CircRNA_0046366 Inhibits Hepatocellular Steatosis by Normalization of PPAR Signaling

Overview

Journal World J Gastroenterol

Publisher Baishideng Publishing Group

Specialty Gastroenterology

Date 2018 Feb 3

PMID 29391755

Citations 49

Authors

Xing-Ya Guo

Fang Sun

Jian-Neng Chen

Yu-Qin Wang

Qin Pan

Jian-Gao Fan

Affiliations

Soon will be listed here.

Abstract

Aim: To investigate micro (mi)R-34a-antagonizing circular (circ)RNA that underlies hepatocellular steatosis.

Methods: The effect of circRNA on miR-34a was recognized by the miRNA response element (MRE), and validated by the dual-luciferase reporter assay. Its association with hepatocellular steatosis was investigated in HepG2-based hepatocellular steatosis induced by free fatty acids (FFAs; 2:1 oleate:palmitate) stimulation. After normalization of the steatosis-related circRNA by expression vector, analysis of miR-34a activity, peroxisome proliferator-activated receptor (PPAR)α level, and expression of downstream genes were carried out so as to reveal its impact on the miR-34a/PPARα regulatory system. Both triglyceride (TG) assessment and cytopathological manifestations uncovered the role of circRNA in miR-34a-dependent hepatosteatogenesis.

Results: Bioinformatic and functional analysis verified circRNA_0046366 to antagonize the activity of miR-34a MRE-based complementation. In contrast to its lowered level during FFA-induced hepatocellular steatosis, circRNA_0046366 up-regulation abolished the miR-34a-dependent inhibition of PPARα that played a critical role in metabolic signaling pathways. PPARα restoration exerted transcriptional improvement to multiple genes responsible for lipid metabolism. TG-specific lipolytic genes [carnitine palmitoyltransferase 1A (CPT1A) and solute-carrier family 27A (SLC27A)] among these showed significant increase in their expression levels. The circRNA_0046366-related rebalancing of lipid homeostasis led to dramatic reduction of TG content, and resulted in the ameliorated phenotype of hepatocellular steatosis.

Conclusion: Dysregulation of circRNA_0046366/miR-34a/PPARα signaling may be a novel epigenetic mechanism underlying hepatocellular steatosis. circRNA_0046366 serves as a potential target for the treatment of hepatic steatosis.

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References

Sobolewski C, Calo N, Portius D, Foti M . MicroRNAs in fatty liver disease. Semin Liver Dis. 2015; 35(1):12-25. DOI: 10.1055/s-0034-1397345. View

Pogribny I, Starlard-Davenport A, Tryndyak V, Han T, Ross S, Rusyn I . Difference in expression of hepatic microRNAs miR-29c, miR-34a, miR-155, and miR-200b is associated with strain-specific susceptibility to dietary nonalcoholic steatohepatitis in mice. Lab Invest. 2010; 90(10):1437-46. PMC: 4281935. DOI: 10.1038/labinvest.2010.113. View

Lenz L, Marx J, Chamulitrat W, Kaiser I, Grone H, Liebisch G . Adipocyte-specific inactivation of Acyl-CoA synthetase fatty acid transport protein 4 (Fatp4) in mice causes adipose hypertrophy and alterations in metabolism of complex lipids under high fat diet. J Biol Chem. 2011; 286(41):35578-35587. PMC: 3195640. DOI: 10.1074/jbc.M111.226530. View

Lin S, Ye S, Long Y, Fan Y, Mao H, Chen M . Circular RNA expression alterations are involved in OGD/R-induced neuron injury. Biochem Biophys Res Commun. 2016; 471(1):52-6. DOI: 10.1016/j.bbrc.2016.01.183. View

Wang K, Long B, Liu F, Wang J, Liu C, Zhao B . A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223. Eur Heart J. 2016; 37(33):2602-11. DOI: 10.1093/eurheartj/ehv713. View

Zhou B, Yu J . A novel identified circular RNA, circRNA_010567, promotes myocardial fibrosis via suppressing miR-141 by targeting TGF-β1. Biochem Biophys Res Commun. 2017; 487(4):769-775. DOI: 10.1016/j.bbrc.2017.04.044. View

Goh G, Kwan C, Lim S, Venkatanarasimha N, Abu-Bakar R, Krishnamoorthy T . Perceptions of non-alcoholic fatty liver disease - an Asian community-based study. Gastroenterol Rep (Oxf). 2015; 4(2):131-5. PMC: 4863187. DOI: 10.1093/gastro/gov047. View

Zheng Q, Bao C, Guo W, Li S, Chen J, Chen B . Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat Commun. 2016; 7:11215. PMC: 4823868. DOI: 10.1038/ncomms11215. View

Feng Y, Xu X, Ji C, Shi C, Guo X, Fu J . Aberrant hepatic microRNA expression in nonalcoholic fatty liver disease. Cell Physiol Biochem. 2015; 34(6):1983-97. DOI: 10.1159/000366394. View

10.

Yang H, Do H, Kim D, Park J, Chang W, Chung H . Transcriptional regulation of human Oct4 by steroidogenic factor-1. J Cell Biochem. 2007; 101(5):1198-209. DOI: 10.1002/jcb.21244. View

11.

Koufaris C, Wright J, Currie R, Gooderham N . Hepatic microRNA profiles offer predictive and mechanistic insights after exposure to genotoxic and epigenetic hepatocarcinogens. Toxicol Sci. 2012; 128(2):532-43. DOI: 10.1093/toxsci/kfs170. View

12.

Yamada H, Suzuki K, Ichino N, Ando Y, Sawada A, Osakabe K . 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. DOI: 10.1016/j.cca.2013.05.021. View

13.

Qiu F, Xie L, Ma J, Luo W, Zhang L, Chao Z . Lower Expression of Enhances Intramuscular Fat Deposition in Chicken via Down-Regulated Fatty Acid Oxidation Mediated by . Front Physiol. 2017; 8:449. PMC: 5489693. DOI: 10.3389/fphys.2017.00449. View

14.

Zhao Y, Alexandrov P, Jaber V, Lukiw W . Deficiency in the Ubiquitin Conjugating Enzyme UBE2A in Alzheimer's Disease (AD) is Linked to Deficits in a Natural Circular miRNA-7 Sponge (circRNA; ciRS-7). Genes (Basel). 2016; 7(12). PMC: 5192492. DOI: 10.3390/genes7120116. View

15.

Gallardo D, Amills M, Quintanilla R, Pena R . Mapping and tissue mRNA expression analysis of the pig solute carrier 27A (SLC27A) multigene family. Gene. 2012; 515(1):220-3. DOI: 10.1016/j.gene.2012.11.029. View

16.

Marchesini G, Marzocchi R . Metabolic syndrome and NASH. Clin Liver Dis. 2007; 11(1):105-17, ix. DOI: 10.1016/j.cld.2007.02.013. View

17.

Kirpich I, Ghare S, Zhang J, Gobejishvili L, Kharebava G, Barve S . Binge alcohol-induced microvesicular liver steatosis and injury are associated with down-regulation of hepatic Hdac 1, 7, 9, 10, 11 and up-regulation of Hdac 3. Alcohol Clin Exp Res. 2012; 36(9):1578-86. PMC: 4867116. DOI: 10.1111/j.1530-0277.2012.01751.x. View

18.

Janssen A, Betzel B, Stoopen G, Berends F, Janssen I, Peijnenburg A . The impact of PPARα activation on whole genome gene expression in human precision cut liver slices. BMC Genomics. 2015; 16:760. PMC: 4599789. DOI: 10.1186/s12864-015-1969-3. View

19.

Kozomara A, Griffiths-Jones S . miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 2013; 42(Database issue):D68-73. PMC: 3965103. DOI: 10.1093/nar/gkt1181. View

20.

Wang F, Fan J, Zhang Z, Gao B, Wang H . The global burden of liver disease: the major impact of China. Hepatology. 2014; 60(6):2099-108. PMC: 4867229. DOI: 10.1002/hep.27406. View