Myeloid cell deletion of Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) induces non-alcoholic steatohepatitis


Autoři: Christopher Scott aff001;  Rebecca Stokes aff001;  Kuan Minn Cha aff001;  Andrew Clouston aff004;  Mohammed Eslam aff002;  Mayda Metwally aff002;  Michael M. Swarbrick aff001;  Jacob George aff002;  Jenny E. Gunton aff001
Působiště autorů: Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia aff001;  Sydney Medical School, The University of Sydney, Sydney, NSW, Australia aff002;  Garvan Institute of Medical Research, Darlinghurst, NSW, Australia aff003;  Envoi Specialist Pathologists, Brisbane, Queensland, Australia aff004;  Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia aff005;  St. Vincent’s Clinical School, University of NSW, Sydney, NSW, Australia aff006
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225332

Souhrn

Background and aim

Non-alcoholic steatohepatitis (NASH) is predicted to become the most common cause of cirrhosis and liver failure. Risk factors include obesity, insulin resistance and diabetes. Macrophages and other myeloid cells play crucial roles in initiating and driving inflammation. Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) is a transcription factor which binds to a range of partners to mediate responses to environmental signals, including the diet. In people with diabetes it is decreased in liver. We hypothesised that myeloid cell ARNT activity may contribute to the development of liver pathology.

Methods

Floxed-ARNT mice were bred with LysM-Cre mice to generate mice with reduced ARNT in myeloid cells. Animals were fed a high fat diet (HFD) and liver pathology was assessed. Histology, mRNA, fat accumulation and metabolism were studied.

Results

Animals with reduced myeloid ARNT developed steatohepatitis on a HFD, with additional alterations of metabolism and fat deposition. Steatohepatitis was accompanied by hepatic macrophage infiltration and expression of both M1 and M2 markers. Expression of mRNAs for Cxcl1, Mcp-1, Tnf-α and Tgf-β1 were increased. Human livers from controls and people with NASH were tested; ARNT mRNA was decreased by 80% (p = 0.0004).

Conclusions

Decreased myeloid ARNT may play a role in the conversion from non-alcoholic fatty liver to steatohepatitis. Increasing ARNT may be a therapeutic strategy to reduce NASH.

Klíčová slova:

Bone marrow cells – Fats – Fatty liver – Gene expression – Histology – Inflammation – Liver diseases – Macrophages


Zdroje

1. Farrell G.C. and Larter C.Z., Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology, 2006. 43(2 Suppl 1): p. S99–S112.

2. Bellentani S. and Marino M., Epidemiology and natural history of non-alcoholic fatty liver disease (NAFLD). Ann Hepatol, 2009. 8 Suppl 1: p. S4–8.

3. Finucane M.M., Stevens G.A., Cowan M.J., Danaei G., Lin J.K., Paciorek C.J., et al., National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet, 2011. 377(9765): p. 557–67. doi: 10.1016/S0140-6736(10)62037-5 21295846

4. Matteoni C.A., Younossi Z.M., Gramlich T., Boparai N., Liu Y.C., and McCullough A.J., Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology, 1999. 116(6): p. 1413–9. doi: 10.1016/s0016-5085(99)70506-8 10348825

5. Poonawala A., Nair S.P., and Thuluvath P.J., Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study. Hepatology, 2000. 32(4 Pt 1): p. 689–92. doi: 10.1053/jhep.2000.17894 11003611

6. Bugianesi E., Leone N., Vanni E., Marchesini G., Brunello F., Carucci P., et al., Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology, 2002. 123(1): p. 134–40. doi: 10.1053/gast.2002.34168 12105842

7. Day C.P. and James O.F., Steatohepatitis: a tale of two "hits"? Gastroenterology, 1998. 114(4): p. 842–5. doi: 10.1016/s0016-5085(98)70599-2 9547102

8. Jou J., Choi S.S., and Diehl A.M., Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis, 2008. 28(4): p. 370–9. doi: 10.1055/s-0028-1091981 18956293

9. Tilg H. and Moschen A.R., Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology, 2010. 52(5): p. 1836–46. doi: 10.1002/hep.24001 21038418

10. Baffy G., Kupffer cells in non-alcoholic fatty liver disease: the emerging view. J Hepatol, 2009. 51(1): p. 212–23. doi: 10.1016/j.jhep.2009.03.008 19447517

11. Lefkowitch J.H., Haythe J.H., and Regent N., Kupffer cell aggregation and perivenular distribution in steatohepatitis. Mod Pathol, 2002. 15(7): p. 699–704. doi: 10.1097/01.MP.0000019579.30842.96 12118106

12. Duffield J.S., Forbes S.J., Constandinou C.M., Clay S., Partolina M., Vuthoori S., et al., Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest, 2005. 115(1): p. 56–65. doi: 10.1172/JCI22675 15630444

13. Weisberg S.P., McCann D., Desai M., Rosenbaum M., Leibel R.L., and Ferrante A.W. Jr., Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest, 2003. 112(12): p. 1796–808. doi: 10.1172/JCI19246 14679176

14. Nomiyama T., Perez-Tilve D., Ogawa D., Gizard F., Zhao Y., Heywood E.B., et al., Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice. J Clin Invest, 2007. 117(10): p. 2877–88. doi: 10.1172/JCI31986 17823662

15. Kanda H., Tateya S., Tamori Y., Kotani K., Hiasa K., Kitazawa R., et al., MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest, 2006. 116(6): p. 1494–505. doi: 10.1172/JCI26498 16691291

16. Lanthier N., Molendi-Coste O., Horsmans Y., van Rooijen N., Cani P.D., and Leclercq I.A., Kupffer cell activation is a causal factor for hepatic insulin resistance. Am J Physiol Gastrointest Liver Physiol, 2010. 298(1): p. G107–16. doi: 10.1152/ajpgi.00391.2009 19875703

17. Gadd V.L., Skoien R., Powell E.E., Fagan K.J., Winterford C., Horsfall L., et al., The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology, 2014. 59(4): p. 1393–405. doi: 10.1002/hep.26937 24254368

18. Koliwad S.K., Streeper R.S., Monetti M., Cornelissen I., Chan L., Terayama K., et al., DGAT1-dependent triacylglycerol storage by macrophages protects mice from diet-induced insulin resistance and inflammation. J Clin Invest, 2010. 120(3): p. 756–67. doi: 10.1172/JCI36066 20124729

19. Sachithanandan N., Graham K.L., Galic S., Honeyman J.E., Fynch S.L., Hewitt K.A., et al., Macrophage deletion of SOCS1 increases sensitivity to LPS and palmitic acid and results in systemic inflammation and hepatic insulin resistance. Diabetes, 2011. 60(8): p. 2023–31. doi: 10.2337/db11-0259 21646388

20. Serre-Beinier V., Toso C., Morel P., Gonelle-Gispert C., Veyrat-Durebex C., Rohner-Jeanrenaud F., et al., Macrophage migration inhibitory factor deficiency leads to age-dependent impairment of glucose homeostasis in mice. J Endocrinol, 2010. 206(3): p. 297–306. doi: 10.1677/JOE-09-0342 20566490

21. Odegaard J.I., Ricardo-Gonzalez R.R., Goforth M.H., Morel C.R., Subramanian V., Mukundan L., et al., Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature, 2007. 447(7148): p. 1116–20. doi: 10.1038/nature05894 17515919

22. Li J., Savransky V., Nanayakkara A., Smith P.L., O'Donnell C.P., and Polotsky V.Y., Hyperlipidemia and lipid peroxidation are dependent on the severity of chronic intermittent hypoxia. J Appl Physiol (1985), 2007. 102(2): p. 557–63.

23. Savransky V., Bevans S., Nanayakkara A., Li J., Smith P.L., Torbenson M.S., et al., Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver. Am J Physiol Gastrointest Liver Physiol, 2007. 293(4): p. G871–7. doi: 10.1152/ajpgi.00145.2007 17690174

24. Tanne F., Gagnadoux F., Chazouilleres O., Fleury B., Wendum D., Lasnier E., et al., Chronic liver injury during obstructive sleep apnea. Hepatology, 2005. 41(6): p. 1290–6. doi: 10.1002/hep.20725 15915459

25. Gunton J.E., Kulkarni R.N., Yim S., Okada T., Hawthorne W.J., Tseng Y.H., et al., Loss of ARNT/HIF1beta Mediates Altered Gene Expression and Pancreatic-Islet Dysfunction in Human Type 2 Diabetes. Cell, 2005. 122(3): p. 337–49. doi: 10.1016/j.cell.2005.05.027 16096055

26. Salceda S., Beck I., and Caro J.F., Absolute requirement of aryl hydrocarbon receptor nuclear translocator protein for gene activation by hypoxia. Arch Biochem Biophys, 1996. 334(2): p. 389–394. doi: 10.1006/abbi.1996.0469 8900415

27. Wang G.L., Jiang B.H., Rue E.A., and Semenza G.L., Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. PNAS, 1995. 92(12): p. 5510–4. doi: 10.1073/pnas.92.12.5510 7539918

28. Thangarajah H., Yao D., Chang E.I., Shi Y., Jazayeri L., Vial I.N., et al., The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues. Proc Natl Acad Sci U S A, 2009. 106(32): p. 13505–10. doi: 10.1073/pnas.0906670106 19666581

29. Botusan I.R., Sunkari V.G., Savu O., Catrina A.I., Grunler J., Lindberg S., et al., Stabilization of HIF-1alpha is critical to improve wound healing in diabetic mice. Proc Natl Acad Sci U S A, 2008. 105(49): p. 19426–31. doi: 10.1073/pnas.0805230105 19057015

30. Mace K.A., Yu D.H., Paydar K.Z., Boudreau N., and Young D.M., Sustained expression of Hif-1alpha in the diabetic environment promotes angiogenesis and cutaneous wound repair. Wound Repair Regen, 2007. 15(5): p. 636–45. doi: 10.1111/j.1524-475X.2007.00278.x 17971009

31. Catrina S.B., Okamoto K., Pereira T., Brismar K., and Poellinger L., Hyperglycemia regulates hypoxia-inducible factor-1alpha protein stability and function. Diabetes, 2004. 53(12): p. 3226–32. doi: 10.2337/diabetes.53.12.3226 15561954

32. Cramer T., Yamanishi Y., Clausen B.E., Forster I., Pawlinski R., Mackman N., et al., HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell, 2003. 112(5): p. 645–57. doi: 10.1016/s0092-8674(03)00154-5 12628185

33. Peyssonnaux C., Datta V., Cramer T., Doedens A., Theodorakis E.A., Gallo R.L., et al., HIF-1alpha expression regulates the bactericidal capacity of phagocytes. J Clin Invest, 2005. 115(7): p. 1806–15. doi: 10.1172/JCI23865 16007254

34. Walmsley S.R., Print C., Farahi N., Peyssonnaux C., Johnson R.S., Cramer T., et al., Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med, 2005. 201(1): p. 105–15. doi: 10.1084/jem.20040624 15630139

35. Imtiyaz H.Z., Williams E.P., Hickey M.M., Patel S.A., Durham A.C., Yuan L.J., et al., Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest, 2010. 120(8): p. 2699–714. doi: 10.1172/JCI39506 20644254

36. Sekine H., Mimura J., Oshima M., Okawa H., Kanno J., Igarashi K., et al., Hypersensitivity of aryl hydrocarbon receptor-deficient mice to lipopolysaccharide-induced septic shock. Mol Cell Biol, 2009. 29(24): p. 6391–400. doi: 10.1128/MCB.00337-09 19822660

37. Kimura A., Naka T., Nakahama T., Chinen I., Masuda K., Nohara K., et al., Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses. J Exp Med, 2009. 206(9): p. 2027–35. doi: 10.1084/jem.20090560 19703987

38. Wang X.L., Suzuki R., Lee K., Tran T., Gunton J.E., Saha A.K., et al., Ablation of ARNT/HIF1beta in liver alters gluconeogenesis, lipogenic gene expression, and serum ketones. Cell Metab, 2009. 9(5): p. 428–39. doi: 10.1016/j.cmet.2009.04.001 19416713

39. Bersten D.C., Sullivan A.E., Peet D.J., and Whitelaw M.L., bHLH-PAS proteins in cancer. Nat Rev Cancer, 2013. 13(12): p. 827–41. doi: 10.1038/nrc3621 24263188

40. Clausen B.E., Burkhardt C., Reith W., Renkawitz R., and Forster I., Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res, 1999. 8(4): p. 265–77. doi: 10.1023/a:1008942828960 10621974

41. Cheng K., Ho K., Stokes R., Scott C., Lau S.M., Hawthorne W.J., et al., Hypoxia-inducible factor-1alpha regulates beta cell function in mouse and human islets. J Clin Invest, 2010. 120(6): p. 2171–83. doi: 10.1172/JCI35846 20440072

42. Hocking S.L., Stewart R.L., Brandon A.E., Suryana E., Stuart E., Baldwin E.M., et al., Subcutaneous fat transplantation alleviates diet-induced glucose intolerance and inflammation in mice. Diabetologia, 2015. (in press).

43. Kleiner D.E., Brunt E.M., Van Natta M., Behling C., Contos M.J., Cummings O.W., et al., Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology, 2005. 41(6): p. 1313–21. doi: 10.1002/hep.20701 15915461

44. Thabet K., Asimakopoulos A., Shojaei M., Romero-Gomez M., Mangia A., Irving W.L., et al., MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C. Nature communications, 2016. 7.

45. Scott C., Bonner J., Min D., Boughton P., Stokes R., Cha K.M., et al., Reduction of ARNT (Aryl hydrocarbon Receptor Nuclear Translocator) in myeloid cells causes immune 2 suppression and delayed wound healing. American Journal of Physiology—Cell Physiology, 2014. 307(4): p. C349–C357. doi: 10.1152/ajpcell.00306.2013 24990649

46. Stern J.H., Rutkowski J.M., and Scherer P.E.J.C.m., Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. 2016. 23(5): p. 770–784.

47. Bertola A., Bonnafous S., Anty R., Patouraux S., Saint-Paul M.C., Iannelli A., et al., Hepatic expression patterns of inflammatory and immune response genes associated with obesity and NASH in morbidly obese patients. PLoS One, 2010. 5(10): p. e13577. doi: 10.1371/journal.pone.0013577 21042596

48. Haukeland J.W., Damas J.K., Konopski Z., Loberg E.M., Haaland T., Goverud I., et al., Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol, 2006. 44(6): p. 1167–74. doi: 10.1016/j.jhep.2006.02.011 16618517

49. Cayon A., Crespo J., Mayorga M., Guerra A., and Pons-Romero F., Increased expression of Ob-Rb and its relationship with the overexpression of TGF-beta1 and the stage of fibrosis in patients with nonalcoholic steatohepatitis. Liver Int, 2006. 26(9): p. 1065–71. doi: 10.1111/j.1478-3231.2006.01337.x 17032406

50. Ananiev J., Penkova M., Tchernev G., and Gulubova M., Macrophages, TGF-β1 expression and iron deposition in development of NASH. Central European Journal of Medicine, 2012. 7(5): p. 599–603.

51. Tosello-Trampont A.C., Landes S.G., Nguyen V., Novobrantseva T.I., and Hahn Y.S., Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-alpha production. J Biol Chem, 2012. 287(48): p. 40161–72. doi: 10.1074/jbc.M112.417014 23066023

52. Miura K., Yang L., van Rooijen N., Ohnishi H., and Seki E., Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am J Physiol Gastrointest Liver Physiol, 2012. 302(11): p. G1310–21. doi: 10.1152/ajpgi.00365.2011 22442158

53. 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(3): p. 416–26. doi: 10.1136/gutjnl-2011-300304 21813474

54. Scott C., Bonner J., Min D., Boughton P., Stokes R., Cha K.M., et al., Reduction of ARNT (Aryl hydrocarbon Receptor Nuclear Translocator) in myeloid cells causes immune suppression and delayed wound healing. Am J Physiol Cell Physiol, 2014.

55. Toussaint M., Fievez L., Drion P.V., Cataldo D., Bureau F., Lekeux P., et al., Myeloid hypoxia-inducible factor 1alpha prevents airway allergy in mice through macrophage-mediated immunoregulation. Mucosal Immunol, 2012.

56. Kobayashi H., Gilbert V., Liu Q., Kapitsinou P.P., Unger T.L., Rha J., et al., Myeloid cell-derived hypoxia-inducible factor attenuates inflammation in unilateral ureteral obstruction-induced kidney injury. J Immunol, 2012. 188(10): p. 5106–15. doi: 10.4049/jimmunol.1103377 22490864

57. Doedens A.L., Stockmann C., Rubinstein M.P., Liao D., Zhang N., DeNardo D.G., et al., Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res, 2010. 70(19): p. 7465–75. doi: 10.1158/0008-5472.CAN-10-1439 20841473

58. Takahashi Y., Soejima Y., and Fukusato T., Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World Journal of Gastroenterology: WJG, 2012. 18(19): p. 2300–2308. doi: 10.3748/wjg.v18.i19.2300 22654421

59. Lee J.H., Wada T., Febbraio M., He J., Matsubara T., Lee M.J., et al., A novel role for the dioxin receptor in fatty acid metabolism and hepatic steatosis. 2010. 139(2): p. 653–663.

60. Foulds C.E., Treviño L.S., York B., and Walker C.L.J.N.R.E., Endocrine-disrupting chemicals and fatty liver disease. 2017. 13(8): p. 445.

61. Bugianesi E., Kalhan S., Burkett E., Marchesini G., and McCullough A., Quantification of gluconeogenesis in cirrhosis: response to glucagon. Gastroenterology, 1998. 115(6): p. 1530–40. doi: 10.1016/s0016-5085(98)70033-2 9834282

62. Changani K.K., Jalan R., Cox I.J., Ala-Korpela M., Bhakoo K., Taylor-Robinson S.D., et al., Evidence for altered hepatic gluconeogenesis in patients with cirrhosis using in vivo 31-phosphorus magnetic resonance spectroscopy. Gut, 2001. 49(4): p. 557–64. doi: 10.1136/gut.49.4.557 11559655


Článek vyšel v časopise

PLOS One


2019 Číslo 12