Role of dietary fatty acids in liver injury caused by vinyl chloride metabolites in mice.
BACKGROUND
Vinyl chloride (VC) causes toxicant-associated steatohepatitis at high exposure levels. Recent work by this group suggests that underlying liver disease may predispose the liver to VC hepatotoxicity at lower exposure levels. The most common form of underlying liver disease in the developed world is non-alcoholic fatty liver disease (NAFLD). It is well-known that the type of dietary fat can play an important role in the pathogenesis of NAFLD. However, whether the combination of dietary fat and VC/metabolites promotes liver injury has not been studied.


METHODS
Mice were administered chloroethanol (CE - a VC metabolite) or vehicle once, 10weeks after being fed diets rich in saturated fatty acids (HSFA), rich in poly-unsaturated fatty acids (HPUFA), or the respective low-fat control diets (LSFA; LPUFA).


RESULTS
In control mice, chloroethanol caused no detectable liver injury, as determined by plasma transaminases and histologic indices of damage. In HSFA-fed mice, chloroethanol increased HSFA-induced liver damage, steatosis, infiltrating inflammatory cells, hepatic expression of proinflammatory cytokines, and markers of endoplasmic reticulum (ER) stress. Moreover, markers of inflammasome activation were increased, while markers of inflammasome inhibition were downregulated. In mice fed HPUFA all of these effects were significantly attenuated.


CONCLUSIONS
Chloroethanol promotes inflammatory liver injury caused by dietary fatty acids. This effect is far more exacerbated with saturated fat, versus poly-unsaturated fat; and strongly correlates with a robust activation of the NLRP3 inflammasome in the saturated fed animals only. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH.
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA; Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
Lisanne C
LC
Anders
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
Heegook
H
Yeo
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
Brenna R
BR
Kaelin
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
Anna L
AL
Lang
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
Adrienne M
AM
Bushau
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
Amanda N
AN
Douglas
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA; Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292, USA; Hepatobiology and Toxicology Program, University of Louisville Health Sciences Center, Louisville, KY 40292, USA; Diabetes and Obesity Center, University of Louisville Health Sciences Center, Louisville, KY 40292, USA; Robley Rex Louisville VAMC, Louisville, KY 40206, USA.
Matt
M
Cave
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA; Hepatobiology and Toxicology Program, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
Gavin E
GE
Arteel
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA; Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292, USA; Hepatobiology and Toxicology Program, University of Louisville Health Sciences Center, Louisville, KY 40292, USA; Diabetes and Obesity Center, University of Louisville Health Sciences Center, Louisville, KY 40292, USA; Robley Rex Louisville VAMC, Louisville, KY 40206, USA.
Craig J
CJ
McClain
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA; Hepatobiology and Toxicology Program, University of Louisville Health Sciences Center, Louisville, KY 40292, USA. Electronic address: juliane.beier@louisville.edu.
Juliane I
JI
Beier
D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress; D005227:Fatty Acids / Q000008:administration & dosage / Q000494:pharmacology*; D015870:Gene Expression; D005951:Glucose Tolerance Test; D018836:Inflammation Mediators / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014752:Vinyl Chloride / Q000633:toxicity*
D004041:Dietary Fats; D005227:Fatty Acids; D018836:Inflammation Mediators; D008055:Lipids; D014752:Vinyl Chloride
Hepatotoxicity; PVC; Plastic; Saturated fat; TASH; Unsaturated fat
J Biochem Toxicol. 1989 Fall;4(3):183-8
2607542
Alcohol Clin Exp Res. 1989 Feb;13(1):15-9
2646971
J Mol Med (Berl). 2012 Nov;90(11):1247-56
22983484
Mucosal Immunol. 2013 Jan;6(1):4-13
23212196
J Nutr Biochem. 2008 Sep;19(9):567-76
18430557
Alcohol. 2013 May;47(3):257-64
23453163
Toxicol Pathol. 2013 Feb;41(2):343-60
23262638
Curr Gastroenterol Rep. 2011 Feb;13(1):56-64
21088999
Hepatology. 2011 Jul;54(1):133-44
21488066
Hepatology. 2009 May;49(5):1545-53
19291788
Occup Med (Lond). 2002 May;52(3):157-64
12063361
Liver Int. 2014 Jul;34(6):918-30
24628836
Hepatology. 2013 Feb;57(2):577-89
22987396
J Mol Med (Berl). 2014 Oct;92 (10 ):1069-82
24861026
Am J Transl Res. 2012;4(1):102-13
22347525
Nutr J. 2016 Aug 02;15(1):72
27485440
World J Gastroenterol. 2016 Feb 28;22(8):2533-44
26937141
World J Gastroenterol. 2014 Feb 21;20(7):1746-55
24587652
Br J Ind Med. 1987 Oct;44(10):711-5
3676124
PLoS One. 2013 Jun 25;8(6):e67532
23825667
Semin Immunol. 2015 Sep;27(5):334-42
26776831
Ther Adv Endocrinol Metab. 2010 Apr;1(2):51-60
23148150
J Clin Invest. 2012 Oct;122(10 ):3476-89
22945633
Cell. 2010 Mar 19;140(6):821-32
20303873
Arch Biochem Biophys. 2009 Feb;482(1-2):104-11
19022218
FEBS Lett. 2006 Mar 20;580(7):1859-64
16516204
J Nutr Biochem. 2007 Mar;18(3):184-95
17296492
Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2557-62
9122234
Gastroenterology. 1995 Aug;109 (2):547-54
7615205
J Pharmacol Exp Ther. 1996 Jun;277(3):1694-700
8667240
Dig Liver Dis. 2015 Mar;47(3):181-90
25739820
Environ Health Perspect. 2000 Jul;108(7):579-88
10905993
Crit Rev Toxicol. 2005 Apr-May;35(4):307-23
15989139
Toxicol Sci. 2016 Jun;151(2):312-23
26962056
Can J Biochem Physiol. 1959 Aug;37(8):911-7
13671378
Gastroenterology. 1998 Apr;114(4):842-5
9547102
Hepatology. 2010 Dec;52(6):1980-91
20967760
Biochem Pharmacol. 2013 Jan 15;85(2):257-64
23103566
J Pharmacol Exp Ther. 2001 Nov;299(2):638-44
11602676
J Clin Gastroenterol. 2006 Mar;40 Suppl 1:S5-10
16540768
Cell Death Dis. 2015 Sep 10;6:e1879
26355342
BMJ. 1997 May 24;314(7093):1545-9
9183207
Environ Health Perspect. 2005 Jul;113(7):809-12
16002366
Arterioscler Thromb Vasc Biol. 2004 Apr;24(4):644-9
14715643