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Environmental Health and Preventive Medicine
Published in: Environmental Health and Preventive Medicine 6/2012

01-11-2012 | Regular Article

Simultaneous changes in high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis and those underlying molecular mechanisms in novel SHRSP5/Dmcr rat

Authors: Takashi Moriya, Kazuya Kitamori, Hisao Naito, Yukie Yanagiba, Yuki Ito, Nozomi Yamagishi, Hazuki Tamada, Xiaofang Jia, Satoru Tsuchikura, Katsumi Ikeda, Yukio Yamori, Tamie Nakajima

Published in: Environmental Health and Preventive Medicine | Issue 6/2012

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Abstract

Objectives

The aim of this study was to identify the molecular mechanisms underlying high-fat and high-cholesterol (HFC) diet-induced steatohepatitis and associated liver fibrosis progression in a novel stroke-prone, spontaneously hypertensive 5/Dmcr (SHRSP5/Dmcr) rat model.

Methods

SHRSP5/Dmcr rats were given the control or HFC-diet for 2, 8, and 16 weeks. Plasma and hepatic gene expression of key molecules involved in fatty acid oxidation, inflammation, oxidative stress, and fibrosis were subsequently analyzed.

Results

Rats fed the HFC-diet showed increased plasma tumor necrosis factor-α (TNF-α) and hepatic p50/p65 signals, but reduced hepatic Cu2+/Zn2+-superoxide dismutase across the treatment period and reduced plasma total adiponectin at 8 weeks. In HFC-diet-fed rats, transforming growth factor-β1 (TGF-β1) was elevated prior to the appearance of obvious liver fibrosis pathology at 2 weeks, followed by elevations in platelet-derived growth factor-B (PDGF-B) and α-smooth muscle actin (α-SMA), corresponding to evident liver fibrosis, at 8 weeks and by α1 type I collagen production at 16 weeks. The HFC-diet increased hepatic total cholesterol accumulation, although hepatic triglyceride declined by 0.3-fold from 2 to 16 weeks due to reduced hepatic triglyceride synthesis, as suggested by the diacylglycerol acyltransferase 1 and 2 measurements.

Conclusions

TNF-α and p50/p65 molecular signals appeared to be major factors for HFC-diet-induced hepatic inflammation and oxidative stress facilitating liver disease progression. While the up-regulation of TGF-β1 prior to the appearance of any evident liver fibrosis could be an early signal for progressive liver fibrosis, elevated PDGF-B and α-SMA levels signified evident liver fibrosis at 8 weeks, and subsequent increased α1 type I collagen production and reduced triglyceride synthesis indicated extensive liver fibrosis at 16 weeks in this novel SHRSP5/Dmcr model.
Appendix
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Literature
1.
Tilg H, Hotamisligil GS. Nonalcoholic fatty liver disease: cytokine-adipokine interplay and regulation of insulin resistance. Gastroenterology. 2006;131:934–45.PubMedCrossRef
2.
3.
Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and prognosis of NASH. J Gastroenterol. 2011;46(Suppl 1):63–9.PubMedCrossRef
4.
Powell EE, Jonsson JR, Clouston AD. Dangerous liaisons: the metabolic syndrome and nonalcoholic fatty liver disease. Ann Intern Med. 2005;143:753–4.PubMed
5.
Larter CZ, Yeh MM. Animal models of NASH: getting both pathology and metabolic context right. J Gastroenterol Hepatol. 2008;23:1635–48.PubMedCrossRef
6.
Svegliati-Baroni G, Candelaresi C, Saccomanno S, Ferretti G, Bachetti T, Marzioni M, et al. A model of insulin resistance and nonalcoholic steatohepatitis in rats: role of peroxisome proliferator-activated receptor-α and –3 polyunsaturated fatty acid treatment on liver injury. Am J Pathol. 2006;169:846–60.PubMedCrossRef
7.
8.
Kitamori K, Naito H, Tamada H, Kobayashi M, Miyazawa D, Yasui Y, et al. Development of novel rat model for high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis progression in SHRSP5/Dmcr. Environ Health Prev Med. doi:10.​1007/​s12199-011-0235-9
9.
Sansawa H, Takahashi M, Tsuchikura S, Endo H. Effect of chlorella and its fractions on blood pressure, cerebral stroke lesions, and life-span in stroke-prone spontaneously hypertensive rats. J Nutr Sci Vitaminol (Tokyo). 2006;52:457–66.PubMedCrossRef
10.
Folch J, Lees M. Sloane Stanley GH. A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem. 1957;226:497–509.PubMed
11.
Ito Y, Yamanoshita O, Asaeda N, Tagawa Y, Lee CH, Aoyama T, et al. Di(2-ethylhexyl)phthalate induces hepatic tumorigenesis through a peroxisome proliferator-activated receptor α-independent pathway. J Occup Health. 2007;49:172–82.PubMedCrossRef
12.
Ramdhan DH, Kamijima M, Yamada N, Ito Y, Yanagiba Y, Nakamura D, et al. Molecular mechanism of trichloroethylene-induced hepatotoxicity mediated by CYP2E1. Toxicol Appl Pharmacol. 2008;231:300–7.PubMedCrossRef
13.
Aoyama T, Peters JM, Iritani N, Nakajima T, Furihata K, Hashimoto T, et al. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARα). J Biol Chem. 1998;273:5678–84.PubMedCrossRef
14.
Okiyama W, Tanaka N, Nakajima T, Tanaka E, Kiyosawa K, Gonzalez FJ, et al. Polyenephosphatidylcholine prevents alcoholic liver disease in PPARα-null mice through attenuation of increases in oxidative stress. J Hepatol. 2009;50:1236–46.PubMedCrossRef
15.
Wilcoxon F. Individual comparisons by ranking methods. Biometrics Bull. 1945;1:80–3.CrossRef
16.
Bauer DF. Constructing confidence sets using rank statistics. J Am Stat Assoc. 1972;67:687–90.CrossRef
17.
Yoo HY, Chang MS, Rho HM. Induction of the rat Cu/Zn superoxide dismutase gene through the peroxisome proliferator-responsive element by arachidonic acid. Gene. 1999;234:87–91.PubMedCrossRef
18.
Ruderman N, Prentki M. AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat Rev Drug Discov. 2004;3:340–51.PubMedCrossRef
19.
Long YC, Zierath JR. AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest. 2006;116:1776–83.PubMedCrossRef
20.
Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med. 2007;13:332–9.PubMedCrossRef
21.
Mandard S, Muller M, Kersten S. Peroxisome proliferator-activated receptor α target genes. Cell Mol Life Sci. 2004;61:393–416.PubMedCrossRef
22.
Yamazaki T, Sasaki E, Kakinuma C, Yano T, Miura S, Ezaki O. Increased very low density lipoprotein secretion and gonadal fat mass in mice overexpressing liver DGAT1. J Biol Chem. 2005;280:21506–14.PubMedCrossRef
23.
Cases S, Stone SJ, Zhou P, Yen E, Tow B, Lardizabal KD, et al. Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members. J Biol Chem. 2001;276:38870–6.PubMedCrossRef
24.
Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology. 2007;45:1366–74.PubMedCrossRef
25.
Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008;88:125–72.PubMedCrossRef
26.
27.
Lewis JR, Mohanty SR. Nonalcoholic fatty liver disease: a review and update. Dig Dis Sci. 2010;55:560–78.PubMedCrossRef
28.
Crespo J, Cayon A, Fernandez-Gil P, Hernandez-Guerra M, Mayorga M, Dominguez-Diez A, et al. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 2001;34:1158–63.PubMedCrossRef
29.
Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99–112.PubMedCrossRef
30.
Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature. 1997;389:610–4.PubMedCrossRef
31.
Fu JH, Xie SR, Kong SJ, Wang Y, Wei W, Shan Y, et al. The combination of a high-fat diet and chronic stress aggravates insulin resistance in Wistar male rats. Exp Clin Endocrinol Diabetes. 2009;117:354–60.PubMedCrossRef
32.
Romestaing C, Piquet MA, Bedu E, Rouleau V, Dautresme M, Hourmand-Ollivier I, et al. Long term highly saturated fat diet does not induce NASH in Wistar rats. Nutr Metab (Lond). 2007;4:4.CrossRef
33.
Plumpe J, Malek NP, Bock CT, Rakemann T, Manns MP, Trautwein C. NF-κB determines between apoptosis and proliferation in hepatocytes during liver regeneration. Am J Physiol Gastrointest Liver Physiol. 2000;278:G173–83.PubMed
34.
Chakraborty JB, Mann DA. NF-κB signalling: embracing complexity to achieve translation. J Hepatol. 2010;52:285–91.PubMedCrossRef
35.
Delerive P, De Bosscher K, Besnard S, Vanden Berghe W, Peters JM, Gonzalez FJ, et al. Peroxisome proliferator-activated receptor α negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-κB and AP-1. J Biol Chem. 1999;274:32048–54.PubMedCrossRef
36.
Delerive P, Gervois P, Fruchart JC, Staels B. Induction of IκBα expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-α activators. J Biol Chem. 2000;275:36703–7.PubMedCrossRef
37.
Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature. 1998;391:79–82.PubMedCrossRef
38.
Nakajima T, Kamijo Y, Tanaka N, Sugiyama E, Tanaka E, Kiyosawa K, et al. Peroxisome proliferator-activated receptor α protects against alcohol-induced liver damage. Hepatology. 2004;40:972–80.PubMed
39.
Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, et al. PPARγ ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes. 2001;50:2094–9.PubMedCrossRef
40.
Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med. 2002;8:731–7.PubMedCrossRef
41.
Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-α or adiponectin? Hepatology. 2004;40:46–54.PubMedCrossRef
42.
Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem. 2000;275:2247–50.PubMedCrossRef
43.
44.
Vergnes L, Phan J, Strauss M, Tafuri S, Reue K. Cholesterol and cholate components of an atherogenic diet induce distinct stages of hepatic inflammatory gene expression. J Biol Chem. 2003;278:42774–84.PubMedCrossRef
45.
Breitkopf K, Roeyen C, Sawitza I, Wickert L, Floege J, Gressner AM. Expression patterns of PDGF-A, -B, -C and -D and the PDGF-receptors α and β in activated rat hepatic stellate cells (HSC). Cytokine. 2005;31:349–57.PubMedCrossRef
46.
Gavrilova O, Haluzik M, Matsusue K, Cutson JJ, Johnson L, Dietz KR, et al. Liver peroxisome proliferator-activated receptor γ contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem. 2003;278:34268–76.PubMedCrossRef
47.
Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8:1288–95.PubMedCrossRef
48.
Tomita K, Azuma T, Kitamura N, Nishida J, Tamiya G, Oka A, et al. Pioglitazone prevents alcohol-induced fatty liver in rats through up-regulation of c-Met. Gastroenterology. 2004;126:873–85.PubMedCrossRef
49.
Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–307.PubMedCrossRef
50.
Musso G, Gambino R, De Michieli F, Cassader M, Rizzetto M, Durazzo M, et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology. 2003;37:909–16.PubMedCrossRef
51.
Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology. 1990;12:1106–10.PubMedCrossRef
52.
Silverman JF, O’Brien KF, Long S, Leggett N, Khazanie PG, Pories WJ, et al. Liver pathology in morbidly obese patients with and without diabetes. Am J Gastroenterol. 1990;85:1349–55.PubMed
53.
Speliotes EK, Massaro JM, Hoffmann U, Vasan RS, Meigs JB, Sahani DV, et al. Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: the Framingham Heart Study. Hepatology. 2010;51:1979–87.PubMedCrossRef
54.
Chitturi S, Wong VW, Farrell G. Nonalcoholic fatty liver in Asia: firmly entrenched and rapidly gaining ground. J Gastroenterol Hepatol. 2011;26[Suppl 1]:163–72.PubMedCrossRef
Metadata
Title
Simultaneous changes in high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis and those underlying molecular mechanisms in novel SHRSP5/Dmcr rat
Authors
Takashi Moriya
Kazuya Kitamori
Hisao Naito
Yukie Yanagiba
Yuki Ito
Nozomi Yamagishi
Hazuki Tamada
Xiaofang Jia
Satoru Tsuchikura
Katsumi Ikeda
Yukio Yamori
Tamie Nakajima
Publication date
01-11-2012
Publisher
Springer Japan
Published in
Environmental Health and Preventive Medicine / Issue 6/2012
Print ISSN: 1342-078X
Electronic ISSN: 1347-4715
DOI
https://doi.org/10.1007/s12199-012-0273-y

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