PMID- 34790723 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220428 IS - 2305-5839 (Print) IS - 2305-5847 (Electronic) IS - 2305-5839 (Linking) VI - 9 IP - 20 DP - 2021 Oct TI - Berberine attenuates atherosclerotic lesions and hepatic steatosis in ApoE(-/-) mice by down-regulating PCSK9 via ERK1/2 pathway. PG - 1517 LID - 10.21037/atm-20-8106 [doi] LID - 1517 AB - 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 ApoE(-/-) mice. METHODS: The eight-week mice were divided into five groups: group 1 (wild type C57BL/6J mice with normal diet), group 2 (ApoE(-/-) mice with normal diet), group 3 [ApoE(-/-) mice with high-fat diet (HFD)], group 4 (ApoE(-/-) mice with HFD, and treatment with low dose BBR of 50 mg/kg/d), and group 5 (ApoE(-/-) mice 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 50 microg/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 ApoE(-/-) mice 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 ApoE(-/-) mice fed with HFD, which was associated with down-regulation of PCSK9 through ERK1/2 pathway. CI - 2021 Annals of Translational Medicine. All rights reserved. FAU - Ma, Chun-Yan AU - Ma CY AD - State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Shi, Xiao-Yun AU - Shi XY AD - Division of Endocrinology, Beijing Chaoyang Integrative Medicine Emergency Medical Center, Beijing, China. FAU - Wu, Ya-Ru AU - Wu YR AD - State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Zhang, Yue AU - Zhang Y AD - State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Yao, Yu-Hong AU - Yao YH AD - State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Qu, Hui-Lin AU - Qu HL AD - State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Zhang, Wei AU - Zhang W AD - State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Guo, Yuan-Lin AU - Guo YL AD - State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Xu, Rui-Xia AU - Xu RX AD - State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Li, Jian-Jun AU - Li JJ AD - State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. LA - eng PT - Journal Article PL - China TA - Ann Transl Med JT - Annals of translational medicine JID - 101617978 PMC - PMC8576642 OTO - NOTNLM OT - ApoE-/- mice OT - Berberine OT - PCSK9 OT - atherosclerosis OT - lipid metabolism COIS- Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-20-8106). The authors have no conflicts of interest to declare. EDAT- 2021/11/19 06:00 MHDA- 2021/11/19 06:01 PMCR- 2021/10/01 CRDT- 2021/11/18 07:02 PHST- 2020/12/21 00:00 [received] PHST- 2021/06/28 00:00 [accepted] PHST- 2021/11/18 07:02 [entrez] PHST- 2021/11/19 06:00 [pubmed] PHST- 2021/11/19 06:01 [medline] PHST- 2021/10/01 00:00 [pmc-release] AID - atm-09-20-1517 [pii] AID - 10.21037/atm-20-8106 [doi] PST - ppublish SO - Ann Transl Med. 2021 Oct;9(20):1517. doi: 10.21037/atm-20-8106.