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

Moriya, Takashi J.; Kitamori, Kazuya; Naito, Hisao; Yanagiba, Yukie; Ito, Yuki; Yamagishi, Noriko; Tamada, Hazuki; Jia, Xiaofang; Tsuchikura, Satoru; Ikeda, Katsumi; Yamori, Yukio; Nakajima, Tamie

doi:10.1007/s12199-012-0273-y

Cited by 24 publications

(15 citation statements)

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“…SOD also plays important roles in antioxidant defense by catalyzing the dismutation of superoxide anions [22]. In our previous study, we demonstrated that the HFC diet decreased the hepatic level of SOD1 in the hypertensive SHRSP5/Dmcr strain [39]. In the present study, we also found that SOD2 expression was suppressed by the HFC diet in the livers of SHRSP5/Dmcr rats but not in those of the WKY and SHR rats.…”

Section: Discussionsupporting

confidence: 68%

Combination of Hypertension and High Fat and Cholesterol Diet Induces Severe Hepatic Inflammation in Rats via a Signaling Network Comprising NF-κB, MAPK, and Nrf2 Pathways

Yuan¹,

Naito²,

Kitamori³

et al. 2017

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Populations with essential hypertension have a high risk of nonalcoholic steatohepatitis (NASH). In this study, we investigated the mechanism that underlies the progression of hypertension-associated NASH by comparing differences in the development of high fat and cholesterol (HFC) diet-induced NASH among three strains of rats, i.e., two hypertensive strains comprising spontaneously hypertensive rats and the stroke-prone spontaneously hypertensive 5/Dmcr, and the original Wistar Kyoto rats as the normotensive control. We investigated histopathological changes and molecular signals related to inflammation in the liver after feeding with the HFC diet for 8 weeks. The diet induced severe lobular inflammation and fibrosis in the livers of the hypertensive rats, whereas it only caused mild steatohepatitis in the normotensive rats. Increased activation of proinflammatory signaling (transforming growth factor-β1/mitogen-activated protein kinases pathway) was observed in the hypertensive strains fed with the HFC diet. In addition, the HFC diet suppressed the nuclear factor erythroid 2-related factor 2 pathway in the hypertensive rats and led to lower increases in the hepatic expression of heme oxygenase-1, which has anti-oxidative and anti-inflammatory activities. In conclusion, these signaling pathways might play crucial roles in the development of hypertension-associated NASH.

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Section: Discussionsupporting

confidence: 68%

Combination of Hypertension and High Fat and Cholesterol Diet Induces Severe Hepatic Inflammation in Rats via a Signaling Network Comprising NF-κB, MAPK, and Nrf2 Pathways

Yuan¹,

Naito²,

Kitamori³

et al. 2017

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“…This model recapitulated histological features of human NASH and exhibited a similar physiological condition to a subgroup of NASH patients without obesity or insulin resistance. In view of the extraordinary cholesterol content (5 % by weight) in the HFC diet, and the hepatic total cholesterol which progressively accumulated as liver disease developed, unlike triglycerides [9, 10], the accumulation of cholesterol, rather than triglycerides, may have played a critical role in the progression of fibrotic steatohepatitis in this dietary rat model.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated Bile Acid Synthesis, Metabolism and Excretion in a High Fat-Cholesterol Diet-Induced Fibrotic Steatohepatitis in Rats

et al. 2013

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Background and AimsCholesterol over-intake is involved in the onset of nonalcoholic steatohepatitis (NASH), and hepatocellular bile acid (BA) accumulation correlates with liver injuries. However, how dietary cholesterol influences cholesterol and BA kinetics in NASH liver remains ambiguous and needs to be clarified.MethodsMolecular markers involved in cholesterol and BA kinetics were investigated at protein and mRNA levels in an already-established stroke-prone spontaneously hypertensive 5/Dmcr rat model with fibrotic steatohepatitis, by feeding a high fat-cholesterol (HFC) diet.ResultsUnlike the control diet, the HFC diet deposited cholesterol greatly in rat livers, where 3-hydroxy-3-methylglutaryl CoA reductase, low-density lipoprotein (LDL) receptor and LDL receptor-related protein-1 were expectedly downregulated, especially at 8 and 14 weeks, suggesting that cholesterol synthesis and uptake in response to cholesterol accumulation may not be disorganized. The HFC diet did not upregulate liver X receptor-α, conversely, it enhanced classic BA synthesis by upregulating cholesterol 7α-hydroxylase but downregulating sterol 12α-hydroxylase, and influenced alternative synthesis by downregulating sterol 27-hydroxylase but upregulating oxysterol 7α-hydroxylase, mainly at 8 and 14 weeks, indicating that there were different productions of primary BA species. Unexpectedly, no feedback inhibition of BA synthesis by farnesoid X receptor occurred. Additionally, the HFC diet impaired BA detoxification by UDP-glucuronosyltransferase and sulfotransferase 2A1, and decreased excretion by bile salt export pump at 8 and 14 weeks, although it induced compensatory export by multidrug resistance-associated protein-3. The disturbed BA detoxification may correlate with suppressed pregnane X receptor and constitutive androstane receptor.ConclusionsThe HFC diet may accumulate BA in rat livers, which influences fibrotic steatohepatitis progression.Electronic supplementary materialThe online version of this article (doi:10.1007/s10620-013-2747-1) contains supplementary material, which is available to authorized users.

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“…Previous studies showed that HFC feeding significantly induces the hepatic profibrogenic proteins TGF-β1 and α-SMA in SHRSP5/Dmcr male rats [25]. Herein, the HFC diet increased hepatic TGF-β1 and α-SMA protein expression levels similarly in both genders at 8 and 14 weeks.…”

Section: Gender Differences In Fibrogenic Indicesmentioning

confidence: 60%

Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet

Yetti

Naito

Yuan

et al. 2017

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: During middle age, women are less susceptible to nonalcoholic steatohepatitis (NASH) than men. Thus, we investigated the underlying molecular mechanisms behind these sexual differences using an established rat model of NASH. Mature female and male stroke-prone spontaneously hypertensive 5/Dmcr rats were fed control or high-fat-cholesterol (HFC) diets for 2, 8, and 14 weeks. Although HFC-induced hepatic fibrosis was markedly less severe in females than in males, only minor gender differences were observed in expression levels of cytochrome P450 enzymes (CYP)7A1, CYP8B1 CYP27A1, and CYP7B1, and multidrug resistance-associated protein 3, and bile salt export pump, which are involved in fibrosis-related bile acid (BA) kinetics. However, the BA detoxification-related enzymes UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) 2A1, and the nuclear receptors constitutive androstene receptor (CAR) and pregnane X receptor (PXR), were strongly suppressed in HFC fed males, and were only slightly changed in HFC-diet fed females. Expression levels of the farnesoid X receptor and its small heterodimer partner were similarly regulated in a gender-dependent fashion following HFC feeding. Hence, the pronounced female resistance to HFC-induced liver damage likely reflects sustained expression of the nuclear receptors CAR and PXR and the BA detoxification enzymes UGT and SULT.Keywords constitutive androstene receptor, cytochrome P450, fibrosis, gender difference, high-fat-cholesterol (HFC) diet, necrosis, stroke-prone spontaneously hypertensive 5/Dmcr rats, 3 sulfotransferase, pregnane X receptor, UGP-glucuronosyltransferase. Research manuscript sections 1. IntroductionNonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed and developing countries [1][2][3]. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD, and leads to cirrhosis, hepatocellular carcinoma, and hepatic failure, and is a serious public health problem [4]. The prevalence of NASH/NAFLD varies with gender and age in humans, and in a study of 193 Japanese patients with biopsy-diagnosed NASH, male gender was more prevalent among patients of 30-40 years of age, whereas female gender was predominant among patients of > 50 years of age [5]. In accordance, a recent prospective study using ultrasound analyses and liver biopsies showed that NAFLD was more frequent in male than in female middle-aged patients [6].Animal experiments using Pten knockout mice demonstrated that females have attenuated hepatic steatosis, inflammation, and carcinogenicity compared with male mice [7]. However, this model was based on modifications of genes that are involved in carcinogenesis. In contrast, female mice were reportedly more susceptible to NAFLD induced by 30% fructose [8], and methionine-choline-deficient diet (MCDD)-induced steatohepatitis was comparable in male and female mice [9]. Hence, although gender differences in the development of NAFLD/NASH have been investigated in several animal studies, contrasti...

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

Cited by 24 publications

References 57 publications

Combination of Hypertension and High Fat and Cholesterol Diet Induces Severe Hepatic Inflammation in Rats via a Signaling Network Comprising NF-κB, MAPK, and Nrf2 Pathways

Combination of Hypertension and High Fat and Cholesterol Diet Induces Severe Hepatic Inflammation in Rats via a Signaling Network Comprising NF-κB, MAPK, and Nrf2 Pathways

Dysregulated Bile Acid Synthesis, Metabolism and Excretion in a High Fat-Cholesterol Diet-Induced Fibrotic Steatohepatitis in Rats

Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet

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

Cited by 24 publications

References 57 publications

Combination of Hypertension and High Fat and Cholesterol Diet Induces Severe Hepatic Inflammation in Rats via a Signaling Network Comprising NF-&kappa;B, MAPK, and Nrf2 Pathways

Combination of Hypertension and High Fat and Cholesterol Diet Induces Severe Hepatic Inflammation in Rats via a Signaling Network Comprising NF-&kappa;B, MAPK, and Nrf2 Pathways

Dysregulated Bile Acid Synthesis, Metabolism and Excretion in a High Fat-Cholesterol Diet-Induced Fibrotic Steatohepatitis in Rats

Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet

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Combination of Hypertension and High Fat and Cholesterol Diet Induces Severe Hepatic Inflammation in Rats via a Signaling Network Comprising NF-κB, MAPK, and Nrf2 Pathways

Combination of Hypertension and High Fat and Cholesterol Diet Induces Severe Hepatic Inflammation in Rats via a Signaling Network Comprising NF-κB, MAPK, and Nrf2 Pathways