The modulation of hepatic adenosine triphosphate and inflammation by eicosapentaenoic acid during severe fibrotic progression in the SHRSP5/Dmcr rat model

Jia, Xiaofang; Naito, Hisao; Yetti, Husna; Tamada, Hazuki; Kitamori, Kazuya; Hayashi, Yoshinori; Yamagishi, Noriko; Wang, Dong; Yanagiba, Yukie; Ito, Yuki; Wang, Juncai; Tanaka, Naoki; Ikeda, Katsumi; Yamori, Yukio; Nakajima, Tamie

doi:10.1016/j.lfs.2012.04.029

Cited by 23 publications

(32 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Male SHRSP5/Dmcr rats were obtained by mating males and females of the SHRSP5/Dmcr strain with high cholesterol levels [9, 11]. All rats were housed in a temperature- and light-controlled environment (23 ± 2 °C, 55 ± 5 % humidity, 12-h light/dark cycle) with free access to the control chow (SP diet) and tap water.…”

Section: Methodsmentioning

confidence: 99%

“…An animal model with fibrotic steatohepatitis was established by our group by feeding a high fat-cholesterol (HFC) diet to stroke-prone spontaneously hypertensive 5/Dmcr (SHRSP5/Dmcr) rats [9–11]. The most profound feature was severe fibrosis.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, we extended our earlier study [11] and used the same liver samples to investigate the abnormalities of cholesterol and BA kinetics in the context of HFC diet-induced fibrotic steatohepatitis in rats.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2013

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…It was suggested further that an adenosine-cAMP signalling pathway mediated this process. In progressive fibrosis, eicosapentaenoic acid replenishes hepatic ATP levels resulting in reduction of inflammation and steatosis [140]. Cirrhosis ATP-MgCl 2 has been used to improve survival following massive hepatectomy among cirrhotic rats [127].…”

Section: Fibrosis and Hscsmentioning

confidence: 99%

Purinergic signalling in the liver in health and disease

Burnstock

Vaughn

Robson

2013

Purinergic Signalling

View full text Add to dashboard Cite

Purinergic signalling is involved in both the physiology and pathophysiology of the liver. Hepatocytes, Kupffer cells, vascular endothelial cells and smooth muscle cells, stellate cells and cholangiocytes all express purinoceptor subtypes activated by adenosine, adenosine 5′-triphosphate, adenosine diphosphate, uridine 5′-triphosphate or UDP. Purinoceptors mediate bile secretion, glycogen and lipid metabolism and indirectly release of insulin. Mechanical stress results in release of ATP from hepatocytes and Kupffer cells and ATP is also released as a cotransmitter with noradrenaline from sympathetic nerves supplying the liver. Ectonucleotidases play important roles in the signalling process. Changes in purinergic signalling occur in vascular injury, inflammation, insulin resistance, hepatic fibrosis, cirrhosis, diabetes, hepatitis, liver regeneration following injury or transplantation and cancer. Purinergic therapeutic strategies for the treatment of these pathologies are being explored.

show abstract

“…In addition, increasing BA levels were confirmed in livers from NASH patients [17] and in serum and liver samples from rats with NASH/NAFLD [18,19]. In a previous study, we established a fibrotic steatohepatitis model by feeding male stroke-prone spontaneously hypertensive rats (SHRSP5/Dmcr) with a high-fat-cholesterol (HFC) diet for 8 weeks, and demonstrated histopathological resemblance to human NASH [13,20]. We also showed that BAs and enzymes and promoters of BA kinetics play crucial roles in hepatic inflammation and fibrogenesis in this rat model [21][22][23].…”

Section: Research Manuscript Sections 1 Introductionmentioning

confidence: 99%

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

Preprint

Self Cite

View full text Add to dashboard Cite

: 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...

show abstract

The modulation of hepatic adenosine triphosphate and inflammation by eicosapentaenoic acid during severe fibrotic progression in the SHRSP5/Dmcr rat model

Cited by 23 publications

References 37 publications

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

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

Purinergic signalling in the liver in health and disease

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

Contact Info

Product

Resources

About