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BMC Complementary Medicine and Therapies
Published in: BMC Complementary Medicine and Therapies 1/2023

Open Access 01-12-2023 | Simvastatin | Research

Fumigaclavine C ameliorates liver steatosis by attenuating hepatic de novo lipogenesis via modulation of the RhoA/ROCK signaling pathway

Authors: Wanguo Yu, Yaxin Gao, Zaoya Zhao, Xiufeng Long, Yi Yi, Shuo Ai

Published in: BMC Complementary Medicine and Therapies | Issue 1/2023

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Abstract

Background

Non-alcoholic fatty liver disease (NAFLD) has been well defined as a common chronic liver metabolism disorder. Statins as a first-line therapeutic treatment had some side effects. Here, we found that Fumigaclavine C (FC) was collected from endophytic Aspergillus terreus via the root of Rhizophora stylosa (Rhizophoraceae), had potential anti-adipogenic and hepatoprotective effects both in vitro and in vivo without obvious adverse side effects. However, the mechanisms of the prevention and management of FC for hepatic steatosis are incompletely delineated.

Methods

The pharmacodynamic effects of FC were measured in high-fat diet (HFD)-induced obese mice. Liver index and blood biochemical were examined. Histopathological examination in the liver was performed by hematoxylin & eosin or oil red O. The levels of serum TG, TC, LDL-c, HDL-c, FFA, T-bili, ALT, AST, creatinine, and creatine kinase were estimated via diagnostic assay kits. The levels of hepatic lipid metabolism-related genes were detected via qRT-PCR. The expression levels of hepatic de novo lipogenesis were quantitated with Western blot analysis. 

Results

FC-treatment markedly reduced hepatic lipid accumulation in HFD-induced obese mice. FC significantly attenuated the hepatic lipid metabolism and ameliorated liver injury without obvious adverse side effects. Moreover, FC also could dose-dependently modulate the expressions of lipid metabolism-related transcription genes. Mechanically, FC notably suppressed sterol response element binding protein-1c mediated de novo lipogenesis via interfering with the RhoA/ROCK signaling pathway by decreasing the levels of geranylgeranyl diphosphate and farnesyl diphosphate.

Conclusions

These findings suggested that FC could improve hepatic steatosis through inhibiting de novo lipogenesis via modulating the RhoA/ROCK signaling pathway.
Appendix
Available only for authorised users
Literature
1.
Gao Z, Song GY, Ren LP, Ma HJ, Ma BQ, Chen SC. β-catenin mediates the effect of GLP-1 receptor agonist on ameliorating hepatic steatosis induced by high fructose diet. Eur J Histochem. 2020;64:225–33.
2.
Tao WW, Wu J, Xie BX, Zhao YY, Shen N, Jiang S, Wang XX, Xu N, Jiang C, Chen S, Gao X, Xue B, Li CJ. Lipid-induced muscle Insulin resistance is mediated by GGPPS via modulation of the RhoA/Rho kinase signaling pathway. J Biol Chem. 2015;33:20086–97.
3.
Rahman MS, Kang I, Lee Y, Habib MA, Choi BJ, Kang JS, Park DS, Kim YS. Bifidobacterium longum subsp infantis YB0411. inhibits adipogenesis in 3T3-L1 Pre-adipocytes and reduces high-fat-diet-induced obesity in mice. J Agric Food Chem. 2021;69:6032–42.PubMed
4.
Tang QL, Jiang S, Jia WJ, Shen D, Qiu YD, Zhao Y, Xue B, Li CJ. Zoledronic acid, an FPPS inhibitor, ameliorates liver steatosis through inhibiting hepatic de novo lipogenesis. Eur J Pharmacol. 2017;814:169–77.PubMed
5.
Lee MR, Kim JE, Park JW, Kang MJ, Choi HJ, Bae SJ, Choi YW, Kim KM, Hong JT, Hwang DY. Fermented mulberry (Morus alba) leaves suppress high fat diet-induced hepatic steatosis through amelioration of the inflammatory response and autophagy pathway. BMC Complementary Med Ther. 2020;20:283.
6.
Yao LY, Sun JY, Liang Y, Feng T, Wang HT, Sun M, Yu WG. Volatile fingerprints of Torreya grandis hydrosols under different downstream processes using HS-GC–IMS and the enhanced stability and bioactivity of hydrosols by high pressure homogenization. Food Control. 2022;139:109058.
7.
Cui HP, Lin YX, Xie L, Zhao J. Urantide decreases hepatic steatosis in rats with experimental atherosclerosis via the MAPK/Erk/JNK pathway. Mol Med Rep. 2021;23:284.PubMedPubMedCentral
8.
Ai S, Qin Y, Hong YX, Liu LY, Yu WG. Removal of C3–C4 diols in ethylene glycol via selective dehydration reactions over Beta zeolite with acidity tailored. J Catal. 2022;413:870–9.
9.
Li WJ, Ren YP, Meng TY, Yang W, Zhang W. miR-129-5p attenuates hypoxia-induced apoptosis in rat H9c2 cardiomyocytes by activating autophagy. J Gene Med. 2020;22:e3200.PubMed
10.
Feng D, Zou J, Su DF, Mai HY, Zhang SS, Li PY, Zheng XM. Curcumin prevents high-fat diet-induced hepatic steatosis in ApoE-/- mice by improving intestinal barrier function and reducing endotoxin and liver TLR4/NF-κB inflammation. Nutr Metab. 2019;16:79.
11.
Zhou C, Zhen MM, Yu ML, Li X, Yu T, Liu JC, Jia W, Liu S, Li L, Li J, Sun ZH, Zhao ZP, Wang XY, Zhang XY, Wang CR, Bai CL. Gadofullerene inhibits the degradation of apolipoprotein B100 and boosts triglyceride transport for reversing hepatic steatosis. Sci Adv. 2020;6:e1586.
12.
Yang Z, Li P, Shang Q, Wang Y, He J, Ge S, Jia R, Fan X. CRISPR-mediated BMP9 ablation promotes liver steatosis via the down-regulation of PPARα expression. Sci Adv. 2020;6:e5022.
13.
Tsai CC, Chen YJ, Yu HR, Huang LT, Tain YL, Lin IC, Sheen JM, Wang PW, Tiao MM. Long term N-acetylcysteine administration rescues liver steatosis via endoplasmic reticulum stress with unfolded protein response in mice. Lipids Health Dis. 2020;19:105.PubMedPubMedCentral
14.
Xu H, Chen GF, Ma YS, Zhang HW, Zhou Y, Liu GH, Chen DY, Ping J, Liu YH, Mou X, Fu D. Hepatic proteomic changes and Sirt1/AMPK signaling activation by oxymatrine treatment in rats with non-alcoholic steatosis. Front Pharmacol. 2020;11:216.PubMedPubMedCentral
15.
Okuyama T, Shirakawa J, Tajima K, Ino Y, Vethe H, Togashi Y, Kyohara M, Inoue R, Miyashita D, Li JH, Goto N, Ichikawa T, Yamasaki S, Ohnuma H, Takayanagi R, Kimura Y, Hirano H, Terauchi Y. Linagliptin ameliorates hepatic steatosis via non-canonical mechanisms in mice treated with a dual inhibitor of insulin receptor and IGF-1 receptor. Int J Mol Sci. 2020;21:7815.PubMedPubMedCentral
16.
Li L, Yang L, Yang F, Zhao XI, Xue SJ, Gong FH. Ginkgo biloba extract 50 (GBE50) ameliorates insulin resistance, hepatic steatosis and liver injury in high fat diet-fed mice. J Inflammation Res. 2021;14:1959–71.
17.
Ai S, Qin Y, Liu LH, Yu WG. Ion-exchange modification of zeolite for the controllable catalytic transformation of diols and selective conversion of 1,2-butanediol to butanal. Compr Mater Chem Phys. 2022;292:126836.
18.
Nakade Y, Kitano R, Yamauchi T, Kimoto S, Sakamoto K, Inoue T, Kobayashi Y, Ohashi T, Sumida Y, Ito K, Yoneda M. Effect of adrenergic agonists on high-fat diet-induced hepatic steatosis in mice. Int J Mol Sci. 2020;21:9392.PubMedPubMedCentral
19.
Wollman A, Daniel T, Rosenzweig T. Sarcopoterium spinosum inhibited the development of non-alcoholic steatosis and steatohepatitis in mice. Nutrients. 2019;11:3044.PubMedPubMedCentral
20.
Wang S, Huang Y, Xu H, Zhu Q, Lu H, Zhang M, Hao S, Fang C, Zhang D, Wu X, Wang X, Sheng J. Oxidized tea polyphenols prevent lipid accumulation in liver and visceral white adipose tissue in rats. Eur J Nutr. 2017;56:2037–48.PubMed
21.
Wang Y, Zhu HW, Tam NFY. Polyphenols, tannins and antioxidant activities of eight truemangrove plant species in South China. Plant Soil. 2014;374:549–63.
22.
Guo WJ, Hu SS, Elgehama A, Shao F, Ren R, Liu W, Zhang WJ, Wang XL, Tan RX, Xu Q, Sun Y, Jiao RH. Fumigaclavine C ameliorates dextran sulfate sodium-induced murine experimental colitis via NLRP3 inflammasome inhibition. J Pharmacol Sci. 2015;129:101–6.PubMed
23.
Zhao Y, Liu JY, Wang J, Wang L, Yin H, Tan RX, Xu Q. Fumigaclavine C improves concanavalin A-induced liver injury in mice mainly via inhibiting TNF-α production and lymphocyte adhesion to extracellular matrices. J Pharm Pharmacol. 2004;56:775–82.PubMed
24.
Tan Y, Wu XX, Sun J, Guo WJ, Gong FY, Shao FL, Tan T, Cao Y, Zheng BF, Gu YH, Sun Y, Xu Q. A fumigaclavine C isostere alleviates Th1-mediated experimental colitis via competing with IFN-γ for binding to IFN-γ receptor 1. Biochem Pharmacol. 2017;123:63–72.PubMed
25.
Yu WG, Qian J, Lu YH. Hepatoprotective Effects 2′,4′-dihydroxy-6′- methoxy-3′,5′-dimethylchalcone on CCl4-induced acute liver injury in mice. J Agric Food Chem. 2011;59:12821–9.PubMed
26.
Yu WG, He H, Qian J, Lu YH. Dual role of 2′,4′-dihydroxy-6′- methoxy-3′,5′-dimethylchalcone in inhibiting high-mobility group box 1 secretion and blocking its Pro-inflammatory activity in hepatic inflammation. J Agric Food Chem. 2014;62:11949–56.PubMed
27.
Yu WG, He H, Yao JY, Zhu YX, Lu YH. Dimethyl cardamonin exhibits anti-inflammatory effects via interfering with the PI3K-PDK1-PKCα signaling pathway. Biomol Ther. 2015;23:549–56.
28.
Yu WG, He Y, Chen YF, Gao XY, Ning WE, Liu CY, Tang TF, Liu Q, Huang XC. Fumigaclavine C attenuates adipogenesis in 3T3-L1 adipocytes and ameliorates lipid accumulation in high-fat diet-induced obese mice. Korean J Physiol Pharmacol. 2019;23:161–9.PubMedPubMedCentral
29.
Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Investig. 2005;115:1343–51.PubMedPubMedCentral
30.
Yu WG, Pan ZH, Zhu YX, An FL, Lu YH. Fumigaclavine C exhibits anti-inflammatory effects by suppressing high mobility group box protein 1 relocation and release. Eur J Pharmacol. 2017;812:234–42.PubMed
31.
Ye Q, Liu Y, Zhang GJ, Deng HJ, Wang XJ, Tuo L, Chen C, Pan XM, Wu K, Fan JG, Pan Q, Wang K, Huang AL, Tang N. Deficiency of gluconeogenic enzyme PCK1 promotes metabolic-associated fatty liver disease through PI3K/AKT/PDGF axis activation in male mice. Nat Commun. 2023;14:1402.PubMedPubMedCentral
32.
Mukerjee N, Das A, Jawarkar RD, Maitra S, Das P, Castrosanto MA, Paul S, Samad A, Zaki MEA, Al-Hussain SA, Masand VH, Hasan MM, Bukhari SNA, Perveen A, Alghamdi BS, Alexiou A, Kamal MA, Dey A, Malik S, Bakal RL, Abuzenadah AM, Ghosh A, Ashraf GM. Repurposing food molecules as a potential BACE1 inhibitor for Alzheimer’s disease. Front Aging Neurosci. 2022;14:878276.PubMedPubMedCentral
33.
An SH, Vo TTL, Son T, Choi H, Kim J, Lee J, Kim BH, Choe M, Ha E, Surh YJ, Kim KW, Seo JH. SAMHD1-induced endosomal FAK signaling promotes human renal clear cell carcinoma metastasis by activating Rac1-mediated lamellipodia protrusion. Exp Mol Med. 2023;55:779–93.PubMedPubMedCentral
34.
Wang XX, Ying P, Diao F, Wang Q, Ye D, Jiang C, Shen N, Xu N, Chen WB, Lai SS, Jiang S, Miao XL, Feng J, Tao WW, Zhao NW, Yao B, Xu ZP, Sun HX, Li JM, Sha JH, Huang XX, Shi QH, Tang H, Gao X, Li CJ. Altered protein prenylation in Sertoli cells is associated with adult infertility resulting from childhood mumps infection. J Exp Med. 2013;210:1559–74.PubMedPubMedCentral
35.
Goalstone ML, Leitner JW, Golovchenko I, Stjernholm MR, Cormont M, Marchand-Brustel YL, Draznin B. Insulin promotes phosphorylation and activation of geranylgeranyltransferase II. J Biol Chem. 1999;29:2880–4.
36.
Du RH, Li EG, Cao Y, Song YC, Tan RX. Fumigaclavine C inhibits tumor necrosis factor α production via suppression of toll-like receptor 4 and nuclear factor κB activation in macrophages. Life Sci. 2011;89:235–40.PubMed
37.
Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014;146:726–35.PubMed
38.
Horton JD, Shimomura I. Sterol regulatory element-binding proteins: activators of cholesterol and fatty acid biosynthesis. Curr Opin Lipidol. 1999;10:143–50.PubMed
39.
Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Investig. 2002;109:1125–31.PubMedPubMedCentral
40.
Brown GT, Kleiner DE. Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Metabolism. 2016;65:1080–6.PubMed
41.
Khan S, Choudhary S, Kumar A, Tripathi AM, Alok A, Adhikari JS, Rizvi MA, Chaudhury NK. Evaluation of sesamol-induced histopathological, biochemical, haematological and genomic alteration after acute oral toxicity in female C57BL/6 mice. Toxicol Rep. 2016;3:880–94.PubMedPubMedCentral
42.
Elizabeth M, Brunt MD. Histological assessment of nonalcoholic fatty liver disease in adults and children. Clin Liver Dis. 2012;4:108–11.
Metadata
Title
Fumigaclavine C ameliorates liver steatosis by attenuating hepatic de novo lipogenesis via modulation of the RhoA/ROCK signaling pathway
Authors
Wanguo Yu
Yaxin Gao
Zaoya Zhao
Xiufeng Long
Yi Yi
Shuo Ai
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2023
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-023-04110-9

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