Epigenetics: A molecular link between environmental factors and type 2 diabetes. Diabetes 2009, 58, 2718–2725. [Google Scholar] [CrossRef] [PubMed]
- Lee, J.; Friso, S.; Choi, S.-W. Epigenetic Mechanisms Underlying the Link between Non-Alcoholic Fatty Liver Diseases and Nutrition. Nutrients 2014, 6, 3303–3325. [Google Scholar] [CrossRef] [PubMed]
- Zhang, C.; Wang, G.; Zheng, Z.; Maddipati, K.R.; Zhang, X.; Dyson, G.; Williams, P.; Duncan, S.A.; Kaufman, R.J.; Zhang, K. Endoplasmic reticulum-tethered transcription factor cAMP responsive element-binding protein, hepatocyte specific, regulates hepatic lipogenesis, fatty acid oxidation, and lipolysis upon metabolic stress in mice. Hepatology 2012, 55, 1070–1082. [Google Scholar] [CrossRef] [PubMed]
- Zhang, K.; Shen, X.; Wu, J.; Sakaki, K.; Saunders, T.; Rutkowski, D.T.; Back, S.H.; Kaufman, R.J. Endoplasmic Reticulum Stress Activates Cleavage of CREBH to Induce a Systemic Inflammatory Response. Cell 2006, 124, 587–599. [Google Scholar] [CrossRef] [PubMed]
- Lee, M.-W.; Chanda, D.; Yang, J.; Oh, H.; Kim, S.S.; Yoon, Y.-S.; Hong, S.; Park, K.-G.; Lee, I.-K.; Choi, C.S.; et al. Regulation of Hepatic Gluconeogenesis by an ER-Bound Transcription Factor, CREBH. Cell Metab. 2010, 11, 331–339. [Google Scholar] [CrossRef] [PubMed]
- Kim, H.; Mendez, R.; Chen, X.; Fang, D.; Zhang, K. Lysine Acetylation of CREBH Regulates Fasting-Induced Hepatic Lipid Metabolism. Mol. Cell. Biol. 2015, 35, 4121–4134. [Google Scholar] [CrossRef] [PubMed]
- Mariani, S.; Fiore, D.; Basciani, S.; Persichetti, A.; Contini, S.; Lubrano, C.; Salvatori, L.; Lenzi, A.; Gnessi, L. Plasma levels of SIRT1 associate with non-alcoholic fatty liver disease in obese patients. Endocrine 2015, 49, 711–716. [Google Scholar] [CrossRef] [PubMed]
- Mukhopadhyay, P.; Horváth, B.; Rajesh, M.; Varga, Z.V.; Gariani, K.; Ryu, D.; Cao, Z.; Holovac, E.; Park, O.; Zhou, Z.; et al. PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis. J. Hepatol. 2017, 66, 589–600. [Google Scholar] [CrossRef] [PubMed]
- Barnett, M.P.G.; Bermingham, E.N.; Young, W.; Bassett, S.A.; Hesketh, J.E.; Maciel-Dominguez, A.; McNabb, W.C.; Roy, N.C. Low folate and selenium in the mouse maternal diet alters liver gene expression patterns in the offspring after weaning. Nutrients 2015, 7, 3370–3386. [Google Scholar] [CrossRef] [PubMed]
- Pogribny, I.P.; Tryndyak, V.P.; Bagnyukova, T.V.; Melnyk, S.; Montgomery, B.; Ross, S.A.; Latendresse, J.R.; Rusyn, I.; Beland, F.A. Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet. J. Hepatol. 2009, 51, 176–186. [Google Scholar] [CrossRef] [PubMed]
- Pirola, C.J.; Gianotti, T.F.; Burgueño, A.L.; Rey-Funes, M.; Loidl, C.F.; Mallardi, P.; Martino, J.S.; Castaño, G.O.; Sookoian, S. Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut 2013, 62, 1356–1363. [Google Scholar] [CrossRef] [PubMed]
- Xu, R.; Wei, W.; Krawczyk, M.; Wang, W.; Luo, H.; Flagg, K.; Yi, S.; Shi, W.; Quan, Q.; Li, K.; et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nat. Mater. 2017, 16, 1155–1161. [Google Scholar] [CrossRef] [PubMed]
- Tian, Y.; Wong, V.W.-S.; Chan, H.L.-Y.; Cheng, A.S.-L. Epigenetic regulation of hepatocellular carcinoma in non-alcoholic fatty liver disease. Semin. Cancer Biol. 2013, 23, 471–482. [Google Scholar] [CrossRef] [PubMed]
- Ahrens, M.; Ammerpohl, O.; von Schönfels, W.; Kolarova, J.; Bens, S.; Itzel, T.; Teufel, A.; Herrmann, A.; Brosch, M.; Hinrichsen, H.; et al. DNA Methylation Analysis in Nonalcoholic Fatty Liver Disease Suggests Distinct Disease-Specific and Remodeling Signatures after Bariatric Surgery. Cell Metab. 2013, 18, 296–302. [Google Scholar] [CrossRef] [PubMed]
- Benton, M.C.; Johnstone, A.; Eccles, D.; Harmon, B.; Hayes, M.T.; Lea, R.A.; Griffiths, L.; Hoffman, E.P.; Stubbs, R.S.; Macartney-Coxson, D. An analysis of DNA methylation in human adipose tissue reveals differential modification of obesity genes before and after gastric bypass and weight loss. Genome Biol. 2015, 16, 8. [Google Scholar] [CrossRef] [PubMed]
- Murphy, S.K.; Yang, H.; Moylan, C.A.; Pang, H.; Dellinger, A.; Abdelmalek, M.F.; Garrett, M.E.; Ashley–Koch, A.; Suzuki, A.; Tillmann, H.L.; et al. Relationship Between Methylome and Transcriptome in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 2013, 145, 1076–1087. [Google Scholar] [CrossRef] [PubMed]
- Teufel, A.; Itzel, T.; Erhart, W.; Brosch, M.; Wang, X.Y.; Kim, Y.O.; von Schönfels, W.; Herrmann, A.; Brückner, S.; Stickel, F.; et al. Comparison of Gene Expression Patterns between Mouse Models of Nonalcoholic Fatty Liver Disease and Liver Tissues from Patients. Gastroenterology 2016, 151, 513–525. [Google Scholar] [CrossRef] [PubMed]
- Zeybel, M.; Hardy, T.; Robinson, S.M.; Fox, C.; Anstee, Q.M.; Ness, T.; Masson, S.; Mathers, J.C.; French, J.; White, S.; et al. Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease. Clin. Epigenetics 2015, 7, 25. [Google Scholar] [CrossRef] [PubMed]
- Hardy, T.; Zeybel, M.; Day, C.P.; Dipper, C.; Masson, S.; McPherson, S.; Henderson, E.; Tiniakos, D.; White, S.; French, J.; et al. Plasma DNA methylation: A potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease. Gut 2017, 66, 1321–1328. [Google Scholar] [CrossRef] [PubMed]
- Giordano, S.; Columbano, A. MicroRNAs: New tools for diagnosis, prognosis, and therapy in hepatocellular carcinoma? Hepatology 2013, 57, 840–847. [Google Scholar] [CrossRef] [PubMed]
- De Conti, A.; Festa Ortega, J.; Tryndyak, V.; Dreval, K.; Salvador Moreno, F.; Rusyn, I.; Beland, F.A.; Pogribny, I.P. MicroRNA deregulation in nonalcoholic steatohepatitis-associated liver carcinogenesis. Oncotarget 2017, 8, 88517–88528. [Google Scholar] [CrossRef] [PubMed]
- Tan, Y.; Ge, G.; Pan, T.; Wen, D.; Gan, J. A Pilot Study of Serum MicroRNAs Panel as Potential Biomarkers for Diagnosis of Nonalcoholic Fatty Liver Disease. PLoS ONE 2014, 9, e105192. [Google Scholar] [CrossRef] [PubMed]
- Sacco, J.; Adeli, K. MicroRNAs. Curr. Opin. Lipidol. 2012, 23, 220–225. [Google Scholar] [CrossRef] [PubMed]
- Pirola, C.J.; Fernández Gianotti, T.; Castaño, G.O.; Mallardi, P.; San Martino, J.; Mora Gonzalez Lopez Ledesma, M.; Flichman, D.; Mirshahi, F.; Sanyal, A.J.; Sookoian, S. Circulating microRNA signature in non-alcoholic fatty liver disease: From serum non-coding RNAs to liver histology and disease pathogenesis. Gut 2015, 64, 800–812. [Google Scholar] [CrossRef] [PubMed]
- Cermelli, S.; Ruggieri, A.; Marrero, J.A.; Ioannou, G.N.; Beretta, L. Circulating MicroRNAs in Patients with Chronic Hepatitis C and Non-Alcoholic Fatty Liver Disease. PLoS ONE 2011, 6, e23937. [Google Scholar] [CrossRef] [PubMed]
- Yamada, H.; Suzuki, K.; Ichino, N.; Ando, Y.; Sawada, A.; Osakabe, K.; Sugimoto, K.; Ohashi, K.; Teradaira, R.; Inoue, T.; et al. Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver. Clin. Chim. Acta 2013, 424, 99–103. [Google Scholar] [CrossRef] [PubMed]
- Liu, X.-L.; Pan, Q.; Zhang, R.-N.; Shen, F.; Yan, S.-Y.; Sun, C.; Xu, Z.-J.; Chen, Y.-W.; Fan, J.-G. Disease-specific miR-34a as diagnostic marker of non-alcoholic steatohepatitis in a Chinese population. World J. Gastroenterol. 2016, 22, 9844–9852. [Google Scholar] [CrossRef] [PubMed]
- Blaya, D.; Aguilar-Bravo, B.; Hao, F.; Casacuberta-Serra, S.; Coll, M.; Perea, L.; Vallverdú, J.; Graupera, I.; Pose, E.; Llovet, L.; et al. Expression of microRNA-155 in inflammatory cells modulates liver injury. Hepatology 2018. [Google Scholar] [CrossRef] [PubMed]
- Cheung, O.; Puri, P.; Eicken, C.; Contos, M.J.; Mirshahi, F.; Maher, J.W.; Kellum, J.M.; Min, H.; Luketic, V.A.; Sanyal, A.J. Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression. Hepatology 2008, 48, 1810–1820. [Google Scholar] [CrossRef] [PubMed]
- Takaki, Y.; Saito, Y.; Takasugi, A.; Toshimitsu, K.; Yamada, S.; Muramatsu, T.; Kimura, M.; Sugiyama, K.; Suzuki, H.; Arai, E.; et al. Silencing of microRNA-122 is an early event during hepatocarcinogenesis from non-alcoholic steatohepatitis. Cancer Sci. 2014, 105, 1254–1260. [Google Scholar] [CrossRef] [PubMed]
- Guo, Y.; Xiong, Y.; Sheng, Q.; Zhao, S.; Wattacheril, J.; Flynn, C.R. A micro-RNA expression signature for human NAFLD progression. J. Gastroenterol. 2016, 51, 1022–1030. [Google Scholar] [CrossRef] [PubMed]
Gene | Function | Phenotype | Variant |
---|---|---|---|
PNPLA3 | Lipid droplets | ↑ NAFLD, NASH, fibrosis, HCC | rs738409 C>G |
MBOAT7 | Phospholipid metabolism | ↑ NAFLD-HCC risk | rs641738 C>T |
APOB | VLDL secretion | ↑ NAFLD, NASH, fibrosis, HCC | Several |
TM6SF2 | VLDL secretion | ↑ NAFLD, NASH, fibrosis | rs58542926 C>T |
GCKR | De novo lipogenesis regulation | ↑ NAFLD, NASH, fibrosis | rs780094 A>G |
KLF6 | De novo lipogenesis regulation; fibrogenesis | ↓ fibrosis | rs3750861 G>A |
IL28B | Innate immunity, alternative IFNL3/4 transcription | ↓ fibrosis | rs12979860 C>T |
SOD2 | Mitochondrial antioxidant | ↑ fibrosis | rs4880 C>T |
miRNA | Pathway | Reference |
---|---|---|
miR-122 | Lipid metabolism, carcinogenesis | [65] |
miR-192 | NAFLD progression | [66] |
miR-34a, miR-16 | Lipid metabolism | [67] |
miR-21, miR-34a | Lipid metabolism | [68] |
miR-1290, miR-27b-3p and miR-192-5p | Several (panel) | [64] |
miR-301a-3p, miR-34a-5p and miR-375 | Several (biomarkers) | [69] |
miR-182 | Fibrogenesis | [70] |
miR-155 | Inflammatory pathway and liver injury | [71] |
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Del Campo, J.A.; Gallego-Durán, R.; Gallego, P.; Grande, L. Genetic and Epigenetic Regulation in Nonalcoholic Fatty Liver Disease (NAFLD). Int. J. Mol. Sci. 2018, 19, 911. https://doi.org/10.3390/ijms19030911
Del Campo JA, Gallego-Durán R, Gallego P, Grande L. Genetic and Epigenetic Regulation in Nonalcoholic Fatty Liver Disease (NAFLD). International Journal of Molecular Sciences. 2018; 19(3):911. https://doi.org/10.3390/ijms19030911
Chicago/Turabian StyleDel Campo, José A, Rocío Gallego-Durán, Paloma Gallego, and Lourdes Grande. 2018. "Genetic and Epigenetic Regulation in Nonalcoholic Fatty Liver Disease (NAFLD)" International Journal of Molecular Sciences 19, no. 3: 911. https://doi.org/10.3390/ijms19030911
APA StyleDel Campo, J. A., Gallego-Durán, R., Gallego, P., & Grande, L. (2018). Genetic and Epigenetic Regulation in Nonalcoholic Fatty Liver Disease (NAFLD). International Journal of Molecular Sciences, 19(3), 911. https://doi.org/10.3390/ijms19030911