A Novel Comparative Pattern Analysis Approach Identifies Chronic Alcohol Mediated Dysregulation of Transcriptomic Dynamics During Liver Regeneration

Overview

Journal BMC Genomics

Publisher Biomed Central

Specialty Genetics

Date 2016 Mar 26

PMID 27012785

Citations 13

Authors

Lakshmi Kuttippurathu

Egle Juskeviciute

Rachael P Dippold

Jan B Hoek

Rajanikanth Vadigepalli

Affiliations

Soon will be listed here.

Abstract

Background: Liver regeneration is inhibited by chronic ethanol consumption and this impaired repair response may contribute to the risk for alcoholic liver disease. We developed and applied a novel data analysis approach to assess the effect of chronic ethanol intake in the mechanisms responsible for liver regeneration. We performed a time series transcriptomic profiling study of the regeneration response after 2/3rd partial hepatectomy (PHx) in ethanol-fed and isocaloric control rats.

Results: We developed a novel data analysis approach focusing on comparative pattern counts (COMPACT) to exhaustively identify the dominant and subtle differential expression patterns. Approximately 6500 genes were differentially regulated in Ethanol or Control groups within 24 h after PHx. Adaptation to chronic ethanol intake significantly altered the immediate early gene expression patterns and nearly completely abrogated the cell cycle induction in hepatocytes post PHx. The patterns highlighted by COMPACT analysis contained several non-parenchymal cell specific markers indicating their aberrant transcriptional response as a novel mechanism through which chronic ethanol intake deregulates the integrated liver tissue response.

Conclusions: Our novel comparative pattern analysis revealed new insights into ethanol-mediated molecular changes in non-parenchymal liver cells as a possible contribution to the defective liver regeneration phenotype. The results revealed for the first time an ethanol-induced shift of hepatic stellate cells from a pro-regenerative phenotype to that of an anti-regenerative state after PHx. Our results can form the basis for novel interventions targeting the non-parenchymal cells in normalizing the dysfunctional repair response process in alcoholic liver disease. Our approach is illustrated online at http://compact.jefferson.edu .

Citing Articles

Hong X, Huang S, Jiang H, Ma Q, Qiu J, Luo Q Front Pharmacol. 2024; 15:1432480.

PMID: 39669199 PMC: 11635172. DOI: 10.3389/fphar.2024.1432480.

Dynamic dysregulation of transcriptomic networks in brainstem autonomic nuclei during hypertension development in the female spontaneously hypertensive rat.

Moss A, Kuttippurathu L, Srivastava A, Schwaber J, Vadigepalli R Physiol Genomics. 2023; 56(3):283-300.

PMID: 38145287 PMC: 11283910. DOI: 10.1152/physiolgenomics.00073.2023.

Cell division cycle-associated 8 is a prognostic biomarker related to immune invasion in hepatocellular carcinoma.

Wu H, Liu S, Wu D, Zhou H, Sui G, Wu G Cancer Med. 2023; 12(8):10138-10155.

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Alcohol-Associated Tissue Injury: Current Views on Pathophysiological Mechanisms.

Simon L, Souza-Smith F, Molina P Annu Rev Physiol. 2022; 84:87-112.

PMID: 35143331 PMC: 11268381. DOI: 10.1146/annurev-physiol-060821-014008.

Dysregulation of miR-21-associated miRNA regulatory networks by chronic ethanol consumption impairs liver regeneration.

Parrish A, Srivastava A, Juskeviciute E, Hoek J, Vadigepalli R Physiol Genomics. 2021; 53(12):546-555.

PMID: 34796728 PMC: 8820682. DOI: 10.1152/physiolgenomics.00113.2021.

References

Wang J, Batey R, George J . Role of ethanol in the regulation of hepatic stellate cell function. World J Gastroenterol. 2006; 12(43):6926-32. PMC: 4087334. DOI: 10.3748/wjg.v12.i43.6926. View

Naumann M, Nieters A, Hatada E, Scheidereit C . NF-kappa B precursor p100 inhibits nuclear translocation and DNA binding of NF-kappa B/rel-factors. Oncogene. 1993; 8(8):2275-81. View

Whitson R, Lucia M, Lambert J . Growth differentiation factor-15 (GDF-15) suppresses in vitro angiogenesis through a novel interaction with connective tissue growth factor (CCN2). J Cell Biochem. 2013; 114(6):1424-33. DOI: 10.1002/jcb.24484. View

Sanchez-Alvarez R, Gayen S, Vadigepalli R, Anni H . Ethanol diverts early neuronal differentiation trajectory of embryonic stem cells by disrupting the balance of lineage specifiers. PLoS One. 2013; 8(5):e63794. PMC: 3665827. DOI: 10.1371/journal.pone.0063794. View

Michalopoulos G, Khan Z . Liver Stem Cells: Experimental Findings and Implications for Human Liver Disease. Gastroenterology. 2015; 149(4):876-882. PMC: 4584191. DOI: 10.1053/j.gastro.2015.08.004. View

Alder J, Georgantas 3rd R, Hildreth R, Kaplan I, Morisot S, Yu X . Kruppel-like factor 4 is essential for inflammatory monocyte differentiation in vivo. J Immunol. 2008; 180(8):5645-52. PMC: 3074963. DOI: 10.4049/jimmunol.180.8.5645. View

Gonzales E, Julien B, Serriere-Lanneau V, Nicou A, Doignon I, Lagoudakis L . ATP release after partial hepatectomy regulates liver regeneration in the rat. J Hepatol. 2009; 52(1):54-62. PMC: 3625734. DOI: 10.1016/j.jhep.2009.10.005. View

Yamada Y, Kirillova I, Peschon J, Fausto N . Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc Natl Acad Sci U S A. 1997; 94(4):1441-6. PMC: 19810. DOI: 10.1073/pnas.94.4.1441. View

Motoyama H, Komiya T, Thuy L, Tamori A, Enomoto M, Morikawa H . Cytoglobin is expressed in hepatic stellate cells, but not in myofibroblasts, in normal and fibrotic human liver. Lab Invest. 2013; 94(2):192-207. DOI: 10.1038/labinvest.2013.135. View

10.

Zhang B, Hornsfield B, Farrell G . Chronic ethanol administration to rats decreases receptor-operated mobilization of intracellular ionic calcium in cultured hepatocytes and inhibits 1,4,5-inositol trisphosphate production: relevance to impaired liver regeneration. J Clin Invest. 1996; 98(5):1237-44. PMC: 507546. DOI: 10.1172/JCI118907. View

11.

Yin H, Kim M, Kim J, Kong G, Kang K, Kim H . Differential gene expression and lipid metabolism in fatty liver induced by acute ethanol treatment in mice. Toxicol Appl Pharmacol. 2007; 223(3):225-33. DOI: 10.1016/j.taap.2007.06.018. View

12.

Cook D, Ogunnaike B, Vadigepalli R . Systems analysis of non-parenchymal cell modulation of liver repair across multiple regeneration modes. BMC Syst Biol. 2015; 9:71. PMC: 4618752. DOI: 10.1186/s12918-015-0220-9. View

13.

Park S, Choi M, Park T . Changes in the hepatic gene expression profile in a rat model of chronic ethanol treatment. Food Chem Toxicol. 2007; 46(4):1378-88. DOI: 10.1016/j.fct.2007.08.029. View

14.

ORREGO H, Crossley I, Saldivia V, Medline A, Varghese G, Israel Y . Long-term ethanol administration and short- and long-term liver regeneration after partial hepatectomy. J Lab Clin Med. 1981; 97(2):221-30. View

15.

Stepniak E, Ricci R, Eferl R, Sumara G, Sumara I, Rath M . c-Jun/AP-1 controls liver regeneration by repressing p53/p21 and p38 MAPK activity. Genes Dev. 2006; 20(16):2306-14. PMC: 1553212. DOI: 10.1101/gad.390506. View

16.

Fernandez A, Matias N, Fucho R, Ribas V, von Montfort C, Nuno N . ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading. J Hepatol. 2013; 59(4):805-13. PMC: 3779525. DOI: 10.1016/j.jhep.2013.05.023. View

17.

Deaciuc I, Peng X, DSouza N, Shedlofsky S, Burikhanov R, Voskresensky I . Microarray gene analysis of the liver in a rat model of chronic, voluntary alcohol intake. Alcohol. 2004; 32(2):113-27. DOI: 10.1016/j.alcohol.2003.12.001. View

18.

Dusabineza A, Van Hul N, Abarca-Quinones J, Starkel P, Najimi M, Leclercq I . Participation of liver progenitor cells in liver regeneration: lack of evidence in the AAF/PH rat model. Lab Invest. 2011; 92(1):72-81. DOI: 10.1038/labinvest.2011.136. View

19.

Hastie T, Tibshirani R, Botstein D, Brown P . Supervised harvesting of expression trees. Genome Biol. 2001; 2(1):RESEARCH0003. PMC: 17599. DOI: 10.1186/gb-2001-2-1-research0003. View

20.

Lu W, Bird T, Boulter L, Tsuchiya A, Cole A, Hay T . Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat Cell Biol. 2015; 17(8):971-983. PMC: 4612439. DOI: 10.1038/ncb3203. View