Mode of action of the bile-acid phospholipid conjugate ursodeoxycholyl-lysophosphatidylethanolamide (UDCA-LPE) on fatty acid uptake in hepatocytes: implication for its therapeutic use in non-alcoholic steatohepatitis (NASH).

胆汁酸磷脂结合物熊去氧胆酰-溶血磷脂酰乙醇酰胺 (UDCA-LPE) 对肝细胞脂肪酸摄取的作用模式：其治疗非酒精性脂肪性肝炎 (NASH) 的意义。

• 批准号: 134226865
• 负责人: Professor Dr. Wolfgang Stremmel
• 金额: --
• 依托单位: Klinik für Gastroenterologie, Infektionskrankheiten, Vergiftungen
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/134226865?language=en
• 关键词: Mode; action; bile; acid; phospholipid

Non-alcoholic steatohepatitis (NASH) is a common metabolic liver disease with doubtful prognosis. The natural cause of the disease is determined by its progression to cirrhosis. Until this date no effective therapy for NASH is available. Therefore we designed a potentially effective drug candidate which is comprised of a phosphatidylcholine precursor, lysophosphatidyletanolamine, and ursodeoxycholic acid (UDCA-LPE). Lysophosphatidyletanolamine (LPE) is a phospholipid which intracellulary is converted to phosphatidylcholin (PC). The rationale for induction of an increase of PC uptake into the liver is derived from the fact that hepatic PC levels are decreased in NASH. PC exerts cytoprotective effects by stabilizing membranes and inhibiting apoptosis. Therefore, it seems logical to supplement for depleted PC as a strategy to treat NASH. For the selective enrichment of LPE in the liver, it was coupled to UDCA which is specifically taken up by hepatocytes via bile salt carrier systems. Accordingly, in preceding experiments it was shown that also the UDCA-LPE conjugate was effectively targeted to the liver. Here it was hydrolyzed to UDCA and LPE which can be metabolized to PC. In cell culture experiments it was demonstrated that UDCA-LPE is protective during cell starvation and TNFα-induced apoptosis. Detailed analyses revealed that UDCA-LPE as an intact conjugate can even be more cytoprotective than its hydrolyzed components. In this DFG application it is planned to pursue more extensive in vivo studies to investigate the prosurvival pathways and anti-inflammatory effects of UDCA-LPE. As an experimental model we chose primary rat hepatocytes where injury will be induced by a mixture of free fatty acids or by methionine- and choline-deficiency (MCD) in the culture medium. Furthermore, the cytoprotective and anti-inflammatory effects of UDCA-LPE in vivo will be investigated using two NASH mouse models: mice on MCD diet and mice on a high-fat diet. These experiments are the basis for evaluation of the efficacy of UDCA-LPE for treatment of NASH in men at the level of clinical trials.

非酒精性脂肪性肝炎（NASH）是一种常见的代谢性肝病，预后存疑。该疾病的自然原因取决于其进展为肝硬化。迄今为止，还没有针对 NASH 的有效疗法。因此，我们设计了一种潜在有效的候选药物，由磷脂酰胆碱前体、溶血磷脂酰乙醇胺和熊去氧胆酸（UDCA-LPE）组成。溶血磷脂酰乙醇胺 (LPE) 是一种磷脂，在细胞内转化为磷脂酰胆碱 (PC)。诱导肝脏 PC 摄取增加的基本原理源自 NASH 中肝脏 PC 水平降低的事实。 PC 通过稳定细胞膜和抑制细胞凋亡发挥细胞保护作用。因此，补充耗尽的PC作为治疗NASH的策略似乎是合乎逻辑的。为了选择性富集肝脏中的 LPE，将其与 UDCA 偶联，UDCA 通过胆汁盐载体系统被肝细胞特异性吸收。因此，在之前的实验中表明UDCA-LPE缀合物也有效地靶向肝脏。在这里它被水解为 UDCA 和 LPE，后者可代谢为 PC。细胞培养实验表明，UDCA-LPE 在细胞饥饿和 TNFα 诱导的细胞凋亡期间具有保护作用。详细分析表明，UDCA-LPE 作为完整的缀合物甚至比其水解成分具有更强的细胞保护作用。在此 DFG 应用中，计划进行更广泛的体内研究，以研究 UDCA-LPE 的促存活途径和抗炎作用。作为实验模型，我们选择原代大鼠肝细胞，其中游离脂肪酸混合物或培养基中的蛋氨酸和胆碱缺乏（MCD）会诱导损伤。此外，将使用两种 NASH 小鼠模型研究 UDCA-LPE 的体内细胞保护和抗炎作用：MCD 饮食的小鼠和高脂饮食的小鼠。这些实验是在临床试验水平上评估 UDCA-LPE 治疗男性 NASH 疗效的基础。

项目成果

Ursodeoxycholyl lysophosphatidylethanolamide inhibits cholestasis- and hypoxia-induced apoptosis by upregulating antiapoptosis proteins

熊去氧胆酰溶血磷脂酰乙醇酰胺通过上调抗凋亡蛋白抑制胆汁淤积和缺氧诱导的细胞凋亡

• DOI: 10.1177/1535370214547157
• 发表时间: 2015
• 期刊: Experimental Biology and Medicine
• 影响因子: 3.2
• 作者: Sellinger M;Pathil A;Stremmel W;Chamulitrat W
• 通讯作者: Chamulitrat W

Plasma membrane phospholipase A2 controls hepatocellular fatty acid uptake and is responsive to pharmacological modulation: implications for nonalcoholic steatohepatitis

质膜磷脂酶 A2 控制肝细胞脂肪酸摄取并对药理学调节有反应：对非酒精性脂肪性肝炎的影响

• DOI: 10.1096/fj.14-249763
• 发表时间: 2014
• 期刊: The FASEB Journal
• 作者: Stremmel W;Staffer S;Wannhoff A;Pathil A;Chamulitrat W
• 通讯作者: Chamulitrat W

Ursodeoxycholyl Lysophosphatidylethanolamide modifies aberrant lipid profiles in NAFLD

• DOI: 10.1111/eci.12486
• 发表时间: 2015-09
• 期刊: European Journal of Clinical Investigation
• 影响因子: 5.5
• 作者: A. Pathil;G. Liebisch;J. Okun;W. Chamulitrat;G. Schmitz;W. Stremmel

Ursodeoxycholyl Lysophosphatidylethanolamide Protects Against CD95/FAS-Induced Fulminant Hepatitis

熊去氧胆酰溶血磷脂酰乙醇酰胺可预防 CD95/FAS 诱导的暴发性肝炎

• DOI: 10.1097/shk.0000000000000831
• 发表时间: 2017
• 期刊: SHOCK
• 影响因子: 3.1
• 作者: Utaipan T;Otto AC;Gan-Schreier H;Chunglok W;Pathil A;Stremmel W;Chamulitrat W
• 通讯作者: Chamulitrat W

URSODEOXYCHOLYL LYSOPHOSPHATIDYLETHANOLAMIDE PROTECTS AGAINST HEPATIC ISCHEMIA AND REPERFUSION INJURY IN MICE

• DOI: 10.1097/shk.0000000000000312
• 发表时间: 2015-04-01
• 期刊: SHOCK
• 影响因子: 3.1
• 作者: Wang, Jiliang;Deng, Xiuling;Chamulitrat, Walee
• 通讯作者: Chamulitrat, Walee