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

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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.

Original languageEnglish
Pages (from-to)2212-2222
Number of pages11
JournalDigestive Diseases and Sciences
Volume58
Issue number8
DOIs
Publication statusPublished - 01-08-2013

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All Science Journal Classification (ASJC) codes

  • Physiology
  • Gastroenterology

Cite this

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, 58(8), 2212-2222. https://doi.org/10.1007/s10620-013-2747-1