Interventional effect and mechanism of berberine on hepatic lipid deposition in high-fat diet-fed mice

Abstract

Abstract: Objective To explore the interventional effect and mechanism of berberine (BBR) on hepatic lipid accumulation in mice with non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet (HFD). Methods Twenty-one male wild-type C57BL/6J mice were randomly divided into an HFD group, an HFD+BBR group, and a normal control group. The HFD+BBR group received oral BBR intervention at a dose of 200 mg/(kg·d) for 12 weeks. Body weight, liver weight, and serum triglyceride levels were compared among the groups, and histopathological analysis, lipidomics, gut microbiome analysis, and fecal metabolomics analysis were performed. Results BBR significantly ameliorated hepatic steatosis in mice: the HFD+BBR group showed an 8.42% reduction in body weight (P<0.01), a 10.33% decrease in liver weight (P=0.027), a 39.5% decline in serum triglyceride levels (P<0.001), as well as marked reductions in hepatic lipid droplets and NAFLD Activity Score (P=0.03). Lipidomic analysis confirmed that BBR inhibited the accumulation of diacylglycerol (P=0.004) and triglyceride (P=0.01), restored phospholipid homeostasis, and reduced total hepatic lipids by 13.9% (P<0.05). Gut microbiome analysis revealed that BBR reshaped the gut microbial community structure (P=0.002), with a significant increase in the abundance of Bacteroides (P<0.001). Fecal metabolomic analysis demonstrated that BBR increased agmatine levels (P=0.05), and agmatine was strongly positively correlated with Bacteroides (r=0.681, P=0.001) while negatively correlated with hepatic neutral lipids. Conclusion BBR ameliorates HFD-induced hepatic steatosis by regulating the gut microbiome to promote agmatine production and bidirectionally modulating hepatic lipid metabolism, revealing that the microbiome-metabolite-host axis may serve as a key mechanism underlying the therapeutic effects of BBR in NAFLD.

Key words: Non-alcoholic fatty liver disease, Berberine , Agmatine, Gut microbiota, Bacteroides

HU Jing-xian, LI Jing, XIE Xiao-lan, HUA Qian, JIANG Miao. Interventional effect and mechanism of berberine on hepatic lipid deposition in high-fat diet-fed mice[J]. Chinese Hepatolgy, 2026, 31(5): 704-710.

References

[1] Younossi Z M, Zelber-Sagi S,Henry L,et al. Lifestyle interventions in nonalcoholic fatty liver disease[J]. Nat Rev Gastroenterol Hepatol,2023,20(11):708-722.
[2] Tilg H,Zmora N,Adolph T E,et al.The intestinal microbiota fuelling metabolic inflammation[J]. Nat Rev Immunol,2020,20(1):40-54.
[3] Zhang Z G,Zhang H Z,Li B, et al.Berberine activates thermogenesis in white and brown adipose tissue[J]. Nat Commun,2014,5:5493.
[4] Yao S S,Yuan Y N,Zheng H Z,et al. Berberine attenuates the abnormal ectopic lipid deposition in skeletal muscle[J]. Free Radic Biol Med,2020,159:66-75.
[5] Kong W J,Wei J,Abidi P et al.Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins[J]. Nat Med,2004,10(12):1344-1351.
[6] Pirillo A, Catapano A L, Berberine, a plant alkaloid with lipid-and glucose-lowering properties:from in vitro evidence to clinical studies[J]. Atherosclerosis,2015,243(2):449-461.
[7] Nie Q L,Li M Y,Huang C Y,et al.The clinical efficacy and safety of berberine in the treatment of non-alcoholic fatty liver disease:a meta-analysis and systematic review[J]. J Transl Med,2024,22(1):225.
[8] Chen H T,Ye C X,Wu C H,et al.Berberine inhibits high fat diet-associated colorectal cancer through modulation of the gut microbiota-mediated lysophosphatidylcholine[J]. Int J Biol Sci,2023,19(7):2097-2113.
[9] Wang C,Yang Y T,Chen J Y,et al.Berberine protects against high-energy and low-protein diet-induced hepatic steatosis:modulation of gut microbiota and bile acid metabolism in laying hens[J]. Int J Mol Sci,2023,24:17304.
[10] Guan B Y,Tong J L,Hao H P,et al.Bile acid coordinates microbiota homeostasis and systemic immunometabolism in cardiometabolic diseases[J]. Acta Pharm Sin B,2022,12(5):2129-2149.
[11] Chávez-Talavera O, Tailleux A, Lefebvre P, et al. Bile acid ccontrol of metabolism and inflammation in Obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease[J]. Gastroenterology, 2017,152(7):1679-1694.
[12] Wang Y, Shou J W, Li X Y, et al.Berberine-induced bioactive metabolites of the gut microbiota improve energy metabolism[J]. Metabolism Clin Exp, 2017,70:72-84.
[13] Ackerman D, Tumanov S, Qiu B, et al. Triglycerides promote lipid homeostasis during hypoxic stress by balancing fatty acid saturation[J]. Cell Rep, 2018,24:2596-2605.
[14] Huang C, Sun Y, Liao S R, et al. Suppression of berberine and probiotics (in vitro and in vivo) on the growth of colon cancer with modulation of gut microbiota and butyrate production[J]. Front Microbiol, 2022, 13:869931.
[15] Zhu T, Hu BF, Ye C, et al. Bletilla striata oligosaccharides improve ulcerative colitis by regulating gut microbiota and intestinal metabolites in dextran sulfate sodium-induced mice[J]. Front Pharmacol, 2022, 13:867525.
[16] Katariya R A, Sammeta S S, Kale M B, et al.Agmatine as a novel intervention for alzheimer’s disease:pathological insights and cognitive benefits[J]. Ageing Res Rev,2024,96:102269.
[17] Rakotonirina-Ricquebourg R, Costa V, Teixeira V, et al.Hello from the other side:membrane contact of lipid droplets with other organelles and subsequent functional implications[J]. Prog Lipid Res, 2022,25,13:867525.
[18] Xu J S,Chen S Y ,Wang W,et al.Hepatic CDP-diacylglycerol synthase 2 deficiency causes mitochondrial dysfunction and promotes rapid progression of NASH and fibrosis[J]. Sci Bull,2022,67(3):299-314.
[19] Krahmer N, Najafi B, Schueder F, et al.Organellar proteomics and phospho-proteomics reveal subcellular reorganization in diet-induced hepatic steatosis[J]. Dev Cell, 2018,47(2):205-221.
[20] Cornell R B, Ridgway N D.CTP:phosphocholine cytidylyltransferase:Function, regulation, and structure of an amphitropic enzyme required for membrane biogenesis[J]. Prog Lipid Res, 2015,59:147-171.
[21] Kowdley K V, Vuppalanchi R, Levy C, et al. A randomized, placebo-controlled, phase Ⅱ study of obeticholic acid for primary sclerosing cholangitis[J]. J Hepatol, 2020:1-8.
[22] Pryor R, Norvaisas P, Marinos G, et al.Host-microbe-drug-nutrient screen identifies Bacterial Effectors of Metformin Therapy[J]. Cell, 2019,178:1-14.
[23] Saha P, Panda S, Holkar A, et al.Neuroprotection by agmatine:possible involvement of the gut microbiome?[J].Ageing Res Rev, 2023,91:102056.
[24] Yun C Y, Yan S, Liao B Y, et al. The microbial metabolite agmatine acts as an FXR agonist to promote polycystic ovary syndrome in female mice[J]. Nat Metab,2024,6(5):947-962.
[25] Sharawy M H, El-Awady M S, Megahed N, et al.Attenuation of insulin resistance in rats by agmatine:role of SREBP-1c, mTOR and GLUT-2[J]. Naunyn Schmiedebergs Arch Pharmacol, 2016,389(1):45-56.
[26] Yang S, Cao S J, Li C Y, et al. Berberrubine, a main metabolite of berberine, alleviates non-alcoholic fatty liver disease via modulating glucose and lipid metabolism and restoring gut microbiota[J]. Front Pharmacol, 2022,8,13:913378.