Dataset Information

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-?, conversely, it enhanced classic BA synthesis by upregulating cholesterol 7?-hydroxylase but downregulating sterol 12?-hydroxylase, and influenced alternative synthesis by downregulating sterol 27-hydroxylase but upregulating oxysterol 7?-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.

SUBMITTER: Jia X

PROVIDER: S-EPMC3731517 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Jia Xiaofang X Naito Hisao H Yetti Husna H Tamada Hazuki H Kitamori Kazuya K Hayashi Yumi Y Wang Dong D Yanagiba Yukie Y Wang Juncai J Ikeda Katsumi K Yamori Yukio Y Nakajima Tamie T

Digestive diseases and sciences 20130704 8

<h4>Background and aims</h4>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.<h4>Methods</h4>Molecular markers involved in cholesterol and BA kinetics were investigated at protein and mRNA levels in an already-established stroke-prone spontaneously hy ...[more]

PMID: 23824403

Similar Datasets

Project description:BackgroundTestosterone deficiency is associated with increased serum cholesterol levels. However, how testosterone deficiency precisely affects cholesterol metabolism remains unclear. Therefore, in the current study, we examined the effect of testosterone deficiency on cholesterol metabolism and liver gene expression in pigs fed a high-fat and high-cholesterol (HFC) diet.MethodsSexually mature male miniature pigs (6-7 months old) were randomly divided into 3 groups as follows: intact male pigs fed an HFC diet (IM+HFC), castrated male pigs fed an HFC diet (CM+HFC), and castrated pigs with testosterone replacement fed an HFC diet (CM+HFC+T). Serum testosterone levels and lipid profiles were measured, and gene expression levels associated with hepatic cholesterol metabolism were determined. Furthermore, total hepatic cholesterol contents and the activities of enzymes mediating hepatic cholesterol metabolism were measured.ResultsSerum testosterone levels were significantly decreased in CM+HFC pigs, and testosterone replacement attenuated castration-induced testosterone deficiency. Castration significantly increased the serum levels of total cholesterol, low-density lipoprotein cholesterol and triglycerides, as well as hepatic lipid contents in pigs fed an HFC diet. Compared with IM+HFC and CM+HFC+T pigs, low-density lipoprotein receptor (LDLR) mRNA expression and protein levels were significantly decreased in the livers of CM+HFC pigs. In contrast, we found that compared with IM+HFC pigs, hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and serum PCSK9 protein levels were significantly increased in CM+HFC pigs. Moreover, testosterone treatment reversed the increase in PCSK9 expression in CM+HFC pigs. However, neither castration nor testosterone replacement affected the expression of the other hepatic genes that were tested.ConclusionsThis study demonstrated that castration-induced testosterone deficiency caused severe hypercholesterolemia in pigs fed an HFC diet; furthermore, these effects could be reversed by testosterone replacement therapy. Altered hepatic PCSK9 and LDLR expression, resulting in reduced LDL-cholesterol clearance, may contribute to the increased serum cholesterol levels induced by testosterone deficiency and an HFC diet. These results deepen our understanding of the underlying molecular mechanisms that mediate the effects of testosterone deficiency on cholesterol metabolism.

Dataset Information

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

Background and aims

Methods

Results

Conclusions

Publications

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

Similar Datasets

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