Berberine attenuates atherosclerotic lesions and hepatic steatosis in ApoE-/- mice by down-regulating PCSK9 via ERK1/2 pathway

Chun-Yan Ma; Xiao-Yun Shi; Ya-Ru Wu; Yue Zhang; Yu-Hong Yao; Hui-Lin Qu; Wei Zhang; Yuan-Lin Guo; Rui-Xia Xu; Jian-Jun Li

doi:10.21037/atm-20-8106

Berberine attenuates atherosclerotic lesions and hepatic steatosis in ApoE^-/- mice by down-regulating PCSK9 via ERK1/2 pathway

Ann Transl Med. 2021 Oct;9(20):1517. doi: 10.21037/atm-20-8106.

Authors

Chun-Yan Ma^#¹, Xiao-Yun Shi^#², Ya-Ru Wu^#¹, Yue Zhang^#¹, Yu-Hong Yao¹, Hui-Lin Qu¹, Wei Zhang¹, Yuan-Lin Guo¹, Rui-Xia Xu¹, Jian-Jun Li¹

Affiliations

¹ 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.
² Division of Endocrinology, Beijing Chaoyang Integrative Medicine Emergency Medical Center, Beijing, China.

^# Contributed equally.

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 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 µg/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.

Keywords: ApoE-/- mice; Berberine; PCSK9; atherosclerosis; lipid metabolism.