Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Dig Dis Sci. 2013 Aug;58(8):2212-22. doi: 10.1007/s10620-013-2747-1. Epub 2013 Jul 4.
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.
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.
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.
The HFC diet may accumulate BA in rat livers, which influences fibrotic steatohepatitis progression.
胆固醇摄入过多与非酒精性脂肪性肝炎（NASH）的发生有关，肝细胞胆汁酸（BA）蓄积与肝损伤相关。然而，饮食胆固醇如何影响 NASH 肝脏中的胆固醇和 BA 动力学仍不清楚，需要进一步阐明。
在已建立的纤维化性脂肪性肝炎自发性高血压 5/Dmcr 大鼠模型中，通过给予高脂肪胆固醇（HFC）饮食，在蛋白质和 mRNA 水平上研究胆固醇和 BA 动力学相关的分子标志物。
与对照饮食相比，HFC 饮食使大鼠肝脏内胆固醇大量沉积，3-羟-3-甲基戊二酰辅酶 A 还原酶、低密度脂蛋白（LDL）受体和 LDL 受体相关蛋白-1 下调，尤其在 8 周和 14 周时，表明胆固醇合成和摄取可能并未因胆固醇蓄积而失调。HFC 饮食未上调肝 X 受体-α，相反，它通过上调胆固醇 7α-羟化酶但下调甾醇 12α-羟化酶增强经典 BA 合成，并通过下调甾醇 27-羟化酶但上调氧化固醇 7α-羟化酶影响替代合成，主要在 8 周和 14 周时，表明初级 BA 种类的产生不同。令人意外的是，法尼醇 X 受体未发生 BA 合成的反馈抑制。此外，HFC 饮食在 8 周和 14 周时损害了 UDP-葡糖醛酸基转移酶和磺基转移酶 2A1 的 BA 解毒作用，并降低了胆盐输出泵的排泄，尽管它通过多药耐药相关蛋白-3 诱导了代偿性输出。BA 解毒作用的紊乱可能与妊娠相关 X 受体和组成型雄烷受体的抑制有关。
HFC 饮食可能使 BA 在大鼠肝脏内蓄积，从而影响纤维化性脂肪性肝炎的进展。
