Effect of obeticholic acid on glucolipid homeostasis in high-fat fed C57BL/6J mice

doi:10.16352/j.issn.1001-6325.2023.05.0755

Abstract

Abstract: Objective To investigate the effects of obeticholic acid (OCA) on glucolipid metabolism in high-fat fed C57BL/6J mice. Methods After 12 weeks of high-fat diet (HFD) feeding, C57BL/6J mice were randomly divided into two groups: model group (model) and OCA intervention group (10 mg/kg, gavage for six weeks), with 10 in each. The C57BL/6J mice were fed with normal diet for 12 weeks as the control group. The model group and the control group were given 0.5% sodium carboxymethyl cellulose (CMC-Na) by gavage. During the experiment, oral glucose and insulin tolerance tests were conducted. At the end of the experiment, the liver function related indicators were measured in serum, and the liver weight was recorded. The lipid-related indicators were measured in liver, and HE staining microscopy was performed. RT-qPCR was used to detected the expression of genes related to lipid metabolism in liver. Results After glucose loading and insulin injection, the blood glucose at each time point and area under curve (AUC) of the model group were significantly higher than those of the control group (P＜0.01). Abnormal glucose tolerance in OCA intervention group was reversed(P＜0.05) and the insulin sensitivity of the model group mice was improved(P＜0.05). The serum level of triglyceride (TG), total cholesterol (TC), free fatty acid (FFA), low density lipoprotein total cholesterol (LDL-C), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the model group was all significantly higher than those in the control group (P＜0.01), and HDL-C level was evidently lower than that in the control group (P＜0.01). The OCA intervention group could significantly reduce the serum levels of TG, TC, FFA, LDL-C, ALT, AST (P＜0.01) and increase the serum HDL-C content in the model group (P＜0.01). The contents of TG, TC, and FFA in the liver of the model group were significantly higher than those in the control group (P＜0.01), and OCA intervention group did alleviate the hepatic steatosis in the model group (P＜0.05). Compared with the control group, the expression of FXR/SREBP pathway related genes in model group was abnormal (P＜0.01), and OCA intervention reversed abnormal expression of FXR/SREBP pathway related genes in model group (P＜0.05). Conclusions OCA may improve the lipid metabolism disorder in the liver of HFD mice by regulating the FXR/SREBP pathway, thus improve the impaired glucose tolerance and insulin resistance in HFD mice.

Key words: obeticholic acid, high-fat diet, C57BL/6J mice, glycolipid metabolism, hepatic steatosis

CLC Number:

R965

WANG Xing, GUO Nan. Effect of obeticholic acid on glucolipid homeostasis in high-fat fed C57BL/6J mice[J]. Basic & Clinical Medicine, 2023, 43(5): 755-761.

References

[1]Sanyal AJ. Past, present and future perspectives in nonalcoholic fatty liver disease[J]. Nat Rev Gastroenterol Hepatol, 2019, 16: 377-386.
[2]Ratziu V. Obeticholic acid for the treatment of nonal-coholic steatohepatitis[J]. Clin Liver Dis (Hoboken), 2021, 17: 398-400.
[3]邢苗苗,张晓燕,管又飞. 奥贝胆酸的研究进展[J]. 基础医学与临床, 2019, 39: 1494-1498.
[4]Petrescu AD, Demorrow S. Farnesoid X receptor as target for therapies to treat cholestasis-induced liver injury[J]. Cells, 2021, 10: 1846. doi: 10.3390/cells10081846.
[5]Zhu N, Huang S, Zhang Q, et al. Metabolomic study of high-fat diet-induced obese (DIO) and DIO plus CCl(4)-induced NASH mice and the effect of obeticholic acid[J]. Metabolites, 2021, 11: 374. doi: 10.3390/metabo11060374.
[6]Neuschwander-tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial[J]. Lancet, 2015, 385: 956-965.
[7]Younossi ZM, Stepanova M, Nader F, et al. Obeticholic acid impact on quality of life in patients with nonalcoholic steatohepatitis: REGENERATE 18-month interim analysis[J]. Clin Gastroenterol Hepatol, 2022,20: 2050-2058.
[8]曹慧, 环奕, 李彩娜,等. 奥贝胆酸对2型糖尿病KKAy小鼠的糖脂稳态影响[J]. 中国新药杂志, 2021, 30: 352-356.
[9]Ali AH, Carey EJ, Lindor KD. Recent advances in the development of farnesoid X receptor agonists[J]. Ann Transl Med, 2015, 3: 5. doi: 10.3978/j.issn.2305-5839.2014.12.06.
[10]Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease[J]. Gastroenterology, 2013, 145: 574-582.
[11]史冬雪, 原佳琪, 丁宝锋,等. 非酒精性脂肪肝病模型小鼠的肝脏病理变化及肝细胞获取方法[J]. 基础医学与临床, 2022, 42: 890-895.
[12]Sun L, Cai J, Gonzalez FJ. The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer[J]. Nat Rev Gastroenterol Hepatol, 2021, 18: 335-347.
[13]Ju UI, Jeong DW, Seo J, et al. Neddylation of sterol regulatory element-binding protein 1c is a potential therapeutic target for nonalcoholic fatty liver treatment[J]. Cell Death Dis, 2020, 11: 283. doi: 10.1038/s41419-020-2472-6.
[14]Yan CX, Zhang YR, Zhang XX, et al. Curcumin regulates endogenous and exogenous metabolism via Nrf2-FXR-LXR pathway in NAFLD mice[J]. Biomed Pharmacother, 2018, 105: 274-281.