洛伐他汀对高脂血症诱导大鼠肝损伤的改善作用及其机制

doi:10.13481/j.1671-587X.20250501

Abstract

Abstract:

Objective To investigate the protective effect of lovastatin on liver injury in the rats induced by hyperlipidemia， and to elucidate its possible mechanism. Methods Fifteen SD rats were randomly divided into control group， hyperlipidemia model group， and lovastatin group， with 5 rats in each group. The rats in control group were fed with standard diet， while the rats in hyperlipidemia model group and lovastatin group were fed high-fat diet for 12 weeks. Starting from the 8th week， the rats were administered treatments via gavage once a day for 4 weeks： the rats in lovastatin group received 2 mg?kg?1 lovastatin， while the rats in control group and hyperlipidemia model group received an equal volume of normal saline. The body weights of the rats in various groups were measured at weeks 1， 8， 9， 10， 11， and 12 after the experiment began； the histopathology of liver tissue of the rats in various groups was observed using HE staining； the serum levels of total cholesterol （TC）， triglycerides （TG）， high-density lipoprotein cholesterol （HDL-C）， low-density lipoprotein cholesterol （LDL-C）， malondialdehyde （MDA）， as well as the activities of superoxide dismutase （SOD）， glutathione peroxidase （GSH-Px）， aspartate aminotransferase （AST）， and alanine aminotransferase （ALT）， and the levels of interleukin-2 （IL-2）， interleukin-6 （IL-6）， interleukin-12 （IL-12）， and tumor necrosis factor-α （TNF-α） of the rats in various groups were detected using commercial kits； the composition of the gut microbiota of the rats in various groups was analyzed by 16S rRNA sequencing. Results Compared with control group， the body weight of the rats in hyperlipidemia model group was significantly increased from the 8th week of high-fat diet feeding （P<0.05 or P<0.01 or P<0.001）. Compared with hyperlipidemia model group， the body weight of the rats in lovastatin group was significantly decreased at weeks 11 and 12 （P<0.05）. Compared with control group， the livers of the rats in hyperlipidemia model group appeared rough， pale， enlarged， with blunt edges， and had a granular and greasy texture. Compared with hyperlipidemia model group， the livers of the rats in lovastatin group were light brownish-red， soft， with slightly blunt edges， reduced volume， and less granularity and greasiness. Compared with control group， the liver cells of the rats in hyperlipidemia model group were swollen and disorganized， with pyknotic nuclei， extensive inflammatory cell infiltration， and numerous vacuolar degenerations. Compared with hyperlipidemia model group， the rats in lovastatin group showed significantly reduced hepatocyte swelling and degeneration， more orderly and intact liver cell arrangement， decreased inflammatory cell infiltration， and reduced vacuolar degeneration. Compared with control group， the serum levels of TC， TG， and LDL-C of the rats in hyperlipidemia model group were significantly increased （P<0.05）， and the serum HDL-C level was decreased （P<0.05）. Compared with hyperlipidemia model group， the serum levels of TC， TG， and LDL-C of the rats in lovastation group were significantly decreased （P<0.05）， and the serum HDL-C level was increased （P<0.05）. Compared with control group， the serum MDA levels and the ALT and AST activities of the rats in hyperlipidemia model group were significantly increased （P<0.05）， and the SOD and GSH-Px activities were significantly decreased （P<0.05）. Compared with hyperlipidemia model group， the serum MDA levels and ALT and AST activities of the rats in lovastatin group were decreased （P<0.05）， and the SOD and GSH-Px activities were increased （P<0.05）. Compared with control group， the serum levels of IL-2， IL-6， IL-12， and TNF-α of the rats in hyperlipidemia model group were significantly increased （P<0.05）. Compared with hyperlipidemia model group， the serum levels of IL-2， IL-6， IL-12， and TNF-α of the rats in lovastatin group were significantly decreased （P<0.05）. Compared with control group， the ACE and Chao1 indexes of the rats in hyperlipidemia model group were significantly decreased （P<0.05）. Compared with hyperlipidemia model group， the ACE and Chao1 indexes of the rats in lovastatin group were significantly increased （P<0.05 or P<0.01）. Compared with control group， the relative abundances of Firmicutes and Proteobacteria of the rats in hyperlipidemia model group were significantly increased （P<0.001）， and the relative abundances of Bacteroidetes and Actinobacteria were decreased （P<0.001）. Compared with hyperlipidemia model group， the relative abundances of Firmicutes and Proteobacteria of the rats in lovastatin group were significantly decreased （P<0.05 or P<0.01）， while the relative abundances of Bacteroidetes and Actinobacteria showed no significant changes. Compared with control group， the relative abundance of Lactobacillus of the rats in hyperlipidemia model group was significantly decreased （P<0.001）， and the relative abundances of Bacteroides， Desulfovibrio， and Clostridium were significantly increased （P<0.01 or P<0.001）. Compared with hyperlipidemia model group， the relative abundance of Lactobacillus of the rats in lovastatin group showed no significant change but the relative abundances of Bacteroides， Desulfovibrio， and Clostridium were significantly decreased （P<0.05 or P<0.01 or P<0.001）. Conclusion Lovastatin ameliorates liver injury induced by hyperlipidemia， and the mechanism may be related to its ability to improve gut microbiota composition and inhibit oxidative stress and inflammatory damage.

Key words: Lovastatin, Hyperlipidemia, Liver injury, Anti-inflammatory, Intestinal microorganism, Oxidative stress

CLC Number:

R589.2

Yi ZHAO,Bing ZHOU,Huirui QIU,Xuan LI,Xiangli CUI. Improvement effect of lovastatin on hyperlipidemia-induced liver injury in rats and its mechanism[J].Journal of Jilin University(Medicine Edition), 2025, 51(5): 1155-1164.

Figures/Tables 9

Fig. 1

Fig. 2

Fig. 3

Tab.1

Tab.2

Tab.3

Tab.4

Tab.5

Tab.6

References 31

[1]	SONG P P， SHEN X C. Proteomic analysis of liver in diet-induced Hyperlipidemic mice under Fructus Rosa roxburghii action ［J］. J Proteomics， 2021， 230： 103982.
[2]	CHENG D Y， ZHANG M， ZHENG Y Z， et al. α-Ketoglutarate prevents hyperlipidemia-induced fatty liver mitochondrial dysfunction and oxidative stress by activating the AMPK-pgc-1α/Nrf2 pathway［J］. Redox Biol， 2024， 74： 103230.
[3]	YAO Y S， LI T D， ZENG Z H. Mechanisms underlying direct actions of hyperlipidemia on myocardium： an updated review ［J］. Lipids Health Dis， 2020， 19（1）： 23.
[4]	WANG S J， REN H H， ZHONG H Z， et al. Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients： a double blinded placebo controlled randomized study［J］. Gut Microbes， 2022， 14（1）： 2003176.
[5]	SVEGLIATI-BARONI G， SACCOMANNO S， RYCHLICKI C， et al. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis［J］. Liver Int， 2011， 31（9）： 1285-1297.
[6]	JAESCHKE H， RAMACHANDRAN A. Mitochondrial dysfunction in the pathophysiology of drug-induced liver injury： two decades of progress ［J］. Nature Revi Gastroenterol Hepatol， 2024， Advance online publication.
[7]	杨俊法，赵吉国，周英楠，等. 降血脂药物洛伐他汀技术研究进展［J］.中国高新科技， 2017， 1（5）： 47-49.
[8]	WEI L X， CHEN L， WANG W M， et al. Effects of lovastatin on hepatic expression of the low-density lipoprotein receptor in nephrotic rats［J］. Genet Mol Res， 2014， 13（1）： 938-944.
[9]	FENG W W， KUANG S Y， TU C， et al. Natural products berberine and curcumin exhibited better ameliorative effects on rats with non-alcohol fatty liver disease than lovastatin［J］. Biomed Pharmacother， 2018， 99： 325-333.
[10]	HENNINGER C， HUELSENBECK J， HUELSENBECK S， et al. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity［J］. Toxicol Appl Pharmacol， 2012， 261（1）：66-73.
[11]	DU TOIT A. Microbiome： Restoring healthy growth in infants［J］. Nat Rev Microbiol， 2016， 14（4）： 191.
[12]	BENDER E. Could a bacteria-stuffed pill cure autoimmune diseases？［J］. Nature， 2020， 577（7792）： S12-S13.
[13]	王政，申春一，黄建敏，等. 富含萝卜硫素的西兰花提取物对小鼠外周血CD8+T淋巴细胞活化及肠道菌群的影响［J］. 郑州大学学报（医学版）， 2024， 59（1）：35-39.
[14]	HE K， HU Y R， MA H， et al. Rhizoma Coptidis alkaloids alleviate hyperlipidemia in B6 mice by modulating gut microbiota and bile acid pathways［J］. Biochim Biophys Acta， 2016， 1862（9）： 1696-1709.
[15]	GARGARI G， DEON V， TAVERNITI V， et al. Evidence of dysbiosis in the intestinal microbial ecosystem of children and adolescents with primary hyperlipidemia and the potential role of regular hazelnut intake［J］. FEMS Microbiol Ecol， 2018， 94（5）.DOI： 10.1093/femsec/fiy045 . doi: 10.1093/femsec/fiy045
[16]	MORENO-INDIAS I， SÁNCHEZ-ALCOHOLADO L， PÉREZ-MARTÍNEZ P， et al. Red wine polyphenols modulate fecal microbiota and reduce markers of the metabolic syndrome in obese patients［J］. Food Funct， 2016， 7（4）： 1775-1787.
[17]	HE X Y， ZHENG N N， HE J J， et al. Gut microbiota modulation attenuated the hypolipidemic effect of simvastatin in high-fat/cholesterol-diet fed mice［J］. J Proteome Res， 2017， 16（5）：1900-1910.
[18]	ZHANG S R， LI H， YUAN L， et al. Molecular characterization of gut microbiota in high-lipid diet-induced hyperlipidemic rats treated with simvastatin［J］. Int J Mol Med， 2020， 45（5）：1601-1615.
[19]	吴小明. 洛伐他汀治疗高脂血症临床效果观察［J］. 右江民族医学院学报， 2001，23（4）： 540.
[20]	张丽芳. 甜菜碱调控肝细胞糖脂代谢的机制研究［D］. 南宁：广西大学， 2019.
[21]	MORENO F， MÉNDEZ L， RANER A， et al. Fish oil supplementation counteracts the effect of high-fat and high-sucrose diets on the carbonylated proteome in the rat cerebral cortex［J］. BiomedPharmacother，2023， 168： 115708.
[22]	韩玉龙. 斑马鱼氧化应激模型优化及药根碱抗LPS介导的氧化应激机制研究［D］. 重庆：西南大学， 2017.
[23]	EZHILARASAN D. Oxidative stress is bane in chronic liver diseases： Clinical and experimental perspective［J］. Arab J Gastroenterol， 2018， 19（2）： 56-64.
[24]	LI S， TAN H Y， WANG N， et al. The role of oxidative stress and antioxidants in liver diseases［J］. Int J Mol Sci， 2015， 16（11）： 26087-26124.
[25]	冯家新，齐涛，黄展森，等. 高脂饮食上调大鼠慢性炎症水平导致勃起功能障碍发生风险增高［J］. 中国男科学杂志， 2020， 34（1）： 12-19.
[26]	RIVA A， BORGO F， LASSANDRO C， et al. Pediatric obesity is associated with an altered gut microbiota and discordant shifts in Firmicutes populations［J］. Environ Microbiol， 2017， 19（1）： 95-105.
[27]	KIM D H， KIM S， LEE J H， et al. Lactobacillus acidophilus suppresses intestinal inflammation by inhibiting endoplasmic reticulum stress［J］. J Gastroenterol and Hepatol， 2019， 34（1）： 178-185.
[28]	孙钰薇，张诗瑶，刘志佳，等. 发酵食品中乳酸菌的健康功效研究进展［J］. 食品与发酵工业， 2021， 47（23）： 280-287.
[29]	朱宏斌，沈伟，王竞，等. 宏基因组研究高脂饮食诱导小鼠的肥胖易感性与肠道菌群的关系［J］. 第三军医大学学报， 2017， 39（8）： 773-780.
[30]	PETERSEN C， BELL R， KLAG K A， et al. T cell-mediated regulation of the microbiota protects against obesity［J］. Science， 2019， 365（6451）： eaat9351.
[31]	LUO Y Q， JIN Y Y， WANG H D， et al. Effects of Clostridium tyrobutyricum on lipid metabolism， intestinal barrier function， and gut microbiota in obese mice induced by high-fat diet［J］. Nutrients， 2024， 16（4）： 493.

Group	TC	TG	HDL-C	LDL-C
Control	2.87±0.06	0.38±0.01	1.22±0.10	0.54±0.11
Hyperlipidemia model	3.61±0.07^*	0.53±0.01^*	0.77±0.05^*	1.37±0.09^*
Lovastain	3.04±0.03^△	0.35±0.01^△	1.19±0.04^△	0.61±0.11^△

Group	ALT [λ_B/(U·L^-1)]	AST [λ_B/(U·L^-1)]	SOD [λ_B/(U·mL^-1)]	GSH-Px [λ_B/(U·mg^-1）]	MDA [（c_B/(μmol·L^-1）]
Control	30.42±5.19	45.08±6.18	239.38±9.09	301.40±16.27	6.41±1.92
Hyperlipidemia model	59.37±7.87^*	86.35±8.29^*	149.64±10.31^*	239.40±13.07^*	16.18±2.32^*
Lovastain	39.82±3.70^△	48.02±5.92^△	226.41±9.99^△	293.42±8.81^△	8.06±1.31^△

Group	IL-2	IL-6	IL-12	TNF-α
Control	305.68±9.18	24.57±1.61	14.25±1.07	100.82±5.58
Hyperlipidemia model	368.82±8.08^*	33.82±2.24^*	18.58±1.04^*	133.79±7.01^*
Lovastain	327.21±12.07^△	28.47±1.28^△	15.62±1.49^△	104.67±4.10^△

Group	ACE index	Chao1 index
Control	563.70±66.62	561.85±66.85
Hyperlipidemia model	464.99±53.37^*	466.04±45.87^*
Lovastain	499.86±65.97^△△	502.54±29.97^△

Group	Firmicutes	Bacteroidetes	Actinobacteria	Proteobacteria
Control	60.07±2.94	34.53±3.26	2.21±0.25	1.63±0.32
Hyperlipidemia model	69.65±2.64^*	22.86±1.75^*	0.50±0.32^*	4.07±0.51^*
Lovastain	63.48±3.73^△	22.11±2.66	0.73±0.30	2.65±0.39^△△

Improvement effect of lovastatin on hyperlipidemia-induced liver injury in rats and its mechanism

RichHTML

PDF (PC)

Like

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 9

References 31

Related Articles 15

Metrics

Comments

Recommended 0

Group	Bacteroides	Lactobacillus	Desulfovibrio	Clostridium
Control	6.85±1.37	7.93±1.09	2.19±0.45	3.03±0.10
Hyperlipidemia model	15.08±0.21^**	1.13±0.39^**	4.76±1.12^*	6.44±1.05^**
Lovastain	12.88±2.11^△	1.65±0.57	2.22±0.38^△△	1.89±0.45^△△△

[1]	Nan LU,Mingxin DONG,Lei YU,Chengbiao SUN,Yan WANG,Na XU,Wensen LIU,Shumin GE. Transcriptome sequencing-based expression profiling of oxidative stress-related genes and circRNAs in ricin toxin-induced macrophage pyroptosis [J]. Journal of Jilin University(Medicine Edition), 2025, 51(4): 1007-1018.
[2]	Kaiqi NIU,He CHANG,Guangfu LYU,Pengyu ZHENG,Xueting CHI,Jia ZHOU,Yuchen WANG,Xiaowei HUANG. Inhibitory effect of astragaloside Ⅳ on cisplatin-induced liver injury in mice and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2025, 51(2): 370-377.
[3]	Yue WANG,Ning MA,Jiajun LU,Chengyao WANG,Linyu CHEN,Yuchen REN,Jingwu LI,Hong SUN. Protective effect of novel composite hydrogels on H₂O₂-induced oxidative stress injury in cardiomyocytes [J]. Journal of Jilin University(Medicine Edition), 2025, 51(2): 352-359.
[4]	Chaohe ZHANG,Xinwei ZHANG,Xiangfeng WANG. Protective effect of Pien-Tze-Huang on acetaminophen-induced liver injury and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2025, 51(1): 105-114.
[5]	Yanyan BAI,Yutong ZHOU,Haijuan SUI,Zhuo LIU. Improvement effect of asiatic acid on damage of lipopolysaccharide-induced hippocampum neuron in rats through Nrf2/HO-1 signaling pathway [J]. Journal of Jilin University(Medicine Edition), 2025, 51(1): 85-95.
[6]	Siqi LI,Guangdao CHEN,Qiyi ZENG. Improvement effect of chrysophanol on hydrogen peroxide-induced apoptosis of EA. hy926 cells and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2024, 50(6): 1512-1518.
[7]	Meng QU,Rui HUANG,Xinda JU,Yuxin LIU,Jichen XIA,Jiaxin HUANG,Chunyan YU,Zhiheng DONG. Ameliorative effect of ginsenoside Rh1 on kidney injury in diabetic mice through activation of Nrf2/HO-1 signaling pathway [J]. Journal of Jilin University(Medicine Edition), 2024, 50(6): 1565-1571.
[8]	Yi LONG,Ziyi YOU,Xiuying TAN,Rou ZHANG,Yuhan ZHANG,Lina YANG. Protective effect of sodium butyrate on acute liver injury in mice induced by lipopolysaccharide combined with D-galactosamine and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2024, 50(6): 1614-1620.
[9]	Fengmei XIONG,Yuxiang CAI,Zhuo LIU,Na SUN,Yang LI. Alleviatory effect of curcumin on cardiomyocyte toxicity induced by doxorubicin by regulating SIRT3/SOD2 signaling pathway [J]. Journal of Jilin University(Medicine Edition), 2024, 50(5): 1339-1347.
[10]	Haoyu WANG,Yuqi WANG,Bingqian WANG,Jinhan NIE,Jiaqing YAN,Min HU. Inhibitory effect of mesalazine on pro-inflammatory factors and peroxides in RAW264.7 cells and its therapeutic effect on periodontitis model rats [J]. Journal of Jilin University(Medicine Edition), 2024, 50(5): 1250-1258.
[11]	Xueting CHI,Fangyuan CHEN,Zifeng PI,Guangfu LYU,Yuchen WANG,Yinqing LI,Xiaowei HUANG,Zhe LIN. Improvement effect of velvet antler polypeptide on postmenopausal osteoporosis in rats and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2024, 50(4): 963-969.
[12]	Jing TANG,Huan LI,Shuo ZHANG,Ligang JING. Analysis on association between serum homocysteine and inflammatory response and oxidative stress in patients with acute ischemic stroke [J]. Journal of Jilin University(Medicine Edition), 2024, 50(3): 786-790.
[13]	Jianan HAN,Zhuorui LIU,Peiyong ZENG,Shuang JIANG,Hongyu LI. Anti-fatigue effect of Wujia Shengmai Yin in mice and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2024, 50(3): 689-696.
[14]	Yingxin RUAN,Junya JIA,Zhanfei WU,Wenya SHANG,Pengyu ZHANG. Effect of NLRP3 inflammatome in renal interstitial fibrosis induced by unilateral ureteral obstruction in rats and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2024, 50(3): 587-595.
[15]	Yuexin LIU,Yongwei LAI,Yanchun WANG,Bo XU,Qian LU,Ying AN,Kuang REN,Hongyan FAN. Improvement effect of total flavonoids of Sophora flavescens on oxidative stress induced by lead acetate in leydig cells in mice and its in effect on Keap1/Nrf2 signaling pathway [J]. Journal of Jilin University(Medicine Edition), 2024, 50(2): 320-325.