[1]谢雨虹,唐波,范崇熙,等.α-酮戊二酸对小鼠胆汁淤积性肝损伤的缓解作用[J].陆军军医大学学报(原第三军医大学学报),2022,44(13):1322-1329.
 XIE Yuhong,TANG Bo,et al.Alpha-ketoglutarate alleviates cholestatic liver injury in mice[J].J Amry Med Univ (J Third Mil Med Univ),2022,44(13):1322-1329.
点击复制

α-酮戊二酸对小鼠胆汁淤积性肝损伤的缓解作用(/HTML )
分享到:

陆军军医大学学报(原第三军医大学学报)[ISSN:1000-5404/CN:51-1095/R]

卷:
44卷
期数:
2022年第13期
页码:
1322-1329
栏目:
基础医学
出版日期:
2022-07-15

文章信息/Info

Title:
Alpha-ketoglutarate alleviates cholestatic liver injury in mice
作者:
谢雨虹唐波范崇熙李白容孙涛宁守斌
安徽医科大学空军临床学院;空军特色医学中心消化内科;陆军军医大学(第三军医大学)第二附属医院消化内科
Author(s):
XIE Yuhong1 2 TANG Bo3 FAN Chongxi2 LI Bairong2 SUN Tao2 NING Shoubin1

21Air Force Clinical College, Anhui Medical University, Hefei, Anhui Province, 230032; 2Department of Gastroenterology, Air Force Medical Center of PLA, Beijing, 100142; 3Department of Gastroenterology, Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, 400037, China

关键词:
&alpha-酮戊二酸胆汁淤积性肝损伤炎症反应细胞凋亡小鼠
Keywords:
alpha-ketoglutarate cholestatic liver injury inflammatory response apoptosis mice
分类号:
R575.05; R963; R977.4
文献标志码:
A
摘要:

目的探讨α-酮戊二酸(alpha-ketoglutarate,AKG)对小鼠胆管结扎(bile duct ligation,BDL)所致胆汁淤积性肝损伤的缓解作用及其机制。方法32只C57BL/6雄性小鼠按随机数字表法分为4组(每组8只):假手术(Sham)组、假手术+AKG(Sham+AKG)组、胆管结扎(BDL)组、胆管结扎+AKG(BDL+AKG)组,所有小鼠均于术后7 d取材。检测血清ALT、AST、TBIL、TBA、ALP水平,HE染色评估各组肝组织损伤程度,免疫组化检测肝组织F4/80、MPO的表达水平,qRT-PCR检测肝组织促炎细胞因子mRNA表达水平,TUNEL染色观察肝细胞凋亡。结果与BDL组相比,BDL+AKG组小鼠血清ALT、AST、TBIL、TBA、ALP水平均明显降低(P<0.05),肝组织损伤程度明显减轻(P<0.05),F4/80、MPO表达减少(P<0.05),肝组织促炎细胞因子mRNA表达明显减少(P<0.05),TUNEL阳性肝细胞数目明显减少(P<0.05)。结论α-酮戊二酸对小鼠胆管结扎所致胆汁淤积性肝损伤具有缓解作用,其机制可能与其抑制炎症反应和减少肝细胞凋亡有关。

Abstract:

Objective  To investigate the alleviating effects of alpha-ketoglutarate (AKG) on bile duct ligation (BDL)-induced cholestatic liver injury in mice and its possible mechanism. MethodsThirty-two C57BL/6 male mice were randomly assigned to 4 groups (n=8): sham operation group (Sham), sham operation+AKG group (Sham+AKG), BDL group and BDL+AKG group. Liver and blood samples were collected from all groups in 7 d after operation, and the serum levels of ALT, AST, TBIL, TBA and ALP were measured. HE staining and immunohistochemistry were used to detect the severity of liver injury and the expression of F4/80 and myeloperoxidase (MPO) in each group, respectively. qRT-PCR was adopted to determine the mRNA expression of pro-inflammatory cytokines. Hepatocyte apoptosis was evaluated by TUNEL assay. ResultsAs compared with the BDL group, the BDL+AKG group showed significantly lower concentrations of ALT, AST, TBIL, TBA and ALP (P<0.05), obviously relieved liver histologic injury (P<0.05), reduced expression levels of F4/80 and MPO as well as pro-inflammatory cytokines (P<0.05), and decreased number of TUNEL positive hepatocytes (P<0.05). ConclusionAKG alleviates hepatic injury in BDL-induced cholestasis model mice, and its mechanism is possibly related to the inhibition of inflammatory response and hepatic cell apoptosis.

参考文献/References:

[1]WILLIAMS R. Global challenges in liver disease[J]. Hepatology, 2006, 44(3): 521-526. DOI:10.1002/hep.21347.
[2]DE OLIVEIRA COSTA E L, DE AZEVEDO G M Jr, PETROIANU A. Morphological changes in the liver and kidneys of rats subjected to terminal ileum exclusion during obstructive cholestasis[J]. Acta Cir Bras, 2014, 29(6): 353-358. DOI:10.1590/s0102-86502014000600001.
[3]LIN T K, HUANG L T, HUANG Y H, et al. The effect of the red wine polyphenol resveratrol on a rat model of biliary obstructed cholestasis: involvement of anti-apoptotic signalling, mitochondrial biogenesis and the induction of autophagy[J]. Apoptosis, 2012, 17(8): 871-879. DOI:10.1007/s10495-012-0732-3.
[4]BEUERS U, TRAUNER M, JANSEN P, et al. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond[J]. J Hepatol, 2015, 62(1 Suppl): S25-S37. DOI:10.1016/j.jhep.2015.02.023.
[5]ALABRABA E, NIGHTINGALE P, GUNSON B, et al. A re-evaluation of the risk factors for the recurrence of primary sclerosing cholangitis in liver allografts[J]. Liver Transpl, 2009, 15(3): 330-340. DOI:10.1002/lt.21679.
[6]MEHRA L, RAWAT H, JAIMINI A, et al. Alpha-ketoglutarate mediated hepatoprotection against alcohol induced toxicity: in vivo functional observation studies in Sprague Dawley rats using gamma scintigraphy[J]. Drug Chem Toxicol, 2020, 43(5): 546-551. DOI:10.1080/01480545.2018.1559183.
[7]BAYLIAK M M, LUSHCHAK V I. Pleiotropic effects of alpha-ketoglutarate as a potential anti-ageing agent[J]. Ageing Res Rev, 2021, 66: 101237. DOI:10.1016/j.arr.2020.101237.
[8]NIEMIEC T, SIKORSKA J, HARRISON A, et al. Alpha-ketoglutarate stabilizes redox homeostasis and improves arterial elasticity in aged mice[J]. J Physiol Pharmacol, 2011, 62(1): 37-43.
[9]KOVALENKO T N, USHAKOVA G A, OSADCHENKO I, et al. The neuroprotective effect of 2-oxoglutarate in the experimental ischemia of hippocampus[J]. J Physiol Pharmacol, 2011, 62(2): 239-246.
[10]DAKSHAYANI K B, SUBRAMANIAN P, MANIVASAGAM T, et al. Metabolic normalization of alpha-ketoglutarate against N-nitrosodiethylamine-induced hepatocarcinogenesis in rats[J]. Fundam Clin Pharmacol, 2006, 20(5): 477-480. DOI:10.1111/j.1472-8206.2006.00422.x.
[11]LONG L, HALLIWELL B. Artefacts in cell culture: α-ketoglutarate can scavenge hydrogen peroxide generated by ascorbate and epigallocatechin gallate in cell culture media[J]. Biochem Biophys Res Commun, 2011, 406(1): 20-24. DOI:10.1016/j.bbrc.2011.01.091.
[12]ZHAO J J, PENG L, CUI R B, et al. Dimethyl α-ketoglutarate reduces CCl4-induced liver fibrosis through inhibition of autophagy in hepatic stellate cells[J]. Biochem Biophys Res Commun, 2016, 481(1/2): 90-96. DOI:10.1016/j.bbrc.2016.11.010.
[13]TULSAWANI R K, DEBNATH M, PANT S C, et al. Effect of sub-acute oral cyanide administration in rats: protective efficacy of alpha-ketoglutarate and sodium thiosulfate[J]. Chem Biol Interact, 2005, 156(1): 1-12. DOI:10.1016/j.cbi.2005.05.001.
[14]WANG L, HOU Y Q, YI D, et al. Dietary supplementation with glutamate precursor α-ketoglutarate attenuates lipopolysaccharide-induced liver injury in young pigs[J]. Amino Acids, 2015, 47(7): 1309-1318. DOI:10.1007/s00726-015-1966-5.
[15]GYANWALI B, LIM Z X, SOH J, et al. Alpha-ketoglutarate dietary supplementation to improve health in humans[J]. Trends Endocrinol Metab, 2022, 33(2): 136-146. DOI:10.1016/j.tem.2021.11.003.
[16]PERNA S, ALALWAN T A, ALAALI Z, et al. The role of glutamine in the complex interaction between gut microbiota and health: a narrative review[J]. Int J Mol Sci, 2019, 20(20): 5232. DOI:10.3390/ijms20205232.
[17]ASADI SHAHMIRZADI A, EDGAR D, LIAO C Y, et al. Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice[J]. Cell Metab, 2020, 32(3): 447-456.e6. DOI:10.1016/j.cmet.2020.08.004.
[18]SHARAWY M H, ABDEL-RAHMAN N, MEGAHED N, et al. Paclitaxel alleviates liver fibrosis induced by bile duct ligation in rats: role of TGF-β1, IL-10 and c-Myc[J]. Life Sci, 2018, 211: 245-251. DOI:10.1016/j.lfs.2018.09.037.
[19]GEORGIEV P, JOCHUM W, HEINRICH S, et al. Characterization of time-related changes after experimental bile duct ligation[J]. Br J Surg, 2008, 95(5): 646-656. DOI:10.1002/bjs.6050.
[20]HEINRICH S, GEORGIEV P, WEBER A, et al. Partial bile duct ligation in mice: a novel model of acute cholestasis[J]. Surgery, 2011, 149(3): 445-451. DOI:10.1016/j.surg.2010.07.046.
[21]ABSHAGEN K, KNIG M, HOPPE A, et al. Pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice[J]. BMC Syst Biol, 2015, 9: 83. DOI:10.1186/s12918-015-0229-0.
[22]CAI S Y, OUYANG X S, CHEN Y L, et al. Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response[J]. JCI Insight, 2017, 2(5): e90780. DOI:10.1172/jci.insight.90780.
[23]SEN A L, OZKAN S, RECEBOVA K, et al. Effects of myrtus communis extract treatment in bile duct ligated rats[J]. J Surg Res, 2016, 205(2): 359-367. DOI:10.1016/j.jss.2016.06.094.
[24]WU J S, LI Y F, LI Y Y, et al. Huangqi Decoction alleviates alpha-naphthylisothiocyanate induced intrahepatic cholestasis by reversing disordered bile acid and glutathione homeostasis in mice[J]. Front Pharmacol, 2017, 8: 938. DOI:10.3389/fphar.2017.00938.
[25]WU J S, FANG S, LI W K, et al. Metabolomics research on the hepatoprotective effect of cultured bear bile powder in α-naphthylisothiocyanate-induced cholestatic mice[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2020, 1153: 122269. DOI:10.1016/j.jchromb.2020.122269.
[26]GUICCIARDI M E, MALHI H, MOTT J L, et al. Apoptosis and necrosis in the liver[J]. Compr Physiol, 2013, 3(2): 977-1010. DOI:10.1002/cphy.c120020.
[27]OGAWA A, TAGAWA T, NISHIMURA H, et al. Toll-like receptors 2 and 4 are differentially involved in Fas dependent apoptosis in Peyer’s patch and the liver at an early stage after bile duct ligation in mice[J]. Gut, 2006, 55(1): 105-113. DOI:10.1136/gut.2005.065318.
[28]ZHOU H Q, LIU W, WANG J, et al. Paeoniflorin attenuates ANIT-induced cholestasis by inhibiting apoptosis in vivo via mitochondria-dependent pathway[J]. Biomed Pharmacother, 2017, 89: 696-704. DOI:10.1016/j.biopha.2017.02.084.
[29]HAN Y, LUO H N, WANG H, et al. SIRT1 induces resistance to apoptosis in human granulosa cells by activating the ERK pathway and inhibiting NF-κB signaling with anti-inflammatory functions[J]. Apoptosis, 2017, 22(10): 1260-1272. DOI:10.1007/s10495-017-1386-y.

更新日期/Last Update: 2022-07-05