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

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

doi:10.1007/s10620-013-2747-1

Cited by 35 publications

(27 citation statements)

References 41 publications

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“…Modification of hepatic bile acid metabolism and transporters[12–14] and/or the gut microbiome[6,15] in NAFLD may alter the predominant bile acid species thereby impacting post-prandial bile acid-dependent signaling and modulating hepatic inflammatory cascades. Examination of bile acid species in patients currently abstinent from ethanol with steatohepatitis and cirrhosis revealed decreased secondary bile acids excreted in the stool and increased glycine- and taurine-conjugated bile acids in the serum.…”

Section: Introductionmentioning

confidence: 99%

Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis

et al. 2015

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Background & Aims The prevalence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is increasing at an alarming rate. The role of bile acids in the development and progression of NAFLD to NASH and cirrhosis is poorly understood. This study aimed to quantify the bile acid metabolome in healthy subjects and patients with non-cirrhotic NASH under fasting conditions and after a standardized meal. Methods Liquid chromatography tandem mass spectroscopy was used to quantify 30 serum and 16 urinary bile acids from 15 healthy volunteers and 7 patients with biopsy-confirmed NASH. Bile acid concentrations were measured at two fasting and four post-prandial timepoints following a high-fat meal to induce gallbladder contraction and bile acid reabsorption from the intestine. Results Patients with NASH had significantly higher total serum bile acid concentrations than healthy subjects under fasting conditions (2.2- to 2.4-fold increase in NASH; NASH: 2595–3549 μM and healthy: 1171–1458 μM) and at all post-prandial time points (1.7- to 2.2-fold increase in NASH; NASH: 4444–5898 μM and healthy: 2634–2829 μM). These changes were driven by increased taurine- and glycine-conjugated primary and secondary bile acids. Patients with NASH exhibited greater variability in their fasting and post-prandial bile acid profile. Conclusions Results indicate that patients with NASH have higher fasting and post-prandial exposure to bile acids, including the more hydrophobic and cytotoxic secondary species. Increased bile acid exposure may be involved in liver injury and the pathogenesis of NAFLD and NASH.

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Section: Introductionmentioning

confidence: 99%

Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis

et al. 2015

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“…However, with the exception of Timp-1 mRNA, these increases were less in female rats than in males, especially at 14 weeks. 7 Previous studies showed that BA synthesis, export, and transformation are dysregulated in HFC-fed male rats [21], and these process have been associated with HFC-induced fibrogenesis [22]. HFC feeding significantly increased CYP7A1 protein levels at 8 and 14 weeks but decreased CYP8B1 (data not shown) protein expression in male and female rats at all time points in comparison with their respective controls (Figure 3).…”

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confidence: 67%

“…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]. Therefore, this model is likely appropriate for further investigations of the mechanisms behind gender differences in HFC-induced fibrotic steatohepatitis.…”

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

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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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“…Chemically induced models use direct hepatotoxic agents such as CCl 4 , dimethyl nitrosamine, and thioacetamide, which initiate hepatic inflammation, activating hepatic stellate cells. NAFLD cirrhosis may arise in mice fed with methionine‐deficient or choline‐deficient or a high‐fat diet. Bile duct ligation creates a mechanical obstruction of the bile duct, inducing cholestasis, cholangiocyte and hepatocyte injury, and fibrosis .…”

Section: Discussionmentioning

confidence: 99%

Rotavirus Reassortant–Induced Murine Model of Liver Fibrosis Parallels Human Biliary Atresia

et al. 2020

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Background and Aims Biliary atresia (BA) is a devastating neonatal cholangiopathy that progresses to fibrosis and end‐stage liver disease by 2 years of age. Portoenterostomy may reestablish biliary drainage, but, despite drainage, virtually all afflicted patients develop fibrosis and progress to end‐stage liver disease requiring liver transplantation for survival. Approach and Results In the murine model of BA, rhesus rotavirus (RRV) infection of newborn pups results in a cholangiopathy paralleling human BA and has been used to study mechanistic aspects of the disease. Unfortunately, nearly all RRV‐infected pups succumb by day of life 14. Thus, in this study we generated an RRV‐TUCH rotavirus reassortant (designated as TR(VP2,VP4)) that when injected into newborn mice causes an obstructive jaundice phenotype with lower mortality rates. Of the mice that survived, 63% developed Ishak stage 3‐5 fibrosis with histopathological signs of inflammation/fibrosis and bile duct obstruction. Conclusions This model of rotavirus‐induced neonatal fibrosis will provide an opportunity to study disease pathogenesis and has potential to be used in preclinical studies with an objective to identify therapeutic targets that may alter the course of BA.

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

Cited by 35 publications

References 41 publications

Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis

Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis

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

Rotavirus Reassortant–Induced Murine Model of Liver Fibrosis Parallels Human Biliary Atresia

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