Iron and non-alcoholic fatty liver disease.
The mechanisms that promote liver injury in non-alcoholic fatty liver disease (NAFLD) are yet to be thoroughly elucidated. As such, effective treatment strategies are lacking and novel therapeutic targets are required. Iron has been widely implicated in the pathogenesis of NAFLD and represents a potential target for treatment. Relationships between serum ferritin concentration and NAFLD are noted in a majority of studies, although serum ferritin is an imprecise measure of iron loading. Numerous mechanisms for a pathogenic role of hepatic iron in NAFLD have been demonstrated in animal and cell culture models. However, the human data linking hepatic iron to liver injury in NAFLD is less clear, with seemingly conflicting evidence, supporting either an effect of iron in hepatocytes or within reticulo-endothelial cells. Adipose tissue has emerged as a key site at which iron may have a pathogenic role in NAFLD. Evidence for this comes indirectly from studies that have evaluated the role of adipose tissue iron with respect to insulin resistance. Adding further complexity, multiple strands of evidence support an effect of NAFLD itself on iron metabolism. In this review, we summarise the human and basic science data that has evaluated the role of iron in NAFLD pathogenesis.
Laurence J Britton, Darrell HG Crawford, Gallipoli Medical Research Institute, The University of Queensland, Greenslopes Private Hospital, Brisbane, Queensland 4120, Australia.
Laurence J
LJ
Britton
Laurence J Britton, Darrell HG Crawford, Gallipoli Medical Research Institute, The University of Queensland, Greenslopes Private Hospital, Brisbane, Queensland 4120, Australia.
V Nathan
VN
Subramaniam
Laurence J Britton, Darrell HG Crawford, Gallipoli Medical Research Institute, The University of Queensland, Greenslopes Private Hospital, Brisbane, Queensland 4120, Australia.
Darrell Hg
DH
Crawford
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D042783:Endothelial Cells / Q000166:cytology; D005234:Fatty Liver / Q000378:metabolism*; D005293:Ferritins / Q000097:blood; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance; D007501:Iron / Q000097:blood / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D009765:Obesity / Q000150:complications
D005293:Ferritins; D007501:Iron
Adipose tissue; Diabetes mellitus; Fatty liver; Insulin resistance; Iron; Liver steatosis; Steatohepatitis
Biometals. 2011 Jun;24(3):489-500
21267633
Nat Med. 2009 Aug;15(8):914-20
19633658
Hepatology. 2012 Jan;55(1):77-85
21953442
J Gastroenterol Hepatol. 2010 Apr;25(4):672-90
20492324
JPEN J Parenter Enteral Nutr. 2011 Sep;35(5 Suppl):14S-20S
21807932
Dig Dis Sci. 2013 Jul;58(7):1899-908
23558563
Nutrition. 2015 Oct;31(10):1266-74
26206271
J Clin Invest. 2005 May;115(5):1343-51
15864352
PLoS One. 2012;7(11):e48804
23144979
Hepatology. 2011 Feb;53(2):448-57
21274866
Diabetes Metab Res Rev. 2014 Jul;30(5):372-94
24327370
J Gastroenterol Hepatol. 2007 Jun;22(6):778-87
17565630
Lancet. 1997 Jan 11;349(9045):95-7
8996422
Am J Physiol Gastrointest Liver Physiol. 2016 Jan 15;310(2):G117-27
26564716
Hepatology. 2013 May;57(5):1806-13
23325576
Curr Opin Gastroenterol. 2010 May;26(3):202-8
20168226
Diabetes Care. 1998 Dec;21(12):2190
9839115
Hepatology. 2015 Sep;62(3):668-70
25914250
J Clin Invest. 2004 May;113(9):1277-87
15124019
Curr Gastroenterol Rep. 2012 Feb;14(1):8-16
22124850
Clin Liver Dis. 2012 Aug;16(3):549-65
22824480
Biochem Pharmacol. 2013 Dec 1;86(11):1517-24
23988487
Nature. 2006 Dec 14;444(7121):881-7
17167477
Am J Clin Nutr. 2002 Dec;76(6):1375-84
12450906
Am J Pathol. 2007 Mar;170(3):967-80
17322381
Semin Liver Dis. 2011 Aug;31(3):260-71
21901656
Diabetes Care. 2013 Feb;36(2):309-15
22961568
Am J Physiol Endocrinol Metab. 2006 Aug;291(2):E275-81
16492686
Hepatol Res. 2005 Oct;33(2):135-7
16257259
J Hepatol. 2011 Nov;55(5):1079-85
21354231
PLoS One. 2015 Feb 03;10(2):e0116855
25647178
Gastroenterology. 2008 Feb;134(2):568-76
18082745
Nat Rev Endocrinol. 2011 May 10;7(8):456-65
21556019
Hepatology. 2005 Jun;41(6):1313-21
15915461
N Engl J Med. 2012 Jan 26;366(4):348-59
22276824
Diabetes Care. 2011 Jul;34(7):1557-63
21709294
J Clin Invest. 2012 Oct;122(10 ):3529-40
22996660
Cell Mol Life Sci. 2009 Oct;66(20):3241-61
19484405
J Gastroenterol. 2011 Feb;46(2):257-68
20842510
Am J Clin Nutr. 2001 Mar;73(3):638-46
11237943
J Biol Chem. 2006 Apr 28;281(17 ):12093-101
16505490
World J Gastroenterol. 2014 Mar 21;20(11):3002-10
24659891
Curr Opin Oncol. 2014 Jan;26(1):100-7
24275855
Diabetes Care. 2011 Jul;34(7):1564-9
21709295
World J Gastroenterol. 2014 Feb 21;20(7):1768-76
24587654
Nature. 2013 Apr 25;496(7446):445-55
23619691
Hepatology. 2004 Jan;39(1):179-87
14752836
Cell Signal. 2006 Apr;18(4):401-8
16182514
Gastroenterology. 1998 Feb;114(2):311-8
9453491
Nat Med. 2009 Aug;15(8):930-9
19633656
Free Radic Biol Med. 2012 Jan 1;52(1):59-69
22064361
J Clin Invest. 2003 Dec;112(12):1796-808
14679176
Clin Gastroenterol Hepatol. 2014 Jul;12(7):1170-8
24269922
JAMA. 2004 Feb 11;291(6):711-7
14871914
Hepatology. 2009 Sep;50(3):957-69
19585655
Am J Physiol Gastrointest Liver Physiol. 2011 Nov;301(5):G865-76
21817060
Hepatology. 2015 May;61(5):1555-64
25524401
J Clin Invest. 2015 Sep;125(9):3681-91
26301810
Diabetes. 2002 Apr;51(4):1000-4
11916918
BMC Med. 2012 May 30;10:54
22647517
J Hepatol. 2011 Oct;55(4):920-32
21718726
Diabetes Care. 2016 Apr;39(4):572-81
26861925
Metab Syndr Relat Disord. 2011 Aug;9(4):287-90
21417913
Hepatology. 2007 Oct;46(4):1071-80
17828789
Eur J Endocrinol. 2015 Nov;173(5):643-53
26294793
Hepatology. 2012 Nov;56(5):1730-40
22611049
Diabetes. 2004 Oct;53(10):2535-41
15448081
Gastroenterology. 2011 Oct;141(4):1249-53
21726509
Semin Liver Dis. 2011 Aug;31(3):280-92
21901658
Hepatology. 2009 Mar;49(3):887-900
19241483
Diabetologia. 2012 Oct;55(10):2613-21
22752055
Gastroenterology. 2006 Sep;131(3):788-96
16952548
J Biol Chem. 2007 Dec 28;282(52):37501-7
17971451
Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1140-9
20215574
Hepatology. 2002 Jul;36(1):142-9
12085358
Nat Rev Gastroenterol Hepatol. 2013 Nov;10(11):686-90
24042449
Metabolism. 2012 Aug;61(8):1182-8
22386931
Cancer Epidemiol Biomarkers Prev. 2009 Feb;18(2):424-32
19190144
Cell Metab. 2013 Mar 5;17(3):329-41
23473030
Lab Invest. 2013 Dec;93(12):1295-312
24126888
J Hepatol. 1999 Sep;31(3):421-9
10488699
Gastroenterology. 2005 Dec;129(6):1937-43
16344062
J Biol Chem. 2007 Feb 23;282(8):5582-8
17172471
Hematology Am Soc Hematol Educ Program. 2009;:195-206
20008199
Nat Rev Gastroenterol Hepatol. 2011 Jan;8(1):35-44
21119613
Gastroenterology. 2002 Apr;122(4):931-9
11910345
J Gastroenterol Hepatol. 2001 Jun;16(6):599-606
11422610
Am J Gastroenterol. 2001 Aug;96(8):2448-55
11513189
Aliment Pharmacol Ther. 2011 Aug;34(3):274-85
21623852
Hepatology. 2010 Aug;52(2):462-71
20683946
Trends Mol Med. 2013 Aug;19(8):487-500
23746697
Gastroenterology. 2010 Mar;138(3):905-12
19931264
Endocr J. 2012;59(9):745-63
22893453
Diabetes Care. 1999 Dec;22(12):1978-83
10587829
J Gastrointestin Liver Dis. 2012 Mar;21(1):53-8
22457860
World J Hepatol. 2015 Aug 28;7(18):2155-61
26328027
World J Gastroenterol. 2014 Oct 21;20(39):14205-18
25339807
Nat Rev Gastroenterol Hepatol. 2013 Jun;10(6):330-44
23507799
Diabetes Metab. 2016 Apr;42(2):105-11
26677772
Diabetes. 2014 May;63(5):1506-18
24379355
Hepatology. 2015 Sep;62(3):751-61
25753988
N Engl J Med. 2008 Jan 17;358(3):221-30
18199861
Cell. 2012 Mar 2;148(5):852-71
22385956
Am J Pathol. 2013 Jun;182(6):2254-63
23578384
Obes Rev. 2013 Oct;14(10):771-9
23841713