Endocannabinoids in liver disease.
Endocannabinoids are lipid mediators of the same cannabinoid (CB) receptors that mediate the effects of marijuana. The endocannabinoid system (ECS) consists of CB receptors, endocannabinoids, and the enzymes involved in their biosynthesis and degradation, and it is present in both brain and peripheral tissues, including the liver. The hepatic ECS is activated in various liver diseases and contributes to the underlying pathologies. In patients with cirrhosis of various etiologies, the activation of vascular and cardiac CB(1) receptors by macrophage-derived and platelet-derived endocannabinoids contributes to the vasodilated state and cardiomyopathy, which can be reversed by CB(1) blockade. In mouse models of liver fibrosis, the activation of CB(1) receptors on hepatic stellate cells is fibrogenic, and CB(1) blockade slows the progression of fibrosis. Fatty liver induced by a high-fat diet or chronic alcohol feeding depends on the activation of peripheral receptors, including hepatic CB(1) receptors, which also contribute to insulin resistance and dyslipidemias. Although the documented therapeutic potential of CB(1) blockade is limited by neuropsychiatric side effects, these may be mitigated by using novel, peripherally restricted CB(1) antagonists.
National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9413, USA.
Joseph
J
Tam
Jie
J
Liu
Bani
B
Mukhopadhyay
Resat
R
Cinar
Grzegorz
G
Godlewski
George
G
Kunos
D000818:Animals; D002185:Cannabidiol / Q000627:therapeutic use; D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D063388:Endocannabinoids; D005234:Fatty Liver / Q000209:etiology; D005235:Fatty Liver, Alcoholic / Q000503:physiopathology; D006501:Hepatic Encephalopathy / Q000503:physiopathology; D019693:Hepatitis, Autoimmune / Q000188:drug therapy; D006801:Humans; D008103:Liver Cirrhosis / Q000503:physiopathology; D008107:Liver Diseases / Q000503:physiopathology*; D024821:Metabolic Syndrome / Q000503:physiopathology; D051379:Mice; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000502:physiology; D043882:Receptors, Cannabinoid / Q000502:physiology*; D015427:Reperfusion Injury / Q000503:physiopathology
D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1; D043882:Receptors, Cannabinoid; D002185:Cannabidiol
Neuroscience. 1998 Feb;82(4):1131-49
9466436
Pharmacol Rev. 2006 Sep;58(3):389-462
16968947
Am J Physiol Regul Integr Comp Physiol. 2009 Apr;296(4):R929-35
19211723
Liver Int. 2007 Mar;27(2):215-9
17311616
Neurosci Lett. 2007 Jan 29;412(2):114-7
17123706
Biochim Biophys Acta. 2000 Dec 15;1535(1):78-86
11113634
Am J Physiol Gastrointest Liver Physiol. 2008 Feb;294(2):G506-19
18096608
Diabetes Obes Metab. 2005 Jan;7(1):65-72
15642077
Int J Obes (Lond). 2008 May;32(5):863-70
18253160
J Clin Invest. 2005 May;115(5):1298-305
15864349
Am J Physiol Gastrointest Liver Physiol. 2001 Jan;280(1):G14-20
11123193
FASEB J. 2007 Aug;21(10):2431-41
17431095
Mol Neurobiol. 2007 Aug;36(1):15-25
17952646
Gastroenterology. 2010 Dec;139(6):1961-1971.e1
20600015
Hepatology. 2010 Sep;52(3):1046-59
20597071
Am J Physiol Endocrinol Metab. 2007 Sep;293(3):E826-32
17595216
J Biol Chem. 2008 Apr 4;283(14):9341-9
18227059
PLoS One. 2009 Jun 09;4(6):e5844
19513120
J Pharmacol Exp Ther. 1997 Jun;281(3):1030-7
9190833
Gastroenterology. 2008 Feb;134(2):432-9
18242211
J Gastroenterol Hepatol. 2010 May;25(5):991-1001
20059638
J Clin Invest. 2010 Aug;120(8):2953-66
20664173
FASEB J. 2007 Sep;21(11):2798-806
17440119
Cell Metab. 2010 Apr 7;11(4):273-85
20374960
J Biol Chem. 2002 Aug 9;277(32):29342-7
12036955
Int J Obes (Lond). 2010 Mar;34(3):547-56
20029379
J Hepatol. 2009 Sep;51(3):528-34
19596476
Hepatology. 2007 Jul;46(1):122-9
17526015
Gut. 2005 Apr;54(4):522-7
15753538
J Am Coll Cardiol. 2001 Dec;38(7):2048-54
11738314
Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E1162-70
19724020
Br J Pharmacol. 2006 Dec;149(7):898-908
17043671
Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):14136-41
10570211
Liver Int. 2007 Oct;27(8):1045-55
17845532
J Biol Chem. 2003 Nov 7;278(45):45034-9
12949078
J Clin Invest. 1961 Feb;40:394-9
13761991
Annu Rev Biochem. 2005;74:411-32
15952893
Pharmacol Ther. 2005 May;106(2):133-45
15866316
Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14561-6
18794527
J Clin Invest. 2008 Sep;118(9):3160-9
18677409
Gastroenterology. 2005 Mar;128(3):742-55
15765409
Eur J Biochem. 1995 Aug 15;232(1):54-61
7556170
Liver Int. 2004 Oct;24(5):477-83
15482346
Apoptosis. 2010 Aug;15(8):904-14
20446039
Int J Obes Relat Metab Disord. 2004 Apr;28(4):640-8
14770190
Lancet. 2006 Nov 11;368(9548):1660-72
17098084
J Biol Chem. 2009 Jan 16;284(3):1803-12
19008231
Handb Exp Pharmacol. 2005;(168):53-79
16596771
Diabetes. 2001 Dec;50(12):2786-91
11723062
Clin Pharmacol Ther. 1974 Aug;16(2):297-302
4851289
Neurobiol Dis. 2006 Jan;21(1):237-45
16102970
Nature. 2005 Jul 21;436(7049):356-62
16034410
Diabetes. 2010 Apr;59(4):926-34
20110567
Mol Pharmacol. 2008 Jul;74(1):20-33
18388242
Biochem Pharmacol. 1995 Jun 29;50(1):83-90
7605349
Am J Gastroenterol. 2008 Dec;103(12):3047-56
19086956
FASEB J. 2007 Jun;21(8):1788-800
17327359
Science. 1992 Dec 18;258(5090):1946-9
1470919
Am J Pathol. 2008 Oct;173(4):993-1001
18772330
J Leukoc Biol. 2007 Dec;82(6):1382-9
17652447
Mol Pharmacol. 2000 May;57(5):1045-50
10779390
Am J Physiol. 1999 Jun;276(6):H2085-93
10362691
Cardiology. 2009;114(3):212-25
19641317
Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13345-50
16938887
J Gastroenterol. 2010;45(1):68-76
19730968
Cell. 2005 Jan 28;120(2):261-73
15680331
Nature. 1997 Dec 4;390(6659):518-21
9394002
Gut. 2009 Aug;58(8):1135-43
19282305
Endocr Rev. 2006 Feb;27(1):73-100
16306385
Nat Clin Pract Gastroenterol Hepatol. 2006 Jun;3(6):329-37
16741552
Hepatology. 2002 Jun;35(6):1544-7
12029644
Gastroenterology. 2002 Jan;122(1):85-93
11781284
Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10819-24
12136125
Liver Int. 2010 Jul;30(6):816-25
19840245
Cancer Genet Cytogenet. 2006 Nov;171(1):31-8
17074588
Hepatology. 2005 Jul;42(1):63-71
15892090
FEBS Lett. 2000 Mar 24;470(2):151-5
10734225
FASEB J. 1998 Aug;12(11):1035-44
9707176
J Pharmacol Exp Ther. 2003 Jan;304(1):179-84
12490589
Eur J Clin Invest. 2004 Apr;34(4):283-9
15086360
Diabetes. 2005 May;54(5):1314-23
15855315
Gastroenterology. 2009 Jul;137(1):341-9
19208344
N Engl J Med. 2005 Nov 17;353(20):2121-34
16291982
J Clin Invest. 2003 Aug;112(3):423-31
12897210
J Anesth. 2006;20(1):11-6
16421670
Int J Obes (Lond). 2005 Feb;29(2):183-7
15558076
Diabetes. 2006 Dec;55(12):3403-10
17130486
Br J Pharmacol. 2005 Oct;146(3):315-23
16025138
Gastroenterology. 2004 Dec;127(6):1798-808
15578517
Gene Expr. 2003;11(2):55-75
12837037
Am J Physiol Regul Integr Comp Physiol. 2003 Feb;284(2):R345-53
12399252
Nat Med. 2006 Jun;12(6):671-6
16715087
Nature. 2001 Apr 12;410(6830):822-5
11298451
J Med Chem. 1983 Feb;26(2):214-7
6827538
Biochem Biophys Res Commun. 1995 Oct 4;215(1):89-97
7575630
Eur J Pharmacol. 2006 Feb 15;531(1-3):282-4
16423347
J Clin Invest. 2000 Jun;105(12):1827-32
10862798
Cell Metab. 2008 Mar;7(3):227-35
18316028
J Pharmacol Exp Ther. 2008 Feb;324(2):475-83
18029545
Science. 2006 Jun 16;312(5780):1656-9
16778057
Hepatol Res. 2009 Apr;39(4):408-14
19207577
Br J Pharmacol. 2008 Jan;153(2):286-9
17952109
Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1689-95
17557913
J Clin Invest. 2005 May;115(5):1343-51
15864352
Nat Med. 2001 Jul;7(7):827-32
11433348
J Biol Chem. 2010 Jun 18;285(25):19002-11
20410309
Eur J Pharmacol. 2007 Jun 22;565(1-3):207-11
17499236