Dysregulated bile acid synthesis, metabolism and excretion in a high fat-cholesterol diet-induced fibrotic steatohepatitis in rats

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

研究成果: Article

19 引用 (Scopus)

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Background and Aims: Cholesterol 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. Methods: Molecular 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. Results: Unlike 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. Conclusions: The HFC diet may accumulate BA in rat livers, which influences fibrotic steatohepatitis progression.

元の言語English
ページ(範囲)2212-2222
ページ数11
ジャーナルDigestive Diseases and Sciences
58
発行部数8
DOI
出版物ステータスPublished - 01-08-2013
外部発表Yes

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High Fat Diet
Fatty Liver
Bile Acids and Salts
Cholesterol
Down-Regulation
Liver
Mixed Function Oxygenases
Cholestanetriol 26-Monooxygenase
Low Density Lipoprotein Receptor-Related Protein-1
Cholesterol 7-alpha-Hydroxylase
Hydroxymethylglutaryl CoA Reductases
Dietary Cholesterol
Sulfotransferases
Glucuronosyltransferase
LDL Receptors
Sterols
Up-Regulation
Stroke
Diet
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Physiology
  • Gastroenterology

これを引用

Jia, Xiaofang ; Naito, Hisao ; Yetti, Husna ; Tamada, Hazuki ; Kitamori, Kazuya ; Hayashi, Yumi ; Wang, Dong ; Yanagiba, Yukie ; Wang, Juncai ; Ikeda, Katsumi ; Yamori, Yukio ; Nakajima, Tamie. / Dysregulated bile acid synthesis, metabolism and excretion in a high fat-cholesterol diet-induced fibrotic steatohepatitis in rats. :: Digestive Diseases and Sciences. 2013 ; 巻 58, 番号 8. pp. 2212-2222.
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title = "Dysregulated bile acid synthesis, metabolism and excretion in a high fat-cholesterol diet-induced fibrotic steatohepatitis in rats",
abstract = "Background and Aims: Cholesterol 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. Methods: Molecular 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. Results: Unlike 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. Conclusions: The HFC diet may accumulate BA in rat livers, which influences fibrotic steatohepatitis progression.",
author = "Xiaofang Jia and Hisao Naito and Husna Yetti and Hazuki Tamada and Kazuya Kitamori and Yumi Hayashi and Dong Wang and Yukie Yanagiba and Juncai Wang and Katsumi Ikeda and Yukio Yamori and Tamie Nakajima",
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Jia, X, Naito, H, Yetti, H, Tamada, H, Kitamori, K, Hayashi, Y, Wang, D, Yanagiba, Y, Wang, J, Ikeda, K, Yamori, Y & Nakajima, T 2013, 'Dysregulated bile acid synthesis, metabolism and excretion in a high fat-cholesterol diet-induced fibrotic steatohepatitis in rats', Digestive Diseases and Sciences, 巻. 58, 番号 8, pp. 2212-2222. https://doi.org/10.1007/s10620-013-2747-1

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, Yumi; Wang, Dong; Yanagiba, Yukie; Wang, Juncai; Ikeda, Katsumi; Yamori, Yukio; Nakajima, Tamie.

:: Digestive Diseases and Sciences, 巻 58, 番号 8, 01.08.2013, p. 2212-2222.

研究成果: Article

TY - JOUR

T1 - Dysregulated bile acid synthesis, metabolism and excretion in a high fat-cholesterol diet-induced fibrotic steatohepatitis in rats

AU - Jia, Xiaofang

AU - Naito, Hisao

AU - Yetti, Husna

AU - Tamada, Hazuki

AU - Kitamori, Kazuya

AU - Hayashi, Yumi

AU - Wang, Dong

AU - Yanagiba, Yukie

AU - Wang, Juncai

AU - Ikeda, Katsumi

AU - Yamori, Yukio

AU - Nakajima, Tamie

PY - 2013/8/1

Y1 - 2013/8/1

N2 - Background and Aims: Cholesterol 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. Methods: Molecular 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. Results: Unlike 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. Conclusions: The HFC diet may accumulate BA in rat livers, which influences fibrotic steatohepatitis progression.

AB - Background and Aims: Cholesterol 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. Methods: Molecular 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. Results: Unlike 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. Conclusions: The HFC diet may accumulate BA in rat livers, which influences fibrotic steatohepatitis progression.

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U2 - 10.1007/s10620-013-2747-1

DO - 10.1007/s10620-013-2747-1

M3 - Article

C2 - 23824403

AN - SCOPUS:84881478751

VL - 58

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EP - 2222

JO - American Journal of Digestive Diseases

JF - American Journal of Digestive Diseases

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