Berberine Prevents Disease Progression of Nonalcoholic Steatohepatitis through Modulating Multiple Pathways
Yanyan Wang,
Yun-Ling Tai,
Derrick Zhao,
Yuan Zhang,
Junkai Yan,
Genta Kakiyama,
Xuan Wang,
Emily C. Gurley,
Jinze Liu,
Jinpeng Liu,
Jimin Liu,
Guanhua Lai,
Phillip B. Hylemon,
William M. Pandak,
Weidong Chen,
Huiping Zhou
Affiliations
Yanyan Wang
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
Yun-Ling Tai
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
Derrick Zhao
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
Yuan Zhang
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
Junkai Yan
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
Genta Kakiyama
Department of Internal Medicine, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA
Xuan Wang
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
Emily C. Gurley
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
Jinze Liu
Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USA
Jinpeng Liu
Department of Computer Science, University of Kentucky, Lexington, KY 40506, USA
Jimin Liu
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L6M0L8, Canada
Guanhua Lai
Department of Pathology, Medical College of Virginia, 23298 Virginia Commonwealth University, Richmond, VA 23298, USA
Phillip B. Hylemon
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
William M. Pandak
Department of Internal Medicine, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA
Weidong Chen
School of Pharmaceutical Science, Anhui University of Chinese Medicine, Qianjiang, Hefei 230012, China
Huiping Zhou
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
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–MS 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’s 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.
