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

Husna Yetti, Hisao Naito, Yuan Yuan, Xiaofang Jia, Yumi Hayashi, Hazuki Tamada, Kazuya Kitamori, Katsumi Ikeda, Yukio Yamori, Tamie Nakajima

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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 androstane 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.

Original languageEnglish
Article numbere0192863
JournalPloS one
Volume13
Issue number2
DOIs
Publication statusPublished - 01-02-2018

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liver cirrhosis
High Fat Diet
bile acids
Nutrition
Bile Acids and Salts
Liver Cirrhosis
Liver
Rats
Fats
Cholesterol
cholesterol
receptors
rats
Enzymes
lipids
enzymes
diet
Sulfotransferases
Glucuronosyltransferase
Detoxification

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Yetti, Husna ; Naito, Hisao ; Yuan, Yuan ; Jia, Xiaofang ; Hayashi, Yumi ; Tamada, Hazuki ; Kitamori, Kazuya ; Ikeda, Katsumi ; Yamori, Yukio ; Nakajima, Tamie. / Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet. In: PloS one. 2018 ; Vol. 13, No. 2.
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abstract = "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 androstane 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.",
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Yetti, H, Naito, H, Yuan, Y, Jia, X, Hayashi, Y, Tamada, H, Kitamori, K, Ikeda, K, Yamori, Y & Nakajima, T 2018, 'Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet', PloS one, vol. 13, no. 2, e0192863. https://doi.org/10.1371/journal.pone.0192863

Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet. / Yetti, Husna; Naito, Hisao; Yuan, Yuan; Jia, Xiaofang; Hayashi, Yumi; Tamada, Hazuki; Kitamori, Kazuya; Ikeda, Katsumi; Yamori, Yukio; Nakajima, Tamie.

In: PloS one, Vol. 13, No. 2, e0192863, 01.02.2018.

Research output: Contribution to journalArticle

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T1 - Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet

AU - Yetti, Husna

AU - Naito, Hisao

AU - Yuan, Yuan

AU - Jia, Xiaofang

AU - Hayashi, Yumi

AU - Tamada, Hazuki

AU - Kitamori, Kazuya

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AU - Yamori, Yukio

AU - Nakajima, Tamie

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N2 - 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 androstane 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.

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