Isochlorogenic Acid C Alleviates High-Fat Diet-Induced Hyperlipemia by Promoting Cholesterol Reverse Transport

Liuyi Zheng; Guangyao Lin; Ruyue Li; Haining Gan; Xuejun Huang; Nan Yao; Dake Cai; Ziming Zhao; Zixuan Hu; Minyi Li; Huazhen Xu; Leyi Li; Sha Peng; Xinxin Zhao; Yijing Lai; Yuxing Chen; Dane Huang

doi:10.3389/fphar.2022.881078

Isochlorogenic Acid C Alleviates High-Fat Diet-Induced Hyperlipemia by Promoting Cholesterol Reverse Transport

Front Pharmacol. 2022 Jul 25:13:881078. doi: 10.3389/fphar.2022.881078. eCollection 2022.

Authors

Liuyi Zheng^{1

2}, Guangyao Lin³, Ruyue Li^{1

2

4}, Haining Gan^{1

2}, Xuejun Huang^{1

2}, Nan Yao^{1

2}, Dake Cai^{1

2}, Ziming Zhao^{1

2}, Zixuan Hu^{1

2}, Minyi Li^{1

2}, Huazhen Xu^{1

2}, Leyi Li^{1

2}, Sha Peng^{1

2}, Xinxin Zhao^{1

2}, Yijing Lai^{1

2}, Yuxing Chen^{1

2}, Dane Huang^{1

2}

Affiliations

¹ The Fifth Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China.
² Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangdong Provincial Second Hospital of Traditional Chinese Medicine (Guangdong Provincial Engineering Technology Research Institute of Traditional Chinese Medicine), Guangzhou, China.
³ School of Marxism, Guangzhou University of Chinese Medicine, Guangzhou, China.
⁴ Department of Pharmacy, Zhengzhou People's Hospital, Zhengzhou, China.

Abstract

Background: Promoting cholesterol reverse transport (RCT) has been proven to be a promising hyperlipidemia therapy since it is more effective for the treatment of atherosclerosis (AS) caused by hyperlipidemia. Liver X receptor (LXR) agonists can accelerate RCT, but most of them trigger undesirable liver steatosis due to the activation of liver LXRα. Aim: We aim to figure out whether isochlorogenic acid C (ICAC) facilitates RCT without causing hepatic steatosis. Methods: In vitro study, we established foam macrophages and macrophages with loaded NBD-cholesterol models to investigate the competence of RCT promoting ICAC. RT-qPCR and Western blot were used to verify ICAC's regulation of RCT and NF-κB inflammatory pathways. In this in vivo study, male 6-week-old C57BL/6 mice were fed a high-fat diet (HFD) to investigate ICAC's anti-hyperlipidemic effect and its functions in regulating RCT. The anti-hyperlipidemic effect of ICAC was evaluated by blood and liver lipid levels, liver hematoxylin, oil red o staining, and liver coefficient. Finally, mRNA levels of genes involved in RCT and inflammation pathways in the liver and intestine were detected by RT-qPCR. Results: ICAC prevented macrophages from foaming by up-regulating the LXRα mediated RCT pathway and down-regulating expression of the cholesterol absorption genes LDLR and CD36, as well as suppressing iNOS, COX2, and IL-1β inflammatory factors. In HFD-fed mice, ICAC significantly lowered the lipid level both in the serum and the liver. Mechanistic studies showed that ICAC strengthened the RCT pathway in the liver and intestine but didn't affect liver LXRα. Furthermore, ICAC impeded both adipogenesis and the inflammatory response in the liver. Conclusion: ICAC accelerated RCT without affecting liver LXRα, thus resulting in a lipid-lowering effect without increasing liver adipogenesis. Our results indicated that ICAC could be a new RCT promoter for hyperlipidemia treatment without causing liver steatosis.

Keywords: cholesterol efflux; foam cells; hyperlipemia; inflammatory; isochlorogenic acid C; reverse cholesterol transport.