Berberine ameliorates nonalcoholic fatty liver disease by decreasing the liver lipid content via reversing the abnormal expression of MTTP and LDLR

Chen,Ping; Li,Yusheng; Xiao,Li

doi:10.3892/etm.2021.10543

Berberine ameliorates nonalcoholic fatty liver disease by decreasing the liver lipid content via reversing the abnormal expression of MTTP and LDLR

Authors:
- Ping Chen
- Yusheng Li
- Li Xiao
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Affiliations: Department of Pharmacy, Affiliated Hospital of Shandong Medical College, Linyi, Shandong 276000, P.R. China, Department of Pharmacy, Linyi Maternal and Child Health Care Hospital, Linyi, Shandong 276000, P.R. China
Published online on: August 3, 2021 https://doi.org/10.3892/etm.2021.10543
Article Number: 1109
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The global incidence of nonalcoholic fatty liver disease (NAFLD) is increasing. The present study explored the effect and mechanism of berberine (BBR) on NAFLD in rats. Thirty‑five Sprague‑Dawley rats were randomly divided into the control and NAFLD groups, which were fed a normal diet or high‑fat diet, respectively, for 8 weeks. Hematoxylin and eosin staining was performed on liver tissues and establishment of the NAFLD model was confirmed by microscopy. NAFLD rats were subsequently randomly subdivided and treated with saline or BBR for 8 weeks. The liver wet weight of rats in each group was measured, the liver tissue structure was observed by microscopy, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), fasting blood glucose (FBG), low‑density lipoprotein (LDL) and high‑density lipoprotein (HDL) levels were detected using a semi‑automatic biochemical detector. Reverse transcription‑quantitative PCR and western blotting were performed to determine the mRNA and protein expression levels of microsomal triglyceride transfer protein (MTTP), apolipoprotein B and low‑density lipoprotein receptor (LDLR). Compared with the control group, the liver wet weight of the NAFLD rats was higher; the liver showed obvious fatty degeneration and liver TG levels increased significantly, as did serum levels of ALT, AST, TC, TG, FBG, HDL and LDL, while expression of MTTP and LDLR significantly decreased. Compared with the saline‑treated NAFLD rats, the BBR‑treated rats had reduced liver wet weight, improved liver steatosis and a significant decrease in liver TG levels, while ALT, AST, TC, TG, and LDL serum levels significantly decreased and MTTP levels were significantly upregulated. In conclusion, BBR treatment ameliorated the fatty liver induced by a high‑fat diet in rats. Furthermore, BBR reversed the abnormal expression of MTTP and LDLR in rats with high‑fat diet induced‑NAFLD. The present findings suggest that fatty liver could be improved by BBR administration, via reversing the abnormal expression of MTTP and LDLR and inhibiting lipid synthesis.

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1	Perumpail BJ, Khan MA, Yoo ER, Cholankeril G, Kim D and Ahmed A: Clinical epidemiology and disease burden of nonalcoholic fatty liver disease. World J Gastroenterol. 23:8263–8276. 2017.PubMed/NCBI View Article : Google Scholar
2	Forbes S, Taylor-Robinson SD, Patel N, Allan P, Walker BR and Johnston DG: Increased prevalence of non-alcoholic fatty liver disease in European women with a history of gestational diabetes. Diabetologia. 54:641–647. 2011.PubMed/NCBI View Article : Google Scholar
3	Chang Y, Jung HS, Yun KE, Cho J, Cho YK and Ryu S: Cohort study of non-alcoholic fatty liver disease, NAFLD fibrosis score, and the risk of incident diabetes in a Korean population. Am J Gastroenterol. 108:1861–1868. 2013.PubMed/NCBI View Article : Google Scholar
4	Yamada T, Fukatsu M, Suzuki S, Wada T, Yoshida T and Joh T: Fatty liver predicts impaired fasting glucose and type 2 diabetes mellitus in Japanese undergoing a health checkup. J Gastroenterol Hepatol. 25:352–356. 2010.PubMed/NCBI View Article : Google Scholar
5	Cohen JC, Horton JD and Hobbs HH: Human fatty liver disease: Old questions and new insights. Science. 332:1519–1523. 2011.PubMed/NCBI View Article : Google Scholar
6	Fabbrini E, Sullivan S and Klein S: Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic, and clinical implications. Hepatology. 51:679–689. 2010.PubMed/NCBI View Article : Google Scholar
7	Sreenivasa Baba C, Alexander G, Kalyani B, Pandey R, Rastogi S, Pandey A and Choudhuri G: Effect of exercise and dietary modification on serum aminotransferase levels in patients with nonalcoholic steatohepatitis. J Gastroenterol Hepatol. 21:191–198. 2006.PubMed/NCBI View Article : Google Scholar
8	Kim WS, Lee YS, Cha SH, Jeong HW, Choe SS, Lee MR, Oh GT, Park HS, Lee KU, Lane MD, et al: Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity. Am J Physiol Endocrinol Metab. 296:E812–E819. 2009.PubMed/NCBI View Article : Google Scholar
9	Qian S, Ma L, Peng S, Xu Y, Wu K, Shen S, Zhang X, Sun Y and Ye J: ATP reduces mitochondrial MECR protein in liver of diet-induced obese mice in mechanism of insulin resistance. Biosci Rep. 40(40)2020.PubMed/NCBI View Article : Google Scholar
10	Qin S, Tang H, Li W, Gong Y, Li S, Huang J, Fang Y, Yuan W, Liu Y, Wang S, et al: AMPK and its activator berberine in the treatment of neurodegenerative diseases. Curr Pharm Des. 26:5054–5066. 2020.PubMed/NCBI View Article : Google Scholar
11	Li Q, Zhao C, Zhang Y, Du H, Xu T, Xu X, Zhang J, Kuang T, Lai X, Fan G, et al: 1H NMR-based metabolomics coupled with molecular docking reveal the anti-diabetic effects and potential active components of berberis vernae on type 2 diabetic rats. Front Pharmacol. 11(932)2020.PubMed/NCBI View Article : Google Scholar
12	Xing LJ, Zhang L, Liu T, Hua YQ, Zheng PY and Ji G: Berberine reducing insulin resistance by up-regulating IRS-2 mRNA expression in nonalcoholic fatty liver disease (NAFLD) rat liver. Eur J Pharmacol. 668:467–471. 2011.PubMed/NCBI View Article : Google Scholar
13	Yang QH, Hu SP, Zhang YP, Xie WN, Li N, Ji GY, Qiao NL, Lin XF, Chen TY and Liu HT: Effect of berberine on expressions of uncoupling protein-2 mRNA and protein in hepatic tissue of non-alcoholic fatty liver disease in rats. Chin J Integr Med. 17:205–211. 2011.PubMed/NCBI View Article : Google Scholar
14	Li S, Xu Y, Guo W, Chen F, Zhang C, Tan HY, Wang N and Feng Y: The impacts of herbal medicines and natural products on regulating the hepatic lipid metabolism. Front Pharmacol. 11(351)2020.PubMed/NCBI View Article : Google Scholar
15	Liu R, Wu K, Li Y, Sun R and Li X: Human antigen R: A potential therapeutic target for liver diseases. Pharmacol Res. 155(104684)2020.PubMed/NCBI View Article : Google Scholar
16	Li CH, Tang SC, Wong CH, Wang Y, Jiang JD and Chen Y: Berberine induces miR-373 expression in hepatocytes to inactivate hepatic steatosis associated AKT-S6 kinase pathway. Eur J Pharmacol. 825:107–118. 2018.PubMed/NCBI View Article : Google Scholar
17	Pan X and Hussain MM: Diurnal regulation of microsomal triglyceride transfer protein and plasma lipid levels. J Biol Chem. 282:24707–24719. 2007.PubMed/NCBI View Article : Google Scholar
18	Yuan F, Wang H, Tian Y, Li Q, He L, Li N and Liu Z: Fish oil alleviated high-fat diet-induced non-alcoholic fatty liver disease via regulating hepatic lipids metabolism and metaflammation: A transcriptomic study. Lipids Health Dis. 15(20)2016.PubMed/NCBI View Article : Google Scholar
19	Lu Z, He B, Chen Z, Yan M and Wu L: Anti-inflammatory activity of berberine in non-alcoholic fatty liver disease via the Angptl2 pathway. BMC Immunol. 21(28)2020.PubMed/NCBI View Article : Google Scholar
20	Mai W, Xu Y, Xu J, Zhao D, Ye L, Yu G, Wang Z, Lu Q, Lin J, Yang T, et al: Berberine inhibits nod-like receptor family pyrin domain containing 3 inflammasome activation and pyroptosis in nonalcoholic steatohepatitis via the ROS/TXNIP axis. Front Pharmacol. 11(185)2020.PubMed/NCBI View Article : Google Scholar
21	Zhu X, Bian H, Wang L, Sun X, Xu X, Yan H, Xia M, Chang X, Lu Y, Li Y, et al: Berberine attenuates nonalcoholic hepatic steatosis through the AMPK-SREBP-1c-SCD1 pathway. Free Radic Biol Med. 141:192–204. 2019.PubMed/NCBI View Article : Google Scholar
22	Bedossa P: Pathology of non-alcoholic fatty liver disease. Liver Int. 37 (Suppl 1):85–89. 2017.PubMed/NCBI View Article : Google Scholar
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
24	Kojima S, Watanabe N, Numata M, Ogawa T and Matsuzaki S: Increase in the prevalence of fatty liver in Japan over the past 12 years: Analysis of clinical background. J Gastroenterol. 38:954–961. 2003.PubMed/NCBI View Article : Google Scholar
25	Adams LA, Angulo P and Lindor KD: Nonalcoholic fatty liver disease. CMAJ. 172:899–905. 2005.PubMed/NCBI View Article : Google Scholar
26	Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G and Bellentani S: Prevalence of and risk factors for nonalcoholic fatty liver disease: The Dionysos nutrition and liver study. Hepatology. 42:44–52. 2005.PubMed/NCBI View Article : Google Scholar
27	Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM and Hobbs HH: Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity. Hepatology. 40:1387–1395. 2004.PubMed/NCBI View Article : Google Scholar
28	Day CP and James OF: Steatohepatitis: A tale of two ‘hits’? Gastroenterology. 114:842–845. 1998.PubMed/NCBI View Article : Google Scholar
29	Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, et al: Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 10:1344–1351. 2004.PubMed/NCBI View Article : Google Scholar
30	Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A and Angulo P: The natural history of nonalcoholic fatty liver disease: A population-based cohort study. Gastroenterology. 129:113–121. 2005.PubMed/NCBI View Article : Google Scholar
31	Gibbons GF: Assembly and secretion of hepatic very-low-density lipoprotein. Biochem J. 268:1–13. 1990.PubMed/NCBI View Article : Google Scholar
32	Gibbons GF, Wiggins D, Brown AM and Hebbachi AM: Synthesis and function of hepatic very-low-density lipoprotein. Biochem Soc Trans. 32:59–64. 2004.PubMed/NCBI View Article : Google Scholar
33	Rutledge AC, Su Q and Adeli K: Apolipoprotein B100 biogenesis: A complex array of intracellular mechanisms regulating folding, stability, and lipoprotein assembly. Biochem Cell Biol. 88:251–267. 2010.PubMed/NCBI View Article : Google Scholar
34	Fisher EA and Ginsberg HN: Complexity in the secretory pathway: The assembly and secretion of apolipoprotein B-containing lipoproteins. J Biol Chem. 277:17377–17380. 2002.PubMed/NCBI View Article : Google Scholar
35	Olofsson SO, Stillemark-Billton P and Asp L: Intracellular assembly of VLDL: Two major steps in separate cell compartments. Trends Cardiovasc Med. 10:338–345. 2000.PubMed/NCBI View Article : Google Scholar
36	Zhou M, Fisher EA and Ginsberg HN: Regulated Co-translational ubiquitination of apolipoprotein B100. A new paradigm for proteasomal degradation of a secretory protein. J Biol Chem. 273:24649–24653. 1998.PubMed/NCBI View Article : Google Scholar
37	Wang Y, Tran K and Yao Z: The activity of microsomal triglyceride transfer protein is essential for accumulation of triglyceride within microsomes in McA-RH7777 cells. A unified model for the assembly of very low density lipoproteins. J Biol Chem. 274:27793–27800. 1999.PubMed/NCBI View Article : Google Scholar
38	Furbee JW Jr, Francone O and Parks JS: In vivo contribution of LCAT to apolipoprotein B lipoprotein cholesteryl esters in LDL receptor and apolipoprotein E knockout mice. J Lipid Res. 43:428–437. 2002.PubMed/NCBI
39	Zou K, Li Z, Zhang Y, Zhang HY, Li B, Zhu WL, Shi JY, Jia Q and Li YM: Advances in the study of berberine and its derivatives: A focus on anti-inflammatory and anti-tumor effects in the digestive system. Acta Pharmacol Sin. 38:157–167. 2017.PubMed/NCBI View Article : Google Scholar
40	Yan YQ, Fu YJ, Wu S, Qin HQ, Zhen X, Song BM, Weng YS, Wang PC, Chen XY and Jiang ZY: Anti-influenza activity of berberine improves prognosis by reducing viral replication in mice. Phytother Res. 32:2560–2567. 2018.PubMed/NCBI View Article : Google Scholar
41	Warowicka A, Nawrot R and Goździcka-Józefiak A: Antiviral activity of berberine. Arch Virol. 165:1935–1945. 2020.PubMed/NCBI View Article : Google Scholar
42	Wu X, Li X, Dang Z and Jia Y: Berberine demonstrates anti-inflammatory properties in Helicobacter pylori-infected mice with chronic gastritis by attenuating the Th17 response triggered by the B cell-activating factor. J Cell Biochem. 119:5373–5381. 2018.PubMed/NCBI View Article : Google Scholar
43	Li CL, Tan LH, Wang YF, Luo CD, Chen HB, Lu Q, Li YC, Yang XB, Chen JN, Liu YH, et al: Comparison of anti-inflammatory effects of berberine, and its natural oxidative and reduced derivatives from Rhizoma Coptidis in vitro and in vivo. Phytomedicine. 52:272–283. 2019.PubMed/NCBI View Article : Google Scholar
44	Chao G, Ye F, Yuan Y and Zhang S: Berberine ameliorates non-steroidal anti-inflammatory drugs-induced intestinal injury by the repair of enteric nervous system. Fundam Clin Pharmacol. 34:238–248. 2020.PubMed/NCBI View Article : Google Scholar
45	Cicero AF and Baggioni A: Berberine and its role in chronic disease. Adv Exp Med Biol. 928:27–45. 2016.PubMed/NCBI View Article : Google Scholar
46	Wang K, Feng X, Chai L, Cao S and Qiu F: The metabolism of berberine and its contribution to the pharmacological effects. Drug Metab Rev. 49:139–157. 2017.PubMed/NCBI View Article : Google Scholar
47	Zang M, Zuccollo A, Hou X, Nagata D, Walsh K, Herscovitz H, Brecher P, Ruderman NB and Cohen RA: AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells. J Biol Chem. 279:47898–47905. 2004.PubMed/NCBI View Article : Google Scholar
48	Brusq J-M, Ancellin N, Grondin P, Guillard R, Martin S, Saintillan Y and Issandou M: Inhibition of lipid synthesis through activation of AMP kinase: An additional mechanism for the hypolipidemic effects of berberine. J Lipid Res. 47:1281–1288. 2006.PubMed/NCBI View Article : Google Scholar
49	Assifi MM, Suchankova G, Constant S, Prentki M, Saha AK and Ruderman NB: AMP-activated protein kinase and coordination of hepatic fatty acid metabolism of starved/carbohydrate-refed rats. Am J Physiol Endocrinol Metab. 289:E794–E800. 2005.PubMed/NCBI View Article : Google Scholar