PMID: Ann Transl Med. 2021 Oct ;9(20):1517. PMID: 34790723 Abstract Title: Berberine attenuates atherosclerotic lesions and hepatic steatosis in ApoEmice by down-regulating PCSK9 via ERK1/2 pathway. Abstract: Background: It has been demonstrated that berberine (BBR), a kind of alkaloid derived from Chinese herbal medicine, has multiple pharmacological effects on human's diseases including anti-atherosclerosis action. However, although the previous studies showed that the beneficial impact of BBR on atherosclerosis might be associated with proprotein convertase subtilisin/kexin type 9 (PCSK9), the exact underlying mechanism are not fully determined. The present study aimed to investigate potential mechanisms of anti-atherosclerosis by BBR using ApoEmice.Methods: The eight-week mice were divided into five groups: group 1 (wild type C57BL/6J mice with normal diet), group 2 (ApoEmice with normal diet), group 3 [ApoEmice with high-fat diet (HFD)], group 4 (ApoEmice with HFD, and treatment with low dose BBR of 50 mg/kg/d), and group 5 (ApoEmice with HFD, and treatment with high dose BBR of 100 mg/kg/d). After a 16-week treatment, the blood sample, aorta and liver were collected for lipid analysis, hematoxylin-eosin (HE) or oil red O staining, and Western blotting respectively. Besides, HepG2 Cells were cultured and treated with different concentrations of BBR (0, 5, 25 and 50µg/mL) for 24 hours. Subsequently, cells were collected for real-time PCR or western blotting assays. Finally, the expression levels of PCSK9, LDL receptor (LDLR), ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), and scavenger receptor class B type I (SR-BI)were examined.Results: Fifty mg/kg/d and 100 mg/kg/d of BBR decreased total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) cholesterol (LDL-C), and increased high-density lipoprotein cholesterol (HDL-C) level. Moreover, BBR reduced aorta atherosclerotic plaque, and ameliorated lipid deposition in ApoEmice fed with HFD. Finally, in vitro study showed that BBR promoted intracellular cholesterol efflux, up-regulated LDLR and down-regulated PCSK9 expression via the ERK1/2 pathway in cultured HepG2 cells.Conclusions: Data indicated that BBR significantly attenuated lipid disorder, reduced aortic plaque formation, and alleviated hepatic lipid accumulation in ApoEmice fed with HFD, which was associated with down-regulation of PCSK9 through ERK1/2 pathway.
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