Pathogenesis of alcoholic liver disease: the role of nuclear receptors.
Ethanol consumption causes fatty liver, which can lead to inflammation, fibrosis, cirrhosis and even liver cancer. The molecular mechanisms by which ethanol exerts its damaging effects are extensively studied, but not fully understood. It is now evident that nuclear receptors (NRs), including retinoid x receptor alpha and peroxisome proliferator-activated receptors, play key roles in the regulation of lipid homeostasis and inflammation during the pathogenesis of alcoholic liver disease (ALD). Given their pivotal roles in physiological processes, NRs represent potential therapeutic targets for the treatment and prevention of numerous metabolic and lipid-related diseases including ALD. This review summarizes the factors that contribute to ALD and the molecular mechanisms of ALD with a focus on the role of NRs.
Gyamfi
Maxwell Afari
MA
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, Kansas 66160-7417, USA.
Wan
Yu-Jui Yvonne
YJ
D000818:Animals; D004195:Disease Models, Animal; D004703:Endocrine System / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000150:complications / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*
D018160:Receptors, Cytoplasmic and Nuclear; D000431:Ethanol
Alcohol Clin Exp Res. 2005 Nov;29(11):2039-45
16340462
Cell. 1992 Jan 24;68(2):377-95
1310259
Toxicol Appl Pharmacol. 2005 Aug 22;207(1):25-38
15885730
Endocrinology. 2000 Nov;141(11):4021-31
11089532
Biochim Biophys Acta. 1997 Jan 3;1350(1):27-32
9003453
Mol Pharmacol. 2004 Mar;65(3):550-7
14978233
Int Immunopharmacol. 2004 Nov;4(12):1445-54
15351314
Nucl Recept. 2004 Aug 16;2(1):4
15312234
Alcohol Clin Exp Res. 2007 Jul;31(7):1231-9
17577393
Arch Biochem Biophys. 1992 May 1;294(2):388-93
1567193
Alcohol Clin Exp Res. 1996 Nov;20(8):1340-5
8947308
Eur J Biochem. 1998 May 15;254(1):25-31
9652389
Eur J Pharm Sci. 2002 Feb;15(1):89-96
11803135
Cell. 1992 Jan 24;68(2):397-406
1310260
Trends Endocrinol Metab. 2002 Mar;13(2):84-9
11854024
J Clin Invest. 2000 Apr;105(8):1095-108
10772654
Gastroenterology. 2001 Jan;120(1):179-89
11208727
Structure. 2002 Sep;10(9):1225-34
12220494
Gastroenterology. 1995 Aug;109(2):547-54
7615205
Semin Liver Dis. 2007 Nov;27(4):367-77
17979073
J Hepatol. 1997;26 Suppl 1:13-22
9138124
Semin Liver Dis. 2004 Aug;24(3):217-32
15349801
Alcohol. 2004 Aug;34(1):39-43
15670664
Gastroenterology. 2003 May;124(5):1488-99
12730887
J Hepatol. 2008 Sep;49(3):441-50
18620774
Pediatrics. 2004 Sep;114(3):714-9
15342844
Pharmacogenet Genomics. 2008 Apr;18(4):325-37
18334917
Hepatology. 1997 Jul;26(1):143-6
9214463
N Engl J Med. 1982 Sep 2;307(10):597-601
7202119
Liver Int. 2008 Mar;28(3):385-92
17999673
Gastroenterology. 2003 Dec;125(6):1818-33
14724834
Curr Mol Med. 2003 Sep;3(6):561-72
14527087
World J Gastroenterol. 2005 Dec 28;11(48):7702-3
16437706
J Pharmacol Exp Ther. 2003 Sep;306(3):846-54
12805475
Mol Endocrinol. 2004 Apr;18(4):888-98
14739254
Alcohol Clin Exp Res. 1994 Jun;18(3):587-91
7943659
J Nutr. 1996 Apr;126(4 Suppl):1086S-91S
8642438
J Stud Alcohol. 1993 Jul;54(4):450-6
8341047
Mol Cell Biol. 2003 Apr;23(7):2587-99
12640139
Clin Pharmacokinet. 2003;42(15):1331-57
14674787
Cell. 2004 Feb 6;116(3):417-29
15016376
IUBMB Life. 2008 Dec;60(12):790-7
18709650
Mol Endocrinol. 2006 Aug;20(8):1715-27
16556735
Curr Opin Genet Dev. 1998 Oct;8(5):576-81
9794815
Toxicol Sci. 2008 Nov;106(1):290-9
18703563
N Engl J Med. 1997 Apr 10;336(15):1066-71
9091804
J Biol Chem. 2003 Mar 21;278(12):10443-9
12531895
J Biol Chem. 2007 Dec 14;282(50):36766-76
17962186
Am J Clin Nutr. 1970 Apr;23(4):474-8
5462407
Blood. 2000 Sep 1;96(5):1723-32
10961870
Chem Biol Interact. 2003 Feb 1;143-144:201-10
12604205
Dig Dis. 2005;23(3-4):181-94
16508282
Genet Test. 1998;2(1):79-83
10464602
Biochem Pharmacol. 2008 Feb 15;75(4):981-95
18036573
Biochemistry. 1996 Apr 9;35(14):4445-56
8605194
Alcohol. 2004 Aug;34(1):21-5
15670661
Alcohol. 2007 Jun;41(4):271-80
17630087
FASEB J. 1996 Jul;10(9):1050-7
8801166
J Biol Chem. 2000 Nov 24;275(47):36703-7
10980195
J Pharmacol Exp Ther. 2004 Jul;310(1):417-24
15016835
Alcohol. 2005 Apr;35(3):251-8
16054987
J Biol Chem. 2006 Jun 2;281(22):15434-40
16551633
Science. 1996 May 31;272(5266):1336-9
8650544
Drug Metab Rev. 1989;20(2-4):697-720
2680404
Alcohol Clin Exp Res. 2008 Jun;32(6):1049-58
18498552
Hepatology. 2004 Oct;40(4):933-41
15382116
Exp Mol Pathol. 2003 Dec;75(3):194-200
14611810
Hepatology. 2004 Oct;40(4):972-80
15382117
Alcohol Clin Exp Res. 1989 Feb;13(1):15-9
2646971
Hum Genet. 2003 Sep;113(4):325-36
12884000
Biochem Cell Biol. 1987 Mar;65(3):230-3
3580171
Hepatology. 2005 Sep;42(3):568-77
16108051
J Biol Chem. 1998 Nov 6;273(45):29577-85
9792666
Kidney Int. 2006 Mar;69(6):1064-72
16528256
Hepatology. 1995 Oct;22(4 Pt 1):1208-14
7557872
Am J Physiol Endocrinol Metab. 2001 Sep;281(3):E420-9
11500296
Alcohol Clin Exp Res. 1986;10(6 Suppl):64S-68S
3544932
J Pharmacol Exp Ther. 2006 Oct;319(1):360-8
16829625
Am J Physiol. 1999 Jul;277(1):E1-10
10409121
Gastroenterology. 2004 Nov;127(5 Suppl 1):S87-96
15508108
Hepatology. 1998 Sep;28(3):805-9
9731576
J Biomed Sci. 2001 Jan-Feb;8(1):20-7
11173972
Science. 2001 Nov 30;294(5548):1866-70
11729302
J Hepatol. 2007 May;46(5):907-14
17321001
Hepatology. 1998 Oct;28(4):901-5
9755223
Cell. 1996 Oct 4;87(1):13-20
8858144
Mol Cell Biol. 1995 Jun;15(6):3012-22
7539101
Clin Immunol. 2007 Aug;124(2):213-20
17586095
J Clin Invest. 1996 Oct 1;98(7):1575-84
8833906
J Clin Invest. 2006 Jul;116(7):1776-83
16823475
Alcohol Clin Exp Res. 2001 Aug;25(8):1181-7
11505049
J Biochem. 2009 May;145(5):609-23
19174548
Annu Rev Physiol. 2006;68:159-91
16460270
J Nutr. 1996 Jun;126(6):1515-33
8648424
Mol Endocrinol. 2003 Feb;17(2):259-72
12554753
Alcohol Alcohol. 1989;24(3):197-211
2667528
Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7473-8
10377439
Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7355-9
8041794
Cardiovasc Res. 2005 Jun 1;66(3):562-73
15914121
Mol Endocrinol. 2001 Oct;15(10):1720-8
11579204
Alcohol Res Health. 2003;27(4):325-30
15540804
J Pharmacol Exp Ther. 2001 Nov;299(2):638-44
11602676
Nature. 1998 Jan 1;391(6662):79-82
9422508
Am J Physiol Gastrointest Liver Physiol. 2001 May;280(5):G1005-12
11292610
Cell. 2000 Sep 15;102(6):731-44
11030617
Toxicol Appl Pharmacol. 1997 Aug;145(2):425-36
9266817
J Biol Chem. 2003 Jan 24;278(4):2461-8
12431986
Hepatology. 1998 Jun;27(6):1463-6
9620314
Ann Intern Med. 1992 Oct 15;117(8):646-54
1530196
Genes Dev. 1996 Jan 1;10(1):80-92
8557197
Biochem J. 2009 Jan 1;417(1):43-54
18778245
Kidney Int. 2009 Jul;76(1):32-43
19357716
J Biol Chem. 2002 Sep 13;277(37):34176-81
12107164
J Clin Invest. 1999 Jun;103(11):1489-98
10359558
Toxicol Pathol. 2006;34(4):373-84
16844665
Alcohol. 2004 Aug;34(1):9-19
15670660
Cell. 1995 Dec 15;83(6):841-50
8521508
Arch Biochem Biophys. 1971 Aug;145(2):669-75
5125212
Cell Mol Immunol. 2006 Oct;3(5):333-40
17092430
Alcohol Alcohol Suppl. 1991;1:271-6
1845549
Alcohol Clin Exp Res. 1996 Feb;20(1):132-8
8651442
Hepatology. 1985 Mar-Apr;5(2):224-32
3979954
Arch Toxicol. 2008 Dec;82(12):959-64
18488193
N Engl J Med. 2000 Nov 16;343(20):1467-76
11078773
J Hepatol. 2003 May;38(5):629-34
12713874
Adv Enzyme Regul. 2002;42:227-47
12123718
Alcohol. 1996 Sep-Oct;13(5):483-6
8888945
J Hepatol. 1992 Nov;16(3):290-7
1487605
Annu Rev Biochem. 1998;67:821-55
9759505
Am J Physiol. 1984 Sep;247(3 Pt 2):R595-9
6433728
J Biol Chem. 2002 Mar 29;277(13):11019-25
11790787
Gut. 2009 May;58(5):613-7
19174416
Trends Mol Med. 2001 Sep;7(9):408-13
11530336
J Biol Chem. 2003 Jul 25;278(30):27997-8004
12791698
Blood. 2003 Jan 15;101(2):545-51
12393563
Alcohol Clin Exp Res. 2003 Mar;27(3):540-62
12658122
Arch Toxicol. 1983 Jun;53(2):151-63
6882216
Life Sci. 1995;56(5):307-17
7837930
Lancet. 1995 Oct 14;346(8981):987-90
7475591
J Biol Chem. 1999 Nov 5;274(45):32048-54
10542237
Alcohol. 2004 Jun;33(2):147-55
15528012
J Nutr. 2004 Apr;134(4):904-12
15051845
Exp Mol Pathol. 2003 Apr;74(2):183-9
12710951
Best Pract Res Clin Gastroenterol. 2003 Aug;17(4):649-62
12828960
Alcohol. 2002 Feb;26(2):65-7
12007580
Scand J Gastroenterol. 2005 Mar;40(3):348-53
15932176
Hepatology. 2007 Nov;46(5):1586-96
17705221
FEBS Lett. 2007 Dec 11;581(29):5617-26
18023279
Gastroenterology. 2007 Mar;132(3):1117-1126
17383432
Toxicol Appl Pharmacol. 2009 Jan 15;234(2):166-78
18952117
J Clin Invest. 2002 May;109(9):1125-31
11994399
Hepatology. 2007 Dec;46(6):2032-9
18046720
Am J Physiol Gastrointest Liver Physiol. 2008 Apr;294(4):G892-8
18239056
J Biol Chem. 2002 Oct 11;277(41):37973-6
12193589
Science. 1996 Nov 22;274(5291):1379-83
8910279
Biochemistry. 1996 Sep 24;35(38):12221-7
8823154
Hepatology. 2006 Jan;43(1):144-53
16374848
J Clin Invest. 2004 May;113(10):1408-18
15146238
Br J Clin Pharmacol. 1978 Mar;5(3):249-54
656270
Proc Soc Exp Biol Med. 2000 Sep;224(4):302-8
10964266
Genes Dev. 2000 Nov 15;14(22):2819-30
11090130
Alcohol Clin Exp Res. 1998 May;22(S3 Pt 1):164S-169S
9622397
Gastroenterology. 2006 Jun;130(7):2099-112
16762632
J Clin Pharmacol. 1981 Oct;21(10):436-42
7031100
J Hepatol. 1986;2(1):33-42
3950362
J Pharmacol Exp Ther. 2008 Feb;324(2):443-53
17975011
J Biol Chem. 2000 Sep 8;275(36):28285-90
10866995
Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9010-4
8799145
Mol Cell Biol. 2000 Jun;20(12):4436-44
10825207
Hepatology. 1996 May;23(5):1025-9
8621128
FEBS Lett. 1998 Apr 24;426(3):362-6
9600267
Alcohol Clin Exp Res. 2004 Jan;28(1):173-81
14745316
Hepatology. 2001 Jan;33(1):91-9
11124825
Semin Liver Dis. 2007 Feb;27(1):44-54
17295176
Proc Nutr Soc. 2004 Feb;63(1):49-63
15099407
J Gastroenterol Hepatol. 2008 Mar;23 Suppl 1:S54-9
18336665
Alcohol Clin Exp Res. 2001 May;25(5 Suppl ISBRA):157S-163S
11391066
Curr Biol. 1998 Mar 12;8(6):335-8
9512423
Hepatol Res. 2006 May;35(1):53-61
16540368
Diabetes. 1998 Apr;47(4):507-14
9568680
J Hepatol. 2006 Nov;45(5):717-24
16879892
Arterioscler Thromb Vasc Biol. 2003 Jul 1;23(7):1262-8
12750120
Gastroenterology. 2008 Apr;134(4):1159-68
18395094
Alcohol Clin Exp Res. 2007 Apr;31(4):704-15
17374050
Alcohol Clin Exp Res. 2004 Aug;28(8):1145-52
15318112
Nat Med. 2002 Nov;8(11):1288-95
12368907
Genes Dev. 1994 May 1;8(9):1007-18
7926783
Cell. 2006 Oct 20;127(2):397-408
17055439
J Biol Chem. 2001 Jan 5;276(1):68-75
11022051
Hepatology. 1989 Oct;10(4):501-10
2673971
J Biol Chem. 2006 Jun 30;281(26):17882-9
16608838
Cell. 2006 Aug 25;126(4):801-10
16923398
Mol Cell Biol. 2001 Feb;21(4):1393-403
11158324
J Biol Chem. 2009 Sep 18;284(38):25984-92
19617349
J Biol Chem. 2009 Apr 3;284(14):9321-30
19176532
J Clin Invest. 2003 Jul;112(1):91-100
12840063
Lab Invest. 2010 Feb;90(2):257-65
19997066
J Biol Chem. 2000 May 26;275(21):16390-9
10747970
Alcohol Clin Exp Res. 2001 Jan;25(1):136-44
11198709
BMJ. 1999 Sep 11;319(7211):666-70
10480821
Alcohol Clin Exp Res. 2001 May;25(5 Suppl ISBRA):60S-66S
11391051
Nat Med. 2001 Aug;7(8):941-6
11479627
Mol Pharmacol. 2008 Apr;73(4):1282-9
18187584
Ann Allergy Asthma Immunol. 1999 Jul;83(1):61-7
10437818
Pediatrics. 2007 Jan;119(1):76-85
17200273
World J Gastroenterol. 2006 Aug 28;12(32):5244-6
16937543
J Clin Invest. 1995 Jul;96(1):620-30
7615836
J Pharmacol Exp Ther. 1996 Jun;277(3):1694-700
8667240
Gut. 2002 Jul;51(1):132-9
12077107
Am J Physiol Gastrointest Liver Physiol. 2008 Oct;295(4):G833-42
18755807
Nat Med. 2003 Feb;9(2):213-9
12524534
Hepatology. 1999 Oct;30(4):934-43
10498645
J Exp Med. 2001 Apr 2;193(7):827-38
11283155
Oncogene. 2002 Jan 3;21(1):32-43
11791174
Endocr Rev. 1999 Oct;20(5):689-725
10529899
Alcohol Clin Exp Res. 1981 Spring;5(2):207-15
7018299
Nat Med. 2003 Feb;9(2):220-4
12514743
Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12861-6
17646659
Alcohol Clin Exp Res. 1998 Aug;22(5 Suppl):231S-237S
9727642
Biochem Pharmacol. 2002 Jan 1;63(1):1-10
11754868
Hepatology. 1997 Jan;25(1):108-11
8985274
Genes Dev. 1992 Mar;6(3):329-44
1312497
Mol Pharmacol. 1998 Jan;53(1):14-22
9443928
Annu Rev Physiol. 2000;62:413-37
10845097
Metabolism. 2007 Feb;56(2):267-79
17224343
Nat Med. 2002 Jul;8(7):731-7
12068289
Exp Biol Med (Maywood). 2008 May;233(5):496-506
18375823
Alcohol. 2002 Jul;27(3):155-62
12163143
Gut. 1997 Dec;41(6):845-50
9462221
J Clin Invest. 2002 Nov;110(10):1503-13
12438448
Clin Liver Dis. 2006 May;10(2):219-37, vii
16971259
J Hepatol. 2005 Mar;42(3):371-7
15710220
Cell. 1994 Sep 23;78(6):987-1003
7923367
J Clin Invest. 1966 Sep;45(9):1400-11
4162127
Recent Dev Alcohol. 1993;11:207-30
8234924
J Biol Chem. 2006 May 26;281(21):15013-20
16556603
Endocrinology. 2003 Feb;144(2):605-11
12538623
Lancet. 1984 Aug 4;2(8397):241-4
6146805
Clin Immunol. 2002 Oct;105(1):57-63
12483994
J Lipid Res. 2001 Mar;42(3):328-37
11254743
Nature. 1996 Nov 7;384(6604):39-43
8900274
J Hepatol. 2009 Jun;50(6):1184-91
19398231