非酒精性脂肪性肝病的肝靶向治疗研究进展

靳雪源; 王慧芬

doi:10.3969/j.issn.1001-5256.2014.05.024

非酒精性脂肪性肝病的肝靶向治疗研究进展

DOI: 10.3969/j.issn.1001-5256.2014.05.024

1. 解放军总医院和解放军医学院
2. 解放军第302医院

基金项目:

国家自然科学基金(30972626)；国家863计划项目(2006AA02A4C6)；

详细信息

中图分类号: R575.5
计量
- 文章访问数: 3041
- HTML全文浏览量: 17
- PDF下载量: 718
- 被引次数: 0
出版历程
- 出版日期: 2014-05-20

Research progress in liver targeted therapy for nonalcoholic fatty liver disease

Research funding:

摘要

摘要:
非酒精性脂肪性肝病（NAFLD）是最常见的进行性疾病,临床上目前尚无疗效确切的治疗药物。介绍了脂肪酸-胆酸偶合物（FABACs）和熊去氧胆酸-溶血磷脂酰乙醇胺偶合物（UDCA-LPE）两种新型的具有NAFLD防治作用的肝靶向药物的研究进展。FABACs通过调节脂代谢,特异性的降低高脂饲料所致NAFLD的肝脏脂肪升高,预防NAFLD的形成;而且对已形成的NAFLD也有治疗作用;Ⅱ期临床研究结果显示其起效快、安全性好。UDCA-LPE在降低NAFLD的肝脏脂肪的同时,能够抑制线粒体损伤和凋亡,促进肝细胞再生,对NAFLD发展过程中的相关炎症具有显著的抑制作用。因此,FABACs和UDCA-LPE对防治NAFLD具有良好的应用前景。
- 脂肪肝 /
- 脂肪酸-胆酸偶合物 /
- 熊去氧胆酸-溶血磷脂酰乙醇胺偶合物 /
- 综述
Abstract:
Nonalcoholic fatty liver disease ( NAFLD) is the most common progressive liver disease worldwide. Currently, there is no satisfying treatment for NAFLD. Research progress in fatty acid bile acid conjugates ( FABACs) and ursodeoxycholyl lysophosphatidylethanolamide ( UDCA- LPE) , which are two novel liver targeted drugs with anti- NAFLD effects, is reviewed. FABACs, which reduce liver fat in patients with NAFLD induced by high- fat diet by regulating lipid metabolism, have been proved effective in preventing and treating NAFLD. The safety and efficacy of FABACs in NAFLD patients have been confirmed in a phase II, randomized, double- blind, placebo- controlled trial. UDCA- LPE can not only reduce liver fat in NAFLD patients, but also inhibit mitochondrial damage and apoptosis and promote hepatocyte regeneration, with a marked anti- inflammatory effect during the development of NAFLD. Therefore, FABACs and UDCA- LPE hold promise for preventing and treating NAFLD.
- fatty liver /
- fatty acid bile acid conjugates /
- ursodeoxycholyl lysophosphatidylethanolamide /
- review

HTML全文

参考文献(36)

[1]NEUSCHWANDER-TETRI BA.Fatty liver and the metabolic syndrome[J].Curr Opin Gastroenterol, 2007, 23 (2) :193-198.

[2]GREENFIELD V, CHEUNG O, SANYAL AJ.Recent advances in nonalcholic fatty liver disease[J].Curr Opin Gastroenterol, 2008, 24 (3) :320-327.

[3]CHALASANI N, YOUNOSSI Z, LAVINE JE, et al.The diagnosis and management of non-alcoholic fatty liver disease:practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology[J].Gastroenterology, 2012, 142 (7) :1592-1609.

[4]DAY CP.Pathogenesis of steatohepatitis[J].Best Pract Res Clin Gastroenterol, 2002, 16 (5) :663-678.

[5]MCCULLOUGH AJ.Pathophysiology of nonalcoholic steatohepatitis[J].Clin Gastroenterol, 2006, 40 (Suppl 1) :s17-s29.

[6]GAGGINI M, MORELLI M, BUZZIGOLI E, et al.Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease[J].Nutrients, 2013, 5 (5) :1544-1560.

[7] BHATIA LS, CURZEN NP, CALDER PC, et al.Non-alcoholic fatty liver disease:a new and important cardiovascular risk factor?[J].Eur Heart J, 2012, 33 (10) :1190-1200.

[8]SUNG KC, WILD SH, KWAG HJ, et al.Fatty liver, insulin resistance, and features of metabolic syndrome:relationships with coronary artery calcium in 10, 153 people[J].Diabetes Care, 2012, 35 (11) :2359-2364.

[9]DAI HH, MEI LQ.Advances in nonalcoholic fatty liver disease and hepatocellular carcinoma research[J].J Clin Hepatol, 2012, 28 (10) :797-800. (in Chinese) 代鸿华, 梅礼强.非酒精性脂肪肝病与肝细胞癌关系的研究进展[J].临床肝胆病杂志, 2012, 28 (10) :797-800.

[10]IBRAHIM MA, KELLENI M, GEDDAWY A.Nonalcoholic fatty liver disease:current and potential therapies[J].Life Science, 2013, 92 (2) :114-118.

[11]NAGASAWA T, INADA Y, NAKANO S, et al.Effects of bezafibrate, PPAR panagonist, and GW501516, PPAR delta agonist, on development of steatohepatitis in mice fed a methionine-and choline-deficient diet[J].Eur J Pharmacol, 2006, 536 (1-2) :182-191.

[12]TAILLEUX A, WOUTERS K, STAELS B.Roles of PPARs in NAFLD:potential therapeutic targets[J].Biochim Biophys Acta, 2012, 1821 (5) :809-818.

[13]FENG MD, TAN MZ, LIANG K, et al.Therapeutic efficacy of atorvastatin in treatment of in patients with type II diabettesmellitus[J].J Clin Hepatol, 2013, 29 (7) :512-515. (in Chinese) 冯梦蝶, 覃敏珍, 梁柯, 等.阿托伐他汀治疗II型糖尿病合并非酒精性脂肪肝病的疗效观察[J].临床肝胆病杂志, 2013, 29 (7) :512-515.

[14]TORRES DM, HARRISON SA.Diagnosis and therapy of nonalcoholic steatohepatitis[J].Gastroenterology, 2008, 134 (6) :1682-1698.

[15]MIN AK, KIM MK, KIM HS, et al.Alpha-lipoic acid attenuates methionine choline deficient diet-induced steatohepatitis in C57BL/6mice[J].Life Sci, 2012, 90 (5-6) :200-205.

[16] LINDOR KD, KOWDLEY KV, HEATHCOTE EJ, et al.Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis:results of a randomized trial[J].Hepatology, 2004, 39 (3) :770-778.

[17]BELFORT R, HARRISON SA, BROWN K, et al.A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis[J].N Engl J Med, 2006, 355 (22) :2297-2307.

[18]PASCHKE R, KALBITZ J, PAETZ C, et al.Cholic acid-carboplatin compounds as models for specific drug delivery[J].J Inorg Biochem, 2003, 94 (4) :335-342.

[19]FIORUCCI S, ANTONELLI E, TOCCHETTI P, et al.Treatment of portal hypertension with NCX-1000, a liver-specific NO donor.a review of its current status[J].Cardiovasc Drug Rev, 2004, 22 (2) :135-146.

[20]FIORUCCI S, ANTONELLI E, MORELLI O, et al.NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively delivers NO to the liver and protects against development of portal hypertension[J].Proc Natl Acad Sci USA, 2001, 98 (15) :8897-8902.

[21]TRANNER M, BOYER JL.Bile salt transporters:molecular characterization, function, and regulation[J].Physiol Rev, 2003, 83 (2) :633-671.

[22]DOMINGUES MF, MACIAS RI, IZCO-BASURCO I, et al.Low in vivo toxicity of a novel cisplatin-ursodexycholic derivative (BametUD2) with enhanced cytostatic activity versus liver tumors[J].J Pharmacol Exp Ther, 2001, 297 (3) :1106-1112.

[23]GILAT T, LEIKIN-FRENKEL A, GOLDIER I, et al.Prevention of diet-induced fatty liver in experimental animal by the oral administration of fatty acid bile acid conjugate (FABAC) [J].Hepatology, 2003, 38 (2) :436-442.

[24]LEIKIN-FRENKEL A, GOLDINER I, LEIKIN-GOBBI D, et al.Treatment of preestablished diet-induced fatty liver by oral fatty acid-bile acid conjugates in rodents[J].Eur J Gastroenterol Hepatol, 2008, 20 (12) :1205-1213.

[25]ZORZI D, LAURENT A, PAWLIK TM, et al.Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases[J].Br J Surg, 2007, 94 (3) :274-286.

[26]KEIZMAN D, MAIMON N, ISH-SHALOM M, et al.An animal model for chemotherapy-associated steatohepatitis and its prevention by the oral administration of fatty acid bile acid conjugate[J].Cancer, 2010, 116 (1) :251-255.

[27]LEIKIN-FRENKEL A, WEINBROUM AA, LEIKIN-GOBBI D, et al.Faecal sterol output is increased by arachidyl amido cholanoic acid (Aramchol) in rats[J].Biochem Soc Trans, 2004, 32 (Pt1) :131-133.

[28]LEIKIN-FRENKEL A, GONEN A, SHAISH A, et al.Fatty acid bile acid conjugate inhibits hepatic stearoyl coenzyme A Desaturase and is non-atherogenic[J].Arch Med Res, 2010, 41 (6) :397-404.

[29]SAFADI R, KONIKOFF FM, OREN R.A phase-2, randomized, double blind, placebo-controlled trial of aramchol for the treatment of nonalcoholic fatty liver disease (NAFLD) [J].J Hepatology, 2012, 56:s558.

[30]VANCE DE, LI Z, JACOBS R.Hepatic phosphatidylethanolamine N-methyltransferase, unexpected roles in animal biochemistry and physiology[J].J Biol Chem, 2008, 282 (46) :33237-33241.

[31]LIEBER CS, WEISS DG, GROSZMANN R, et al.II.Veterans affairs cooperative study of polyenylphosphatidylcholine in alcoholic liver disease[J].Alcohol Clin Exp Res, 2003, 27 (11) :1765-1772.

[32]CHAMULITRAT W, BURHENNE J, REHLEN T, et al.Bile salt-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide as a hepatoprotective agent[J].Hepatology, 2009, 50 (1) :143-154.

[33]PATHIL A, MUELLER J, WARTH A, et al.Ursodeoxycholyl lysophosphatidylethanolamide improves steatosis and inflammation in murine models of nonalcoholic fatty liver disease[J].Hepatology, 2012, 55 (5) :1369-1378.

[34]PATHIL A, WARTH A, CHAMULITRAT W, et al.The synthetic bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide suppresses TNFα-induced liver injury[J].J Hepatology, 2011, 54 (4) :674-684.

[35]CHAMULITRAT W, ZHANG W, XU W, et al.Hepatoprotectant ursodeoxycholyl lysophosphatidylethanolamide increasing phosphatidylcholine levels as a potential therapy of acute liver injury[J].Front Physiol, 2012, 3:24.

[36]CHAMULITRAT W, LIEBISCH G, XU W, et al.Ursodeoxycholyl lysophosphatidyl-ethanolamide inhibits lipoapoptosis by shifting fatty acid pools toward monosaturated and polyunsaturated fatty acids in mouse hepatocytes[J].Mol Pharmacol, 2013, 84 (5) :696-709.

施引文献

资源附件(0)

访问统计