胆固醇与肝再生关系及其在肝衰竭治疗中的意义和潜在价值

林镛; 颜耿杰; 冯逢; 彭子明; 龙富立; 韦艾凌; 王明刚; 姚春

doi:10.3969/j.issn.1001-5256.2022.03.044

胆固醇与肝再生关系及其在肝衰竭治疗中的意义和潜在价值

DOI: 10.3969/j.issn.1001-5256.2022.03.044

林镛¹,
颜耿杰¹,
冯逢¹,
彭子明¹,
龙富立^{1, 2},
韦艾凌²,
王明刚²,
姚春^3, , ,

1.
广西中医药大学研究生院，南宁 530200
2.
广西中医药大学第一附属医院肝病二区，南宁 530023
3.
广西中医药大学，南宁 530000

基金项目:

国家自然科学基金 (81704021);

国家自然科学基金 (81760844);

国家自然科学基金 (8170150729);

国家科技重大专项 (2018ZX10725505-001-011);

广西科技计划项目 (2020GXNSFAA297098);

广西中医药大学校级硕士研究生创新项目 (YCXJ2021034)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：林镛负责课题设计，资料分析，撰写论文；颜耿杰、冯逢、彭子明、韦艾凌、龙富立参与收集数据，修改论文；王明刚、姚春负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
姚春，1197840425@qq.com

计量
- 文章访问数: 1122
- HTML全文浏览量: 629
- PDF下载量: 73
- 被引次数: 0
出版历程
- 收稿日期: 2021-07-13
- 录用日期: 2021-08-13
- 出版日期: 2022-03-20

Association between cholesterol and liver regeneration and its significance and potential value in clinical treatment of liver failure

1.
Graduate School of Guangxi University of Chinese Medicine, Nanning 530200, China
2.
Second Ward of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China
3.
Guangxi University of Chinese Medicine, Nanning 530000, China

Research funding:

National Natural Science Foundation of China (81704021);

National Natural Science Foundation of China (81760844);

National Natural Science Foundation of China (8170150729);

National Major Science Technology Project (2018ZX10725505-001-011);

Guangxi Science and Technology Plan Project (2020GXNSFAA297098);

Postgraduate Innovation Project of Guangxi University of Chinese Medicine (YCXJ2021034)

More Information

Corresponding author: YAO Chun, 1197840425@qq.com(ORCID: 0000-0002-6612-874X)

摘要

摘要: 肝衰竭为临床上常见的严重肝病症候群，属内科危急重症之一。其病理学是以大面积肝细胞死亡为特征，核心机制是内毒素、免疫反应和炎症级联反应等。肝细胞有效再生以代偿肝功能是促进肝衰竭良好转归的生理基础，并直接影响肝衰竭患者的预后和生存质量。临床实践中已发现血清胆固醇水平低的肝衰竭患者病死率极高，但胆固醇作为肝细胞合成代谢指标，其与肝细胞再生的关系并未引起足够的重视。本文从胆固醇与肝再生关系出发，综述其在肝衰竭临床治疗中的意义和潜在价值，以期从另一角度了解肝衰竭的发病机制，为肝衰竭的诊疗、药物研发提供新思路。
- 肝功能衰竭 /
- 胆固醇 /
- 肝再生
Abstract: Liver failure is a common severe liver disease syndrome in clinical practice and is one of the critical medical conditions in internal medicine. Massive hepatocyte death is the main pathological feature of liver failure, and its core mechanisms include endotoxin, immune response, and inflammatory cascade reaction. Effective regeneration of hepatocytes to compensate liver function is the physiological basis for promoting the good prognosis of liver failure, which directly affects the prognosis and quality of life of patients with liver failure. It has been found in clinical practice that liver failure patients with a low serum level of cholesterol tend to have an extremely high mortality rate, but as an index of hepatocyte anabolism, the association between cholesterol and hepatocyte regeneration has not been taken seriously. Based on the association between cholesterol and liver regeneration, this article reviews its significance and potential value in the clinical treatment of liver failure, in order to understand the pathogenesis of liver failure from another perspective and provide new ideas for the diagnosis and treatment of liver failure and the development of drugs.
- Liver Failure /
- Cholesterol /
- Liver Regeneration

HTML全文

图 1 影响肝脏再生的相关分子及反应过程

注：FGF，成纤维细胞生长因子；YAP、GPC-3为靶点蛋白；LtxB，P450单加氧酶。

下载: 全尺寸图片幻灯片

图 2 胆固醇-胆汁酸的代谢循环

注：SHP，小异二聚体伴侣；CYP8B1，胆固醇12α-羟化酶；BSEP，胆盐输出泵；ABCB4，胆汁酸合成基因；FGFR，成纤维细胞生长因子受体。

下载: 全尺寸图片幻灯片

参考文献(55)

[1]	WU J, YIN F, ZHOU X. Efficacy of nucleoside analogues for hepatitis B virus-related liver failure: A network meta-analysis[J]. Acta Pharm, 2018, 68(1): 19-30. DOI: 10.2478/acph-2018-0010.
[2]	LEE CW, CHEN YF, WU HH, et al. Historical perspectives and advances in mesenchymal stem cell research for the treatment of liver diseases[J]. Gastroenterology, 2018, 154(1): 46-56. DOI: 10.1053/j.gastro.2017.09.049.
[3]	KOK B, KARVELLAS CJ. Management of cerebral edema in acute liver failure[J]. Semin Respir Crit Care Med, 2017, 38(6): 821-829. DOI: 10.1055/s-0037-1608772.
[4]	TORRES S, BAULIES A, INSAUSTI-URKIA N, et al. Endoplasmic reticulum stress-induced upregulation of STARD1 promotes acetaminophen-induced acute liver failure[J]. Gastroenterology, 2019, 157(2): 552-568. DOI: 10.1053/j.gastro.2019.04.023.
[5]	YAN N, YAN T, XIA Y, et al. The pathophysiological function of non-gastrointestinal farnesoid X receptor[J]. Pharmacol Ther, 2021, 226: 107867. DOI: 10.1016/j.pharmthera.2021.107867.
[6]	WILLIAMS CM, HARPER CALDERON J, E H, et al. Monomeric/dimeric forms of Fgf15/FGF19 show differential activity in hepatocyte proliferation and metabolic function[J]. FASEB J, 2021, 35(2): e21286. DOI: 10.1096/fj.202002203R.
[7]	GULFO J, ROTONDO F, ÁVALOS de LEÓN CG, et al. FGF15 improves outcomes after brain dead donor liver transplantation with steatotic and non-steatotic grafts in rats[J]. J Hepatol, 2020, 73(5): 1131-1143. DOI: 10.1016/j.jhep.2020.05.007.
[8]	BAI Q, ZHANG X, XU L, et al. Oxysterol sulfation by cytosolic sulfotransferase suppresses liver X receptor/sterol regulatory element binding protein-1c signaling pathway and reduces serum and hepatic lipids in mouse models of nonalcoholic fatty liver disease[J]. Metabolism, 2012, 61(6): 836-845. DOI: 10.1016/j.metabol.2011.11.014.
[9]	CHEN YY, LAN YM, WANG MG, et al. Mechanism of action of bile acid-farnesoid X receptor-intestinal microecological axis in the development of liver failure and liver regeneration[J]. J Clin Hepatol, 2021, 37(2): 480-484. DOI: 10.3969/j.issn.1001-5256.2021.02.049. 陈研焰, 蓝艳梅, 王明刚, 等. 胆汁酸-法尼醇核受体R-肠道微生态轴在肝衰竭发生及肝再生中的作用机制[J]. 临床肝胆病杂志, 2021, 37(2): 480-484. DOI: 10.3969/j.issn.1001-5256.2021.02.049.
[10]	LONG FL, LIN Y, PENG ZM, et al. Research advances in animal models of acute liver failure[J]. J Clin Hepatol, 2021, 37(1): 204-208. DOI: 10.3969/j.issn.1001-5256.2021.01.045. 龙富立, 林镛, 彭子明, 等. 急性肝衰竭动物模型的研究进展[J]. 临床肝胆病杂志, 2021, 37(1): 204-208. DOI: 10.3969/j.issn.1001-5256.2021.01.045.
[11]	van MIERLO KM, SCHAAP FG, DEJONG CH, et al. Liver resection for cancer: New developments in prediction, prevention and management of postresectional liver failure[J]. J Hepatol, 2016, 65(6): 1217-1231. DOI: 10.1016/j.jhep.2016.06.006.
[12]	HASHEMI GORADEL N, DARABI M, SHAMSASENJAN K, et al. Methods of liver stem cell therapy in rodents as models of human liver regeneration in hepatic failure[J]. Adv Pharm Bull, 2015, 5(3): 293-298. DOI: 10.5681/apb.2015.041.
[13]	MICHALOPOULOS GK. Hepatostat: Liver regeneration and normal liver tissue maintenance[J]. Hepatology, 2017, 65(4): 1384-1392. DOI: 10.1002/hep.28988.
[14]	KHOLODENKO IV, YARYGIN KN. Cellular mechanisms of liver regeneration and cell-based therapies of liver diseases[J]. Biomed Res Int, 2017, 2017: 8910821. DOI: 10.1155/2017/8910821.
[15]	ADAMEK B, ZALEWSKA-ZIOB M, STRZELCZYK JK, et al. Hepatocyte growth factor and epidermal growth factor activity during later stages of rat liver regeneration upon interferon α-2b influence[J]. Clin Exp Hepatol, 2017, 3(1): 9-15. DOI: 10.5114/ceh.2017.65499.
[16]	MURTHA-LEMEKHOVA A, FUCHS J, GHAMARNEJAD O, et al. Influence of cytokines, circulating markers and growth factors on liver regeneration and post-hepatectomy liver failure: A systematic review and meta-analysis[J]. Sci Rep, 2021, 11(1): 13739. DOI: 10.1038/s41598-021-92888-4.
[17]	DOIGNON I, JULIEN B, SERRIÈRE-LANNEAU V, et al. Immediate neuroendocrine signaling after partial hepatectomy through acute portal hyperpressure and cholestasis[J]. J Hepatol, 2011, 54(3): 481-488. DOI: 10.1016/j.jhep.2010.07.012.
[18]	SOUSA IP Jr, CARVALHO C, GOMES A. Current understanding of the role of cholesterol in the life cycle of alphaviruses[J]. Viruses, 2020, 13(1): 35. DOI: 10.3390/v13010035.
[19]	GUZIOR DV, QUINN RA. Review: Microbial transformations of human bile acids[J]. Microbiome, 2021, 9(1): 140. DOI: 10.1186/s40168-021-01101-1.
[20]	MATHUR B, SHAJAHAN A, ARIF W, et al. Nuclear receptors FXR and SHP regulate protein N-glycan modifications in the liver[J]. Sci Adv, 2021, 7(17): eabf4865. DOI: 10.1126/sciadv.abf4865.
[21]	TRAUNER M, BOYER JL. Bile salt transporters: Molecular characterization, function, and regulation[J]. Physiol Rev, 2003, 83(2): 633-671. DOI: 10.1152/physrev.00027.2002.
[22]	HOFMANN AF. The enterohepatic circulation of bile acids in mammals: Form and functions[J]. Front Biosci (Landmark Ed), 2009, 14: 2584-2598. DOI: 10.2741/3399.
[23]	PEREZ MJ, BRIZ O. Bile-acid-induced cell injury and protection[J]. World J Gastroenterol, 2009, 15(14): 1677-1689. DOI: 10.3748/wjg.15.1677.
[24]	ALVAREZ-SOLA G, URIARTE I, LATASA MU, et al. Bile acids, FGF15/19 and liver regeneration: From mechanisms to clinical applications[J]. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(4 Pt B): 1326-1334. DOI: 10.1016/j.bbadis.2017.06.025.
[25]	PANZITT K, WAGNER M. FXR in liver physiology: Multiple faces to regulate liver metabolism[J]. Biochim Biophys Acta Mol Basis Dis, 2021, 1867(7): 166133. DOI: 10.1016/j.bbadis.2021.166133.
[26]	MEYER K, MORALES-NAVARRETE H, SEIFERT S, et al. Bile canaliculi remodeling activates YAP via the actin cytoskeleton during liver regeneration[J]. Mol Syst Biol, 2020, 16(2): e8985. DOI: 10.15252/msb.20198985.
[27]	PENG J, YU J, XU H, et al. Enhanced liver regeneration after partial hepatectomy in sterol regulatory element-binding protein (SREBP)-1c-null mice is associated with increased hepatocellular cholesterol availability[J]. Cell Physiol Biochem, 2018, 47(2): 784-799. DOI: 10.1159/000490030.
[28]	DE GIORGI M, JARRETT KE, BURTON JC, et al. Depletion of essential isoprenoids and ER stress induction following acute liver-specific deletion of HMG-CoA reductase[J]. J Lipid Res, 2020, 61(12): 1675-1686. DOI: 10.1194/jlr.RA120001006.
[29]	NUÑEZ-GARCIA M, GOMEZ-SANTOS B, SAENZ de URTURI D, et al. Atorvastatin provides a new lipidome improving early regeneration after partial hepatectomy in osteopontin deficient mice[J]. Sci Rep, 2018, 8(1): 14626. DOI: 10.1038/s41598-018-32919-9.
[30]	JANG YO, KIM SH, CHO MY, et al. Synergistic effects of simvastatin and bone marrow-derived mesenchymal stem cells on hepatic fibrosis[J]. Biochem Biophys Res Commun, 2018, 497(1): 264-271. DOI: 10.1016/j.bbrc.2018.02.067.
[31]	TOKUNAGA T, IKEGAMI T, YOSHIZUMI T, et al. Beneficial effects of fluvastatin on liver microcirculation and regeneration after massive hepatectomy in rats[J]. Dig Dis Sci, 2008, 53(11): 2989-2994. DOI: 10.1007/s10620-008-0241-y.
[32]	ZHANG L, HUANG X, MENG Z, et al. Significance and mechanism of CYP7a1 gene regulation during the acute phase of liver regeneration[J]. Mol Endocrinol, 2009, 23(2): 137-145. DOI: 10.1210/me.2008-0198.
[33]	IBRAHIM S, DAYOUB R, SABERI V, et al. Augmenter of Liver Regeneration (ALR) regulates bile acid synthesis and attenuates bile acid-induced apoptosis via glycogen synthase kinase-3β (GSK-3β) inhibition[J]. Exp Cell Res, 2020, 397(1): 112343. DOI: 10.1016/j.yexcr.2020.112343.
[34]	HAKIM A, MOLL M, BRANCALE J, et al. Genetic variation in the mitochondrial glycerol-3-phosphate acyltransferase is associated with liver injury[J]. Hepatology, 2021, 74(6): 3394-3408. DOI: 10.1002/hep.32038.
[35]	ZHANG J, LI J, CHEN Y, et al. Prognostic factors related to the mortality rate of acute-on-chronic liver failure patients[J]. Diabetes Metab Syndr Obes, 2021, 14: 2573-2580. DOI: 10.2147/DMSO.S309641.
[36]	DELGADO-COELLO B, BRIONES-ORTA MA, MACíAS-SILVA M, et al. Cholesterol: Recapitulation of its active role during liver regeneration[J]. Liver Int, 2011, 31(9): 1271-1284. DOI: 10.1111/j.1478-3231.2011.02542.x.
[37]	DAL K, BULUR O, ATA N, et al. The role of insulin - like growth factor - 1 on steatohepatitis[J]. Acta Gastroenterol Belg, 2017, 80(1): 21-24.
[38]	DING BS, LIU CH, SUN Y, et al. HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver[J]. JCI Insight, 2016, 1(21): e87058. DOI: 10.1172/jci.insight.87058.
[39]	SYDOR S, GU Y, SCHLATTJAN M, et al. Steatosis does not impair liver regeneration after partial hepatectomy[J]. Lab Invest, 2013, 93(1): 20-30. DOI: 10.1038/labinvest.2012.142.
[40]	WANG G, CHEN QM, MINUK GY, et al. Enhanced expression of cytosolic fatty acid binding protein and fatty acid uptake during liver regeneration in rats[J]. Mol Cell Biochem, 2004, 262(1-2): 41-49. DOI: 10.1023/b:mcbi.0000038214.52184.82.
[41]	CICOGNANI C, MALAVOLTI M, MORSELLI-LABATE AM, et al. Serum lipid and lipoprotein patterns in patients with liver cirrhosis and chronic active hepatitis[J]. Arch Intern Med, 1997, 157(7): 792-796.
[42]	BAUMBERGER C, ULEVITCH RJ, DAYER JM. Modulation of endotoxic activity of lipopolysaccharide by high-density lipoprotein[J]. Pathobiology, 1991, 59(6): 378-383. DOI: 10.1159/000163681.
[43]	GALBOIS A, THABUT D, TAZI KA, et al. Ex vivo effects of high-density lipoprotein exposure on the lipopolysaccharide-induced inflammatory response in patients with severe cirrhosis[J]. Hepatology, 2009, 49(1): 175-184. DOI: 10.1002/hep.22582.
[44]	GUO L, AI J, ZHENG Z, et al. High density lipoprotein protects against polymicrobe-induced sepsis in mice[J]. J Biol Chem, 2013, 288(25): 17947-17953. DOI: 10.1074/jbc.M112.442699.
[45]	ETOGO-ASSE FE, VINCENT RP, HUGHES SA, et al. High density lipoprotein in patients with liver failure; relation to sepsis, adrenal function and outcome of illness[J]. Liver Int, 2012, 32(1): 128-136. DOI: 10.1111/j.1478-3231.2011.02657.x.
[46]	MANKA P, OLLIGES V, BECHMANN LP, et al. Low levels of blood lipids are associated with etiology and lethal outcome in acute liver failure[J]. PLoS One, 2014, 9(7): e102351. DOI: 10.1371/journal.pone.0102351.
[47]	ŽALOUDKOVÁ L, TICHÁ A, NEKVINDOVÁ J, et al. Different forms of ursolic acid and their effect on liver regeneration[J]. Evid Based Complement Alternat Med, 2020, 2020: 4074068. DOI: 10.1155/2020/4074068.
[48]	XU L, KIM JK, BAI Q, et al. 5-cholesten-3β, 25-diol 3-sulfate decreases lipid accumulation in diet-induced nonalcoholic fatty liver disease mouse model[J]. Mol Pharmacol, 2013, 83(3): 648-658. DOI: 10.1124/mol.112.081505.
[49]	ZHANG X, BAI Q, XU L, et al. Cytosolic sulfotransferase 2B1b promotes hepatocyte proliferation gene expression in vivo and in vitro[J]. Am J Physiol Gastrointest Liver Physiol, 2012, 303(3): g344-g355. DOI: 10.1152/ajpgi.00403.2011.
[50]	XU L, SHEN S, MA Y, et al. 25-Hydroxycholesterol-3-sulfate attenuates inflammatory response via PPARγ signaling in human THP-1 macrophages[J]. Am J Physiol Endocrinol Metab, 2012, 302(7): e788-e799. DOI: 10.1152/ajpendo.00337.2011.
[51]	SALADIN R, FAJAS L, DANA S, et al. Differential regulation of peroxisome proliferator activated receptor gamma1 (PPARgamma1) and PPARgamma2 messenger RNA expression in the early stages of adipogenesis[J]. Cell Growth Differ, 1999, 10(1): 43-48.
[52]	NING Y, KIM JK, MIN HK, et al. Cholesterol metabolites alleviate injured liver function and decrease mortality in an LPS-induced mouse model[J]. Metabolism, 2017, 71: 83-93. DOI: 10.1016/j.metabol.2016.12.007.
[53]	INOUE M, SHINOHARA ML. The role of interferon-β in the treatment of multiple sclerosis and experimental autoimmune encephalomyelitis-in the perspective of inflammasomes[J]. Immunology, 2013, 139(1): 11-18. DOI: 10.1111/imm.12081.
[54]	RUSSELL DW. The enzymes, regulation, and genetics of bile acid synthesis[J]. Annu Rev Biochem, 2003, 72: 137-174. DOI: 10.1146/annurev.biochem.72.121801.161712.
[55]	REBOLDI A, DANG EV, MCDONALD JG, et al. Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon[J]. Science, 2014, 345(6197): 679-684. DOI: 10.1126/science.1254790.