Integrated spatial metabolomics and transcriptomics decipher the hepatoprotection mechanisms of wedelolactone and demethylwedelolactone on non-alcoholic fatty liver disease

Panpan Chen; Zihan Zhu; Haoyuan Geng; Xiaoqing Cui; Yuhao Han; Lei Wang; Yaqi Zhang; Heng Lu; Xiao Wang; Yun Zhang; Chenglong Sun

doi:10.1016/j.jpha.2023.11.017

Volume 14 Issue 4

Apr. 2024

Turn off MathJax

Article Contents

Article Navigation > Journal of Pharmaceutical Analysis > 2024 > 14(4): 100910

Panpan Chen, Zihan Zhu, Haoyuan Geng, Xiaoqing Cui, Yuhao Han, Lei Wang, Yaqi Zhang, Heng Lu, Xiao Wang, Yun Zhang, Chenglong Sun. Integrated spatial metabolomics and transcriptomics decipher the hepatoprotection mechanisms of wedelolactone and demethylwedelolactone on non-alcoholic fatty liver disease[J]. Journal of Pharmaceutical Analysis, 2024, 14(4): 100910. doi: 10.1016/j.jpha.2023.11.017

Citation:

Panpan Chen, Zihan Zhu, Haoyuan Geng, Xiaoqing Cui, Yuhao Han, Lei Wang, Yaqi Zhang, Heng Lu, Xiao Wang, Yun Zhang, Chenglong Sun. Integrated spatial metabolomics and transcriptomics decipher the hepatoprotection mechanisms of wedelolactone and demethylwedelolactone on non-alcoholic fatty liver disease[J]. Journal of Pharmaceutical Analysis, 2024, 14(4): 100910. doi: 10.1016/j.jpha.2023.11.017

Citation:

Panpan Chen, Zihan Zhu, Haoyuan Geng, Xiaoqing Cui, Yuhao Han, Lei Wang, Yaqi Zhang, Heng Lu, Xiao Wang, Yun Zhang, Chenglong Sun. Integrated spatial metabolomics and transcriptomics decipher the hepatoprotection mechanisms of wedelolactone and demethylwedelolactone on non-alcoholic fatty liver disease[J]. Journal of Pharmaceutical Analysis, 2024, 14(4): 100910. doi: 10.1016/j.jpha.2023.11.017

PDF( 4654 KB)

Integrated spatial metabolomics and transcriptomics decipher the hepatoprotection mechanisms of wedelolactone and demethylwedelolactone on non-alcoholic fatty liver disease

doi: 10.1016/j.jpha.2023.11.017

Panpan Chen^a,b,
Zihan Zhu^a,b,c,
Haoyuan Geng^b,
Xiaoqing Cui^a,b,
Yuhao Han^b,
Lei Wang^b,
Yaqi Zhang^b,
Heng Lu^a,b,
Xiao Wang^a,b,
Yun Zhang^{d
,
,},
Chenglong Sun^{a,b
,
,}

a. Key Laboratory for Natural Active Pharmaceutical Constituents Research in Universities of Shandong Province, School of Pharmaceutical Sciences, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250014, China;
b. Key Laboratory for Applied Technology of Sophisticated Analytical Instruments of Shandong Province, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250014, China;
c. School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China;
d. Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250103, China

Funds:

This study was supported by the National Natural Science Foundation of China (Grant No.: 82273888), Natural Science Foundation of Shandong Province (Grant Nos. ZR2022QH257, and ZR2020YQ60), Shandong Major Technological Innovation Project (Project No.: 2021CXGC010508), Taishan Scholars Program of Shandong Province (Program Nos.: tsqn202103096, and tsqn202211204), and Shandong Province Science and Technology Small and Medium Enterprises Innovation Ability Enhancement Project (Project No.: 2022TSGC2210).

Received Date: Jul. 27, 2023
Accepted Date: Nov. 27, 2023
Rev Recd Date: Nov. 12, 2023
Publish Date: Nov. 29, 2023

Abstract

Abstract

Eclipta prostrata L. has been used in traditional medicine and known for its liver-protective properties for centuries. Wedelolactone (WEL) and demethylwedelolactone (DWEL) are the major coumarins found in E. prostrata L. However, the comprehensive characterization of these two compounds on non-alcoholic fatty liver disease (NAFLD) still remains to be explored. Utilizing a well-established zebrafish model of thioacetamide (TAA)-induced liver injury, the present study sought to investigate the impacts and mechanisms of WEL and DWEL on NAFLD through integrative spatial metabolomics with liver-specific transcriptomics analysis. Our results showed that WEL and DWEL significantly improved liver function and reduced the accumulation of fat in the liver. The biodistributions and metabolism of these two compounds in whole-body zebrafish were successfully mapped, and the discriminatory endogenous metabolites reversely regulated by WEL and DWEL treatments were also characterized. Based on spatial metabolomics and transcriptomics, we identified that steroid biosynthesis and fatty acid metabolism are mainly involved in the hepatoprotective effects of WEL instead of DWEL. Our study unveils the distinct mechanism of WEL and DWEL in ameliorating NAFLD, and presents a “multi-omics” platform of spatial metabolomics and liver-specific transcriptomics to develop highly effective compounds for further improved therapy.
- Spatial metabolomics,
- Transcriptomics,
- Non-alcoholic fatty liver disease,
- Wedelolactone,
- Demethylwedelolactone

FullText(HTML)

References(47)

References

[1]	J.J. Maher, J.M. Schattenberg, Nonalcoholic fatty liver disease in 2020, Gastroenterology 158 (2020) 1849-1850.
[2]	Z. Younossi, Q.M. Anstee, M. Marietti, et al., Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention, Nat. Rev. Gastroenterol. Hepatol. 15 (2018) 11-20.
[3]	M. Eslam, A.J. Sanyal, J. George, MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease, Gastroenterology 158 (2020) 1999-2014.el.
[4]	P. Burra, C. Becchetti, G. Germani, NAFLD and liver transplantation: Disease burden, current management and future challenges, JHEP Rep. 2 (2020), 100192.
[5]	T. Liu, H. Yang, F. Zhuo, et al., Atypical E3 ligase ZFP91 promotes small-molecule-induced E2F2 transcription factor degradation for cancer therapy, EBioMedicine 86 (2022), 104353.
[6]	S. Sarma, S. Sockalingam, S. Dash, Obesity as a multisystem disease: Trends in obesity rates and obesity-related complications, Diabetes Obes. Metab. 23 (2021) 3-16.
[7]	H. Kitade, G. Chen, Y. Ni, et al., Nonalcoholic fatty liver disease and insulin resistance: New insights and potential new treatments, Nutrients. 9 (2017), 387.
[8]	Z.M. Younossi, A.B. Koenig, D. Abdelatif, et al., Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes, Hepatol. Baltim. Md. 64 (2016) 73-84.
[9]	M.K. Lee, N.R. Ha, H. Yang, et al., Antiproliferative activity of triterpenoids from Eclipta prostrata on hepatic stellate cells, Phytomedicine 15 (2008) 775-780.
[10]	H. Tang, H. Li, Y. Li, et al., Protective effects of a traditional Chinese herbal formula Jiang-Xian HuGan on Concanavalin A-induced mouse hepatitis via NF-κB and Nrf2 signaling pathways, J. Ethnopharmacol. 217 (2018) 118-125.
[11]	K. Rai, K. Yadav, M. Das, et al., Effect of carbon quantum dots derived from extracts of UV-B-exposed Eclipta alba on alcohol-induced liver cirrhosis in Golden Hamster, Photochem. Photobiol. Sci. 22 (2023) 1543-1559.
[12]	A. Svrlanska, A. Ruhland, M. Marschall, et al., Wedelolactone inhibits human cytomegalovirus replication by targeting distinct steps of the viral replication cycle, Antivir. Res. 174 (2020), 104677.
[13]	F. Yuan, J. Chen, P. Sun, et al., Wedelolactone inhibits LPS-induced pro-inflammation via NF-κB pathway in RAW 264.7 cells, J. Biomed. Sci. 20 (2013), 84.
[14]	Y. Xia, J. Chen, Y. Cao, et al., Wedelolactone exhibits anti-fibrotic effects on human hepatic stellate cell line LX-2, Eur. J. Pharmacol. 714 (2013) 105-111.
[15]	Y. Zhao, L. Peng, L.C. Yang, et al., Wedelolactone regulates lipid metabolism and improves hepatic steatosis partly by AMPK activation and up-regulation of expression of PPARα/LPL and LDLR, PLoS One. 10 (2015) e0132720.
[16]	W. Goessling, K.C. Sadler, Zebrafish: An important tool for liver disease research, Gastroenterology 149 (2015) 1361-1377.
[17]	N. Osmani, J.G. Goetz, Multiscale imaging of metastasis in zebrafish, Trends Cancer 5 (2019) 766-778.
[18]	P. Song, N. Jiang, K. Zhang, et al., Ecotoxicological evaluation of zebrafish liver (Danio rerio) induced by dibutyl phthalate, J. Hazard. Mater. 425 (2022), 128027.
[19]	B.J. Wilkins, M. Pack, Zebrafish models of human liver development and disease, Compr. Physiol. 3 (2013) 1213-1230.
[20]	C. Zhang, C. Li, K. Liu, et al., Characterization of Zearalenone-induced hepatotoxicity and its mechanisms by transcriptomics in zebrafish model, Chemosphere. 309 (2022), 136637.
[21]	Y. Zhang, L. Han, Q. He, et al., A rapid assessment for predicting drug-induced hepatotoxicity using zebrafish, J. Pharmacol. Toxicol. Methods 84 (2017) 102-110.
[22]	J. Zhang, L. Qian, C. Wang, et al., UPLC-TOF-MS/MS metabolomics analysis of zebrafish metabolism by spirotetramat, Environ. Pollut. 266 (2020), 115310.
[23]	T. He, M. Wang, J. Kong, et al., Integrating network pharmacology and non-targeted metabolomics to explore the common mechanism of Coptis Categorized Formula improving T2DM zebrafish, J. Ethnopharmacol. 284 (2022), 114784.
[24]	M. Teng, W. Zhu, D. Wang, et al., Metabolomics and transcriptomics reveal the toxicity of difenoconazole to the early life stages of zebrafish (Danio rerio), Aquat. Toxicol. 194 (2018) 112-120.
[25]	X. Tian, G. Zhang, Z. Zou, et al., Anticancer drug affects metabolomic profiles in multicellular spheroids: Studies using mass spectrometry imaging combined with machine learning, Anal. Chem. 91 (2019) 5802-5809.
[26]	Y. Chen, T. Wang, P. Xie, et al., Mass spectrometry imaging revealed alterations of lipid metabolites in multicellular tumor spheroids in response to hydroxychloroquine, Anal. Chim. Acta. 1184 (2021), 339011.
[27]	C. Sun, A. Wang, Y. Zhou, et al., Spatially resolved multi-omics highlights cell-specific metabolic remodeling and interactions in gastric cancer, Nat. Commun. 14 (2023), 2692.
[28]	C. Sun, T. Li, X. Song, et al., Spatially resolved metabolomics to discover tumor-associated metabolic alterations, Proc. Natl. Acad. Sci. U. S. A. 116 (2019) 52-57.
[29]	B. Jin, X. Pang, Q. Zang, et al., Spatiotemporally resolved metabolomics and isotope tracing reveal CNS drug targets, Acta Pharm. Sin. B 13 (2023) 1699-1710.
[30]	A.M. Bolger, M. Lohse, B. Usadel, Trimmomatic: A flexible trimmer for Illumina sequence data, Bioinformatics. 30 (2014) 2114-2120.
[31]	D. Kim, B. Langmead, S.L. Salzberg, HISAT: A fast spliced aligner with low memory requirements, Nat. Methods. 12 (2015) 357-360.
[32]	M.I. Love, W. Huber, S. Anders, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2, Genome Biol. 15 (2014), 550.
[33]	S. Hanzelmann, R. Castelo, J. Guinney, GSVA: Gene set variation analysis for microarray and RNA-seq data, BMC Bioinformatics 14 (2013) 7.
[34]	K.S. Jones, A.P. Alimov, H.L. Rilo, et al., A high throughput live transparent animal bioassay to identify non-toxic small molecules or genes that regulate vertebrate fat metabolism for obesity drug development, Nutr. Metab. 5 (2008), 23.
[35]	H. Ye, S. Ma, Z. Qiu, et al., Poria cocos polysaccharides rescue pyroptosis-driven gut vascular barrier disruption in order to alleviates non-alcoholic steatohepatitis, J. Ethnopharmacol. 296 (2022), 115457.
[36]	L. Li, X. Huang, J. Peng, et al., Wedelolactone metabolism in rats through regioselective glucuronidation catalyzed by uridine diphosphate-glucuronosyltransferases 1As (UGT1As), Phytomedicine 23 (2016) 340-349.
[37]	R.J. DeBerardinis, A. Mancuso, E. Daikhin, et al., Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis, Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 19345-19350.
[38]	H.W. Chao, S.W. Chao, H. Lin, et al., Homeostasis of glucose and lipid in non-alcoholic fatty liver disease, Int. J. Mol. Sci. 20 (2019), 298.
[39]	N. Alkhouri, C. Carter-Kent, A.E. Feldstein, Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications, Expert Rev. Gastroenterol. Hepatol. 5 (2011) 201-212.
[40]	J.M. Eng, J.L. Estall, Diet-induced models of non-alcoholic fatty liver disease: Food for thought on sugar, fat, and cholesterol, Cells. 10 (2021), 1805.
[41]	P. Malhotra, R.K. Gill, S. Saksena, et al., Disturbances in cholesterol homeostasis and non-alcoholic fatty liver diseases, Front. Med. 7 (2020), 467.
[42]	D.H. Ipsen, J. Lykkesfeldt, P. Tveden-Nyborg, Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease, Cell. Mol. Life Sci. 75 (2018) 3313-3327.
[43]	W.D. Nes, Biosynthesis of cholesterol and other sterols, Chem. Rev. 111 (2011) 6423-6451.
[44]	S. Silve, P.H. Dupuy, C. Labit-Lebouteiller, et al., Emopamil-binding protein, a mammalian protein that binds a series of structurally diverse neuroprotective agents, exhibits delta8-delta7 sterol isomerase activity in yeast, J. Biol. Chem. 271 (1996) 22434-22440.
[45]	C. Chitraju, T.C. Walther, R.V. Farese, The triglyceride synthesis enzymes DGAT1 and DGAT2 have distinct and overlapping functions in adipocytes, J. Lipid Res. 60 (2019) 1112-1120.
[46]	M.A. Mitsche, H.H. Hobbs, J.C. Cohen, Patatin-like phospholipase domain-containing protein 3 promotes transfer of essential fatty acids from triglycerides to phospholipids in hepatic lipid droplets, J. Biol. Chem. 293 (2018) 6958-6968.
[47]	R.R. Crawford, E.T. Prescott, C.F. Sylvester, et al., Human CHAC1 protein degrades glutathione, and mRNA induction is regulated by the transcription factors ATF4 and ATF3 and a bipartite ATF/CRE regulatory element, J. Biol. Chem. 290 (2015) 15878-15891.