{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T22:37:20Z","timestamp":1790116640296,"version":"4.0.1"},"reference-count":63,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T00:00:00Z","timestamp":1611187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 DK104893, R01DK-057543, 1 R21 AA026629-01; NIH-NCI Cancer Center Support Grant P30 CA 016059."],"award-info":[{"award-number":["R01 DK104893, R01DK-057543, 1 R21 AA026629-01; NIH-NCI Cancer Center Support Grant P30 CA 016059."]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["I01BX004033; Research Career Scientist Award (IK6BX004477); ShEEP grant (1 IS1 BX004777-01)"],"award-info":[{"award-number":["I01BX004033; Research Career Scientist Award (IK6BX004477); ShEEP grant (1 IS1 BX004777-01)"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background and Aims: The disease progression of nonalcoholic fatty liver disease (NAFLD) from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is driven by multiple factors. Berberine (BBR) is an ancient Chinese medicine and has various beneficial effects on metabolic diseases, including NAFLD\/NASH. However, the underlying mechanisms remain incompletely understood due to the limitation of the NASH animal models used. Methods: A high-fat and high-fructose diet-induced mouse model of NAFLD, the best available preclinical NASH mouse model, was used. RNAseq, histological, and metabolic pathway analyses were used to identify the potential signaling pathways modulated by BBR. LC\u2013MS was used to measure bile acid levels in the serum and liver. The real-time RT-PCR and Western blot analysis were used to validate the RNAseq data. Results: BBR not only significantly reduced hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also restored the bile acid homeostasis by targeting multiple pathways. In addition, BBR markedly inhibited inflammation by reducing immune cell infiltration and inhibition of neutrophil activation and inflammatory gene expression. Furthermore, BBR was able to inhibit hepatic fibrosis by modulating the expression of multiple genes involved in hepatic stellate cell activation and cholangiocyte proliferation. Consistent with our previous findings, BBR\u2019s beneficial effects are linked with the downregulation of microRNA34a and long noncoding RNA H19, which are two important players in promoting NASH progression and liver fibrosis. Conclusion: BBR is a promising therapeutic agent for NASH by targeting multiple pathways. These results provide a strong foundation for a future clinical investigation.<\/jats:p>","DOI":"10.3390\/cells10020210","type":"journal-article","created":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T09:49:21Z","timestamp":1611222561000},"page":"210","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Berberine Prevents Disease Progression of Nonalcoholic Steatohepatitis through Modulating Multiple Pathways"],"prefix":"10.3390","volume":"10","author":[{"given":"Yanyan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, 1220 East Broad Street, MMRB-5044, Richmond, VA 23298, USA"},{"name":"School of Pharmaceutical Science, Anhui University of Chinese Medicine, Qianjiang, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Ling","family":"Tai","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, 1220 East Broad Street, MMRB-5044, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derrick","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, 1220 East Broad Street, MMRB-5044, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, 1220 East Broad Street, MMRB-5044, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junkai","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, 1220 East Broad Street, MMRB-5044, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0366-6903","authenticated-orcid":false,"given":"Genta","family":"Kakiyama","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, 1220 East Broad Street, MMRB-5044, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily C.","family":"Gurley","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, 1220 East Broad Street, MMRB-5044, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinze","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinpeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1145-3999","authenticated-orcid":false,"given":"Jimin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L6M0L8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanhua","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical College of Virginia, 23298 Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip B.","family":"Hylemon","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, 1220 East Broad Street, MMRB-5044, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M.","family":"Pandak","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Anhui University of Chinese Medicine, Qianjiang, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiping","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, 1220 East Broad Street, MMRB-5044, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S47","DOI":"10.1016\/j.jhep.2014.12.012","article-title":"NAFLD: A multisystem disease","volume":"62","author":"Byrne","year":"2015","journal-title":"J. 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