利福昔明对代谢功能障碍相关脂肪性肝病继发肝细胞癌动物模型表观遗传学和自噬的影响

Rifaximin on epigenetics and autophagy in animal model of hepatocellular carcinoma secondary to metabolic-dysfunction associated steatotic liver disease.

作者信息

Michalczuk Matheus Truccolo, Longo Larisse, Keingeski Melina Belén, Basso Bruno de Souza, Guerreiro Gabriel Tayguara Silveira, Ferrari Jessica T, Vargas José Eduardo, Oliveira Cláudia P, Uribe-Cruz Carolina, Cerski Carlos Thadeu Schmidt, Filippi-Chiela Eduardo, Álvares-da-Silva Mário Reis

机构信息

Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil.

Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil.

出版信息

World J Hepatol. 2024 Jan 27;16(1):75-90. doi: 10.4254/wjh.v16.i1.75.

DOI:10.4254/wjh.v16.i1.75

PMID:38313241

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10835481/

Abstract

BACKGROUND

Prevalence of hepatocellular carcinoma (HCC) is increasing, especially in patients with metabolic dysfunction-associated steatotic liver disease (MASLD).

AIM

To investigate rifaximin (RIF) effects on epigenetic/autophagy markers in animals.

METHODS

Adult Sprague-Dawley rats were randomly assigned ( = 8, each) and treated from 5-16 wk: Control [standard diet, water plus gavage with vehicle (Veh)], HCC [high-fat choline deficient diet (HFCD), diethylnitrosamine (DEN) in drinking water and Veh gavage], and RIF [HFCD, DEN and RIF (50 mg/kg/d) gavage]. Gene expression of epigenetic/autophagy markers and circulating miRNAs were obtained.

RESULTS

All HCC and RIF animals developed metabolic-dysfunction associated steatohepatitis fibrosis, and cirrhosis, but three RIF-group did not develop HCC. Comparing animals who developed HCC with those who did not, miR-122, miR-34a, tubulin alpha-1c , metalloproteinases2 , and metalloproteinases9 were significantly higher in the HCC-group. The opposite occurred with , coactivator associated arginine methyltransferase-1 (), enhancer of zeste homolog-2 (), autophagy-related factor LC3A/B , and sequestosome-1 (SQSTM1protein Comparing with controls, , and were lower in HCC and RIF-groups ( < 0.05). was lower in HCC compared to RIF ( < 0.05). Hepatic expression of was higher in HCC in relation to the control; the opposite was observed for ( < 0.05). Expression of p62/SQSTM1 protein was lower in the RIF-group compared to the control ( = 0.024). There was no difference among groups for , Aldolase-B, alpha-fetoprotein, and ( > 0.05). miR-122 was higher in HCC, and miR-34a in RIF compared to controls ( < 0.05). miR-26b was lower in HCC compared to RIF, and the inverse was observed for miR-224 ( < 0.05). There was no difference among groups regarding miR-33a, miR-143, miR-155, miR-375 and miR-21 ( > 0.05).

CONCLUSION

RIF might have a possible beneficial effect on preventing/delaying liver carcinogenesis through epigenetic modulation in a rat model of MASLD-HCC.

摘要

背景

肝细胞癌（HCC）的患病率正在上升，尤其是在代谢功能障碍相关脂肪性肝病（MASLD）患者中。

目的

研究利福昔明（RIF）对动物表观遗传/自噬标志物的影响。

方法

将成年Sprague-Dawley大鼠随机分组（每组n = 8），并在5至16周进行治疗：对照组[标准饮食，饮用水加赋形剂（Veh）灌胃]，HCC组[高脂胆碱缺乏饮食（HFCD），饮用水中添加二乙基亚硝胺（DEN）并进行Veh灌胃]，以及RIF组[HFCD，DEN和RIF（50 mg/kg/d）灌胃]。获取表观遗传/自噬标志物的基因表达和循环miRNA。

结果

所有HCC组和RIF组动物均发生了代谢功能障碍相关脂肪性肝炎纤维化和肝硬化，但RIF组中有3只未发生HCC。将发生HCC的动物与未发生HCC的动物进行比较，HCC组中的miR-122、miR-34a、微管蛋白α-1c、金属蛋白酶2和金属蛋白酶9显著更高。而在自噬相关因子LC3A/B、聚集体蛋白1（SQSTM1蛋白）方面则相反。与对照组相比，HCC组和RIF组中的自噬相关因子、共激活因子相关精氨酸甲基转移酶-1（CARM1）、zeste同源物2（EZH2）较低（P < 0.05）。与RIF组相比，HCC组中的自噬相关因子更低（P < 0.05）。与对照组相比，HCC组中自噬相关因子的肝脏表达更高；而对于EZH2则观察到相反情况（P < 0.05）。与对照组相比，RIF组中p62/SQSTM1蛋白的表达更低（P = 0.024）。各组之间在自噬相关因子、醛缩酶-B、甲胎蛋白和方面无差异（P > 0.05）。与对照组相比，HCC组中的miR-122更高，RIF组中的miR-34a更高（P < 0.05）。与RIF组相比，HCC组中的miR-26b更低，而miR-224则相反（P < 0.05）。各组之间在miR-33a、miR-143、miR-155、miR-375和miR-21方面无差异（P > 0.05）。