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In a previous study, we have indicated that berberrubine (M3), a major metabolite of BBR in vivo, displays the most potential hypolipidemic effects via upregulating LDLR expression in human hepatoma (HepG2) cells compared with BBR and 3 other metabolites. Accordingly,\u00a09 M3 analogs (A1\u2010A9) were modified at the C9 position. We aimed to find a new promising agent by evaluating the cholesterol\u2010lowering effect and clarifying the related molecular mechanism. In the current study, the cellular cholesterol content was assayed with a commercial cholesterol assay kit. Real\u2010time polymerase chain reaction and Western blot assay were used to explore the molecular mechanism of M3 and its analogs on the hypolipidemic effect. Among M3 and its analogs, hydroxypropyl\u2010berberrubine (A8) exhibited the highest potential effects on the upregulation of LDLR expression, which was accompanied by a steady decline of proprotein convertase subtilisin\/kexin type 9 (PCSK9) messenger RNA and protein levels. Furthermore, inhibition of extracellular signal\u2010regulated kinase (ERK) activity with PD98059 prevented the upregulation of LDLR and downregulation of PCSK9 induced by A8. The current study revealed that M3 and its structurally modified analog, A8, could regulate hepatic LDLR and PCSK9 expression to exert lipid\u2010lowering effects via the ERK signal pathway, while A8 showed a stronger effect and might be a promising drug candidate against hyperlipidemia.<\/jats:p>","DOI":"10.1002\/jcb.27102","type":"journal-article","created":{"date-parts":[[2018,10,18]],"date-time":"2018-10-18T13:31:51Z","timestamp":1539869511000},"page":"1340-1349","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Berberrubine and its analog, hydroxypropyl\u2010berberrubine, regulate LDLR and PCSK9 expression via the ERK signal pathway to exert cholesterol\u2010lowering effects in human hepatoma HepG2 cells"],"prefix":"10.1002","volume":"120","author":[{"given":"Shijie","family":"Cao","sequence":"first","affiliation":[{"name":"Tianjin State Key Laboratory of Modern Chinese Medicine Tianjin University of 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