“Second Hit” Models of Alcoholic Liver Disease

Hidekazu Tsukamoto; Keigo Machida; Alla Dynnyk; Hasmik Mkrtchyan

doi:10.1055/s-0029-1214373

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2009; 29(2): 178-187
DOI: 10.1055/s-0029-1214373

“Second Hit” Models of Alcoholic Liver Disease

Hidekazu Tsukamoto¹ ^, ² ^, ⁴ , Keigo Machida¹ ^, ³ , Alla Dynnyk¹ ^, ² , Hasmik Mkrtchyan¹ ^, ²

¹Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern California
²Department of Pathology, Keck School of Medicine of the University of Southern California
³Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California
⁴Department of Veterans Affairs, Greater Los Angeles Healthcare System, Los Angeles, California

Abstract

ABSTRACT

Alcoholic liver disease (ALD) is a lifestyle disease with its pathogenesis and individual predisposition governed by gene–environment interactions. Based on the “second hit” or “multiple hits” hypothesis, patients are predisposed to progressive ALD when a magic combination of gene and environmental interactions exists. Reproduction of second or multiple hits in animal models serves to test a combination and to gain mechanistic insights into synergism achieved by such combination. Numerous environmental factors have been incorporated into animal models, largely classified into nutritional, xenobiotic/pharmacologic, hemodynamic, and viral groups. A loss or gain of function genetic model has become a popular experimental approach to test the role of a gene as a second hit. Future research will need to test more subtle or natural hits combined with excessive alcohol intake to test multiple hits in the genesis of ALD. Additionally, animal models of comorbidities are urgently needed particularly for synergistic liver disease and oncogenesis caused by alcohol, obesity, and hepatitis virus.

KEYWORDS

Gene-environment interactions - alcoholic liver disease - alcoholic steatohepatitis - nonalcoholic steatohepatitis - nonalcoholic fatty liver disease - animal models

Full Text

References

REFERENCES

1 Younossi Z M. Epidemiology of alcohol-induced liver disease. In: McCullough AJ Clinics in Liver Disease. Philadelphia; WB Saunders 1998: 661-671
2 Day C P, James O F. Steatohepatitis: a tale of two “hits”?. Gastroenterology. 1998; 114(4) 842-845
3 Yoo J S, Ning S M, Pantuck C B, Pantuck E J, Yang C S. Regulation of hepatic microsomal cytochrome P450IIE1 level by dietary lipids and carbohydrates in rats. J Nutr. 1991; 121(7) 959-965
4 Tsukamoto H, Towner S J, Ciofalo L M, French S W. Ethanol-induced liver fibrosis in rats fed high fat diet. Hepatology. 1986; 6(5) 814-822
5 Tsukada H, Wang P Y, Kaneko T, Wang Y, Nakano M, Sato A. Dietary carbohydrate intake plays an important role in preventing alcoholic fatty liver in the rat. J Hepatol. 1998; 29(5) 715-724
6 Korourian S, Hakkak R, Ronis M J et al.. Diet and risk of ethanol-induced hepatotoxicity: carbohydrate-fat relationships in rats. Toxicol Sci. 1999; 47(1) 110-117
7 Tomita K, Azuma T, Kitamura N et al.. Leptin deficiency enhances sensitivity of rats to alcoholic steatohepatitis through suppression of metallothionein. Am J Physiol Gastrointest Liver Physiol. 2004; 287(5) G1078-G1085
8 Schattenberg J M, Wang Y, Singh R, Rigoli R M, Czaja M J. Hepatocyte CYP2E1 overexpression and steatohepatitis lead to impaired hepatic insulin signaling. J Biol Chem. 2005; 280(11) 9887-9894
9 Ozcan U, Cao Q, Yilmaz E et al.. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004; 306(5695) 457-461
10 Kim D S, Jeong S K, Kim H R, Kim D S, Chae S W, Chae H J. Effects of triglyceride on ER stress and insulin resistance. Biochem Biophys Res Commun. 2007; 363(1) 140-145
11 Kaplowitz N, Than T A, Shinohara M, Ji C. Endoplasmic reticulum stress and liver injury. Semin Liver Dis. 2007; 27(4) 367-377
12 Nanji A A, Khwaja S, Tahan S R, Sadrzadeh S M. Plasma levels of a novel noncyclooxygenase-derived prostanoid (8-isoprostane) correlate with severity of liver injury in experimental alcoholic liver disease. J Pharmacol Exp Ther. 1994; 269(3) 1280-1285
13 Tipoe G L, Liong E C, Casey C A et al.. A voluntary oral ethanol-feeding rat model associated with necroinflammatory liver injury. Alcohol Clin Exp Res. 2008; 32(4) 669-682
14 Larter C Z, Yeh M M, Cheng J et al.. Activation of peroxisome proliferator-activated receptor alpha by dietary fish oil attenuates steatosis, but does not prevent experimental steatohepatitis because of hepatic lipoperoxide accumulation. J Gastroenterol Hepatol. 2008; 23(2) 267-275
15 Wada S, Yamazaki T, Kawano Y, Miura S, Ezaki O. Fish oil fed prior to ethanol administration prevents acute ethanol-induced fatty liver in mice. J Hepatol. 2008; 49(3) 441-450
16 Powell L W. The role of alcoholism in hepatic iron storage disease. Ann N Y Acad Sci. 1975; 252 124-134
17 Sadrzadeh S M, Nanji A A, Price P L. The oral iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one reduces hepatic-free iron, lipid peroxidation and fat accumulation in chronically ethanol-fed rats. J Pharmacol Exp Ther. 1994; 269(2) 632-636
18 Lin M, Rippe R A, Niemela O, Brittenham G, Tsukamoto H. Role of iron in NF-kappa B activation and cytokine gene expression by rat hepatic macrophages. Am J Physiol. 1997; 272(6 Pt 1) G1355-G1364
19 Tsukamoto H, Horne W, Kamimura S et al.. Experimental liver cirrhosis induced by alcohol and iron. J Clin Invest. 1995; 96(1) 620-630
20 Tsukamoto H, Lin M, Ohata M, Giulivi C, French S W, Brittenham G. Iron primes hepatic macrophages for NF-kappaB activation in alcoholic liver injury. Am J Physiol. 1999; 277(6 Pt 1) G1240-G1250
21 Otogawa K, Kinoshita K, Fujii H et al.. Erythrophagocytosis by liver macrophages (Kupffer cells) promotes oxidative stress, inflammation, and fibrosis in a rabbit model of steatohepatitis: implications for the pathogenesis of human nonalcoholic steatohepatitis. Am J Pathol. 2007; 170(3) 967-980
22 Xiong S, She H, Zhang A S et al.. Hepatic macrophage iron aggravates experimental alcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 2008; 295(3) G512-G521
23 McClain C J, Antonow D R, Cohen D A, Shedlofsky S I. Zinc metabolism in alcoholic liver disease. Alcohol Clin Exp Res. 1986; 10(6) 582-589
24 Cravo M L, Gloria L M, Selhub J et al.. Hyperhomocysteinemia in chronic alcoholism: correlation with folate, vitamin B-12, and vitamin B-6 status. Am J Clin Nutr. 1996; 63(2) 220-224
25 Barak A J, Tuma D J, Sorrell M F. Relationship of ethanol to choline metabolism in the liver: a review. Am J Clin Nutr. 1973; 26(11) 1234-1241
26 Halsted C H, Villanueva J A, Devlin A M et al.. Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig. Proc Natl Acad Sci U S A. 2002; 99(15) 10072-10077
27 Nieto N, Rojkind M. Repeated whiskey binges promote liver injury in rats fed a choline-deficient diet. J Hepatol. 2007; 46(2) 330-339
28 Lu S C, Tsukamoto H, Mato J M. Role of abnormal methionine metabolism in alcoholic liver injury. Alcohol. 2002; 27(3) 155-162
29 Barak A J, Beckenhauer H C, Tuma D J. Methionine synthase. a possible prime site of the ethanolic lesion in liver. Alcohol. 2002; 26(2) 65-67
30 Barak A J, Beckenhauer H C, Junnila M, Tuma D J. Dietary betaine promotes generation of hepatic S-adenosylmethionine and protects the liver from ethanol-induced fatty infiltration. Alcohol Clin Exp Res. 1993; 17(3) 552-555
31 Ji C, Kaplowitz N. Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology. 2003; 124(5) 1488-1499
32 Ji C, Shinohara M, Vance D et al.. Effect of transgenic extrahepatic expression of betaine-homocysteine methyltransferase on alcohol or homocysteine-induced fatty liver. Alcohol Clin Exp Res. 2008; 32(6) 1049-1058
33 Martinez-Chantar M L, Vazquez-Chantada M, Ariz U et al.. Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice. Hepatology. 2008; 47(4) 1191-1199
34 Avila M A, Berasain C, Torres L et al.. Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. J Hepatol. 2000; 33(6) 907-914
35 Tseng T L, Shih Y P, Huang Y C et al.. Genotypic and phenotypic characterization of a putative tumor susceptibility gene, GNMT, in liver cancer. Cancer Res. 2003; 63(3) 647-654
36 Bhagwandeen B S, Apte M, Manwarring L, Dickeson J. Endotoxin induced hepatic necrosis in rats on an alcohol diet. J Pathol. 1987; 152(1) 47-53
37 Wheeler M D, Kono H, Yin M et al.. The role of Kupffer cell oxidant production in early ethanol-induced liver disease. Free Radic Biol Med. 2001; 31(12) 1544-1549
38 Gustot T, Lemmers A, Moreno C et al.. Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver. Hepatology. 2006; 43(5) 989-1000
39 Cao Q, Batey R, Pang G, Clancy R. Ethanol-altered liver-associated T cells mediate liver injury in rats administered Concanavalin A (Con A) or lipopolysaccharide (LPS). Alcohol Clin Exp Res. 1999; 23(10) 1660-1667
40 Yokoyama H, Ishii H, Nagata S, Kato S, Kamegaya K, Tsuchiya M. Experimental hepatitis induced by ethanol after immunization with acetaldehyde adducts. Hepatology. 1993; 17(1) 14-19
41 Yokoyama H, Nagata S, Moriya S et al.. Hepatic fibrosis produced in guinea pigs by chronic ethanol administration and immunization with acetaldehyde adducts. Hepatology. 1995; 21(5) 1438-1442
42 Tuma D J. Role of malondialdehyde-acetaldehyde adducts in liver injury. Free Radic Biol Med. 2002; 32(4) 303-308
43 Thiele G M, Duryee M J, Freeman T L et al.. Rat sinusoidal liver endothelial cells (SECs) produce pro-fibrotic factors in response to adducts formed from the metabolites of ethanol. Biochem Pharmacol. 2005; 70(11) 1593-1600
44 Lu Y, Cederbaum A I. Enhancement by pyrazole of lipopolysaccharide-induced liver injury in mice: role of cytochrome P450 2E1 and 2A5. Hepatology. 2006; 44(1) 263-274
45 Bosma A, Brouwer A, Seifert W F, Knook D L. Synergism between ethanol and carbon tetrachloride in the generation of liver fibrosis. J Pathol. 1988; 156(1) 15-21
46 Hall P D, Plummer J L, Ilsley A H, Cousins M J. Hepatic fibrosis and cirrhosis after chronic administration of alcohol and “low-dose” carbon tetrachloride vapor in the rat. Hepatology. 1991; 13(5) 815-819
47 Maddrey W C. Hepatic effects of acetaminophen. Enhanced toxicity in alcoholics. J Clin Gastroenterol. 1987; 9(2) 180-185
48 Hanawa N, Shinohara M, Saberi B, Gaarde W A, Han D, Kaplowitz N. Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. J Biol Chem. 2008; 283(20) 13565-13577
49 McCuskey R S, Bethea N W, Wong J et al.. Ethanol binging exacerbates sinusoidal endothelial and parenchymal injury elicited by acetaminophen. J Hepatol. 2005; 42(3) 371-377
50 von M C, Beier J I, Guo L, Kaiser J P, Arteel G E. Contribution of the sympathetic hormone epinephrine to the sensitizing effect of ethanol on LPS-induced liver damage in mice. Am J Physiol Gastrointest Liver Physiol. 2008; 294(5) G1227-G1234
51 Li J, French B A, Fu P, French S W. Liver necrosis induced by thyroid hormone administration in rats fed ethanol. Exp Mol Pathol. 2001; 71(1) 79-88
52 Yuki T, Thurman R G. The swift increase in alcohol metabolism. Time course for the increase in hepatic oxygen uptake and the involvement of glycolysis. Biochem J. 1980; 186(1) 119-126
53 Israel Y, Kalant H, Orrego H, Khanna J M, Videla L, Phillips J M. Experimental alcohol-induced hepatic necrosis: suppression by propylthiouracil. Proc Natl Acad Sci U S A. 1975; 72(3) 1137-1141
54 Bergheim I, Guo L, Davis M A et al.. Metformin prevents alcohol-induced liver injury in the mouse: critical role of plasminogen activator inhibitor-1. Gastroenterology. 2006; 130(7) 2099-2112
55 Seth D, Hogg P J, Gorrell M D, McCaughan G W, Haber P S. Direct effects of alcohol on hepatic fibrinolytic balance: implications for alcoholic liver disease. J Hepatol. 2008; 48(4) 614-627
56 Tsukamoto H, Xi X P. Incomplete compensation of enhanced hepatic oxygen consumption in rats with alcoholic centrilobular liver necrosis. Hepatology. 1989; 9(2) 302-306
57 Yamada S, Iida T, Tabata T et al.. Alcoholic fatty liver differentially induces a neutrophil-chemokine and hepatic necrosis after ischemia-reperfusion in rat. Hepatology. 2000; 32(2) 278-288
58 French S W, Benson N C, Sun P S. Centrilobular liver necrosis induced by hypoxia in chronic ethanol-fed rats. Hepatology. 1984; 4(5) 912-917
59 Moriya K, Nakagawa K, Santa T et al.. Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res. 2001; 61(11) 4365-4370
60 Perlemuter G, Sabile A, Letteron P et al.. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FASEB J. 2002; 16(2) 185-194
61 Kawaguchi T, Yoshida T, Harada M et al.. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004; 165(5) 1499-1508
62 Miyamoto H, Moriishi K, Moriya K et al.. Involvement of the PA28gamma-dependent pathway in insulin resistance induced by hepatitis C virus core protein. J Virol. 2007; 81(4) 1727-1735
63 Banerjee S, Saito K, Ait-Goughoulte M, Meyer K, Ray R B, Ray R. Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signaling pathway for insulin resistance. J Virol. 2008; 82(6) 2606-2612
64 Koike K, Tsutsumi T, Miyoshi H et al.. Molecular basis for the synergy between alcohol and hepatitis C virus in hepatocarcinogenesis. J Gastroenterol Hepatol. 2008; 23(Suppl 1) S87-S91
65 Machida K, Tsukamoto H, Mkrtchyan H et al.. Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog. Proc Natl Acad Sci U S A. 2009; 106(5) 1548-1553
66 Morgan K, French S W, Morgan T R. Production of a cytochrome P450 2E1 transgenic mouse and initial evaluation of alcoholic liver damage. Hepatology. 2002; 36(1) 122-134
67 Lamle J, Marhenke S, Borlak J et al.. Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury. Gastroenterology. 2008; 134(4) 1159-1168
68 Kessova I G, Ho Y S, Thung S, Cederbaum A I. Alcohol-induced liver injury in mice lacking Cu, Zn-superoxide dismutase. Hepatology. 2003; 38(5) 1136-1145
69 El-Assal O, Hong F, Kim W H, Radaeva S, Gao B. IL-6-deficient mice are susceptible to ethanol-induced hepatic steatosis: IL-6 protects against ethanol-induced oxidative stress and mitochondrial permeability transition in the liver. Cell Mol Immunol. 2004; 1(3) 205-211
70 Esfandiari F, Medici V, Wong D H et al.. Methyl regulation of ethanol induced steatosis in CBS deficient mouse. Alcohol Clin Exp Res. 2008; 343A
71 Iimuro Y, Frankenberg M V, Arteel G E, Bradford B U, Wall C A, Thurman R G. Female rats exhibit greater susceptibility to early alcohol-induced liver injury than males. Am J Physiol. 1997; 272(5 Pt 1) G1186-G1194
72 Baraona E, Abittan C S, Dohmen K et al.. Gender differences in pharmacokinetics of alcohol. Alcohol Clin Exp Res. 2001; 25(4) 502-507
73 Kono H, Wheeler M D, Rusyn I et al.. Gender differences in early alcohol-induced liver injury: role of CD14, NF-kappaB, and TNF-alpha. Am J Physiol Gastrointest Liver Physiol. 2000; 278(4) G652-G661
74 Ikejima K, Enomoto N, Iimuro Y et al.. Estrogen increases sensitivity of hepatic Kupffer cells to endotoxin. Am J Physiol. 1998; 274(4 Pt 1) G669-G676
75 Donohue T M, Curry-McCoy T V, Nanji A A et al.. Lysosomal leakage and lack of adaptation of hepatoprotective enzyme contribute to enhanced susceptibility to ethanol-induced liver injury in female rats. Alcohol Clin Exp Res. 2007; 31(11) 1944-1952
76 Banerjee A, Apte U M, Smith R, Ramaiah S K. Higher neutrophil infiltration mediated by osteopontin is a likely contributing factor to the increased susceptibility of females to alcoholic liver disease. J Pathol. 2006; 208(4) 473-485
77 Chan K, Han X D, Kan Y W. An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc Natl Acad Sci U S A. 2001; 98(8) 4611-4616
78 Cullinan S B, Zhang D, Hannink M, Arvisais E, Kaufman R J, Diehl J A. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol. 2003; 23(20) 7198-7209
79 Horiguchi N, Wang L, Mukhopadhyay P et al.. Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury. Gastroenterology. 2008; 134(4) 1148-1158
80 Takada A, Matsuda Y, Takase S. Effects of dietary fat on alcohol-pyrazole hepatitis in rats: the pathogenetic role of the nonalcohol dehydrogenase pathway in alcohol-induced hepatic cell injury. Alcohol Clin Exp Res. 1986; 10(4) 403-411
81 Karaa A, Thompson K J, McKillop I H, Clemens M G, Schrum L W. S-adenosyl-L-methionine attenuates oxidative stress and hepatic stellate cell activation in an ethanol-LPS-induced fibrotic rat model. Shock. 2008; 30(2) 197-205

Hidekazu TsukamotoD.V.M. Ph.D.

Keck School of Medicine of the University of Southern California

1333 San Pablo Street, MMR-402, Los Angeles, CA 90033

Email: htsukamo@usc.edu