Rat strain differences in susceptibility to alcohol-induced chronic liver injury and hepatic insulin resistance.
The finding of more severe steatohepatitis in alcohol fed Long Evans (LE) compared with Sprague Dawley (SD) and Fisher 344 (FS) rats prompted us to determine whether host factors related to alcohol metabolism, inflammation, and insulin/IGF signaling predict proneness to alcohol-mediated liver injury. Adult FS, SD, and LE rats were fed liquid diets containing 0% or 37% (calories) ethanol for 8 weeks. Among controls, LE rats had significantly higher ALT and reduced GAPDH relative to SD and FS rats. Among ethanol-fed rats, despite similar blood alcohol levels, LE rats had more pronounced steatohepatitis and fibrosis, higher levels of ALT, DNA damage, pro-inflammatory cytokines, ADH, ALDH, catalase, GFAP, desmin, and collagen expression, and reduced insulin receptor binding relative to FS rats. Ethanol-exposed SD rats had intermediate degrees of steatohepatitis, increased ALT, ADH and profibrogenesis gene expression, and suppressed insulin receptor binding and GAPDH expression, while pro-inflammatory cytokines were similarly increased as in LE rats. Ethanol feeding in FS rats only reduced IL-6, ALDH1-3, CYP2E1, and GAPDH expression in liver. In conclusion, susceptibility to chronic steatohepatitis may be driven by factors related to efficiency of ethanol metabolism and degree to which ethanol exposure causes hepatic insulin resistance and cytokine activation.
Denucci
Sarah M
SM
Departments of Medicine and Pathology, Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Pierre Galletti Research Building, 55 Claverick Street, Room 421, Providence, RI 02903, USA.
Tong
Ming
M
Longato
Lisa
L
Lawton
Margot
M
Setshedi
Mashiko
M
Carlson
Rolf I
RI
Wands
Jack R
JR
de la Monte
Suzanne M
SM
Microvasc Res. 1995 May;49(3):350-63
7643754
Alcohol Clin Exp Res. 1998 Dec;22(9):2093-101
9884156
Curr Med Chem. 2008;15(13):1316-29
18537611
Physiol Rev. 2008 Jan;88(1):125-72
18195085
Gastroenterology. 1979 Sep;77(3):528-31
572315
Biochem Biophys Res Commun. 1985 Apr 30;128(2):767-74
3888219
Adv Enzyme Regul. 1992;32:149-59
1386708
Ital J Anat Embryol. 2005 Oct-Dec;110(4):193-207
16536051
Semin Liver Dis. 2007 Feb;27(1):44-54
17295176
In Vitr Mol Toxicol. 2001 Fall;14(3):177-90
11846991
Biol Proced Online. 2006;8:1-10
16446781
Gastroenterology. 1998 Dec;115(6):1558-65
9834285
Free Radic Biol Med. 2001 Dec 15;31(12):1539-43
11744327
Gastroenterology. 1990 Oct;99(4):1105-12
2394331
Alcohol Clin Exp Res. 2003 Aug;27(8 Suppl):52S-57S
12960508
Mol Pharmacol. 2004 Sep;66(3):749-60
15322268
J Hepatol. 2010 Mar;52(3):407-16
20129692
Gut. 1982 Jan;23(1):8-13
7056500
Gastroenterology. 2003 Dec;125(6):1818-33
14724834
BMC Mol Biol. 2005 Apr 26;6:10
15854230
Gastroenterology. 2008 May;134(6):1655-69
18471545
Hepatol Res. 2011 Apr;41(4):386-98
21426453
J Alzheimers Dis. 2006 Mar;9(1):13-33
16627931
J Biol Chem. 2003 Jul 18;278(29):26929-37
12700235
Am J Physiol. 1991 Aug;261(2 Pt 1):G199-205
1678584
J Alzheimers Dis. 2009;16(4):715-29
19387108
J Alzheimers Dis. 2005 Feb;7(1):45-61
15750214
Alcohol Res Health. 2006;29(4):245-54
17718403
Cell Mol Life Sci. 2006 Sep;63(17):2039-56
16909201
Alcohol Clin Exp Res. 1999 May;23(5):904-10
10371412
J Lipid Res. 1985 Jul;26(7):781-9
4031658
Shock. 2005 Nov;24(5):447-54
16247331
Alcohol. 2010 Mar;44(2):157-69
20116195
J Gastroenterol Hepatol. 2008 Aug;23(8 Pt 2):e477-86
18505416
Cell Mol Life Sci. 2005 May;62(10):1131-45
15870954
J Hepatol. 2009 Jun;50(6):1192-201
19398227
Alcohol Clin Exp Res. 2006 Nov;30(11):1906-15
17067356
Methods Mol Biol. 2004;282:85-101
15105558
J Alzheimers Dis. 2008 Sep;15(1):29-44
18780965
Liver Transpl. 2008 Jun;14(6):756-8
18508367
Semin Liver Dis. 2007 May;27(2):173-93
17520517
Hepatology. 2008 May;47(5):1483-94
18393316
J Histochem Cytochem. 1985 Aug;33(8):833-6
4020099
Alcohol Alcohol Suppl. 1994;29(1):99-106
9063828
Adv Exp Med Biol. 1980;132:663-70
7191626
Biochem Biophys Res Commun. 1994 Feb 28;199(1):403-9
7510107
Hepatology. 2003 Sep;38(3):703-14
12939597
Hepatology. 2007 Dec;46(6):1791-800
18027876
Clin Liver Dis. 2008 Nov;12(4):769-90, viii
18984466
Alcohol Clin Exp Res. 2007 Sep;31(9):1558-73
17645580
Wei Sheng Yan Jiu. 2006 May;35(3):294-6
16921752
Alcohol. 2004 Aug;34(1):81-7
15670669
Liver. 2002 Oct;22(5):394-403
12390475
Gastroenterology. 2004 Mar;126(3):873-85
14988841