McMillin Matthew, Grant Stephanie, Frampton Gabriel, Petrescu Anca D, Kain Jessica, Williams Elaina, Haines Rebecca, Canady Lauren, DeMorrow Sharon
Central Texas Veterans Healthcare System, Temple, Texas.
Department of Medical Physiology, Texas A&M College of Medicine, Temple, Texas.
Cell Mol Gastroenterol Hepatol. 2018 Mar 6;6(1):47-63. doi: 10.1016/j.jcmgh.2018.02.008. eCollection 2018.
BACKGROUND & AIMS: Hepatic encephalopathy is a serious neurologic complication of acute and chronic liver diseases. We previously showed that aberrant bile acid signaling contributes to the development of hepatic encephalopathy via farnesoid X receptor (FXR)-mediated mechanisms in neurons. In the brain, a novel alternative bile acid synthesis pathway, catalyzed by cytochrome p450 46A1 (Cyp46A1), is the primary mechanism by which the brain regulates cholesterol homeostasis. The aim of this study was to determine if FXR activation in the brain altered cholesterol homeostasis during hepatic encephalopathy.
Cyp7A1 mice or C57Bl/6 mice pretreated with central infusion of FXR vivo morpholino, 2-hydroxypropyl-β-cyclodextrin, or fed a cholestyramine-supplemented diet were injected with azoxymethane (AOM). Cognitive and neuromuscular impairment as well as liver damage and expression of Cyp46A1 were assessed using standard techniques. The subsequent cholesterol content in the frontal cortex was measured using commercially available kits and by Filipin III and Nile Red staining.
There was an increase in membrane-bound and intracellular cholesterol in the cortex of mice treated with AOM that was associated with decreased Cyp46A1 expression. Strategies to inhibit FXR signaling prevented the down-regulation of Cyp46A1 and the accumulation of cholesterol. Treatment of mice with 2-hydroxypropyl-β-cyclodextrin attenuated the AOM-induced cholesterol accumulation in the brain and the cognitive and neuromuscular deficits without altering the underlying liver pathology.
During hepatic encephalopathy, FXR signaling increases brain cholesterol and contributes to neurologic decline. Targeting cholesterol accumulation in the brain may be a possible therapeutic target for the management of hepatic encephalopathy.
肝性脑病是急慢性肝病的一种严重神经并发症。我们之前表明，异常胆汁酸信号通过神经元中法尼醇X受体（FXR）介导的机制促进肝性脑病的发展。在大脑中，由细胞色素P450 46A1（Cyp46A1）催化的一种新的替代性胆汁酸合成途径是大脑调节胆固醇稳态的主要机制。本研究的目的是确定肝性脑病期间大脑中FXR激活是否会改变胆固醇稳态。
给经中枢注射FXR体内吗啉代寡核苷酸、2-羟丙基-β-环糊精预处理的Cyp7A1小鼠或C57Bl/6小鼠，或喂食补充消胆胺饮食的小鼠注射偶氮甲烷（AOM）。使用标准技术评估认知和神经肌肉损伤以及肝损伤和Cyp46A1的表达。使用市售试剂盒以及Filipin III和尼罗红染色法测量额叶皮质中随后的胆固醇含量。
用AOM处理的小鼠皮质中膜结合胆固醇和细胞内胆固醇增加，这与Cyp46A1表达降低有关。抑制FXR信号的策略可防止Cyp46A1的下调和胆固醇的积累。用2-羟丙基-β-环糊精处理小鼠可减轻AOM诱导的大脑胆固醇积累以及认知和神经肌肉缺陷，而不会改变潜在的肝脏病理状况。
在肝性脑病期间，FXR信号增加大脑胆固醇并导致神经功能衰退。针对大脑中胆固醇积累可能是肝性脑病治疗的一个潜在靶点。
