Caffeine can alleviate non-alcoholic fatty liver disease by augmenting LDLR expression via targeting EGFR.

Increasing low-density lipoprotein receptor (LDLR) protein levels represents a key strategy for the prevention and treatment. Berberine can reportedly alleviate non-alcoholic fatty liver disease (NAFLD) by increasing the LDLR expression in an ERK1/2 signaling-dependent manner of NAFLD. Studies have shown that caffeine can inhibit fat deposition in the livers of mice; however, caffeine has not been reported to alleviate NAFLD by augmenting the LDLR expression via targeting EGFR. Here, an MTT assay, western blotting, RT-qPCR, immunohistochemistry, and surface plasmon resonance (SPR) analysis were used to investigate the role of caffeine in low-density lipoprotein cholesterol (LDL-C) clearance both in vitro and in vivo. In vitro, we found that caffeine could activate the EGFR-ERK1/2 signaling pathway in HepG2 cells, leading to increased LDLR mRNA and protein expression, and this effect could be inhibited by cetuximab. The SPR assay results have indicated that caffeine may increase the LDLR expression by directly binding to the EGFR extracellular domain and activating the EGFR-ERK1/2 signaling pathway. In vivo, caffeine markedly improved fatty liver and related blood indices in ApoE KO mice with high-fat-diet-induced NAFLD. Consistent with our in vitro results, we found that caffeine could also activate EGFR-ERK1/2 signaling and promote the LDLR expression in ApoE KO mice. In summary, caffeine can enhance the LDLR expression by directly binding to EGFR and activating the EGFR-ERK1/2 signaling pathway. EGFR signaling may represent a novel target for the prevention and treatment of NAFLD.

20(S)-Protopanaxadiol decreases atherosclerosis in ApoE KO mice by increasing the levels of LDLR and inhibiting its binding with PCSK9.

Chinese medicinal and edible plants such as Panax notoginseng and ginseng are widely used for the treatment of atherosclerosis (AS). AS is the main pathological basis of cardiac-cerebral vascular disease, which seriously threatens human health and quality of life. Low-density lipoprotein (LDL) is the main pathogenic factor of AS. The LDL receptor (LDLR) is an important protein that functions to mediate the uptake and degradation of plasma LDL. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) can mediate the internalization and degradation of LDLR. So, increasing the LDLR level by inhibiting PCSK9 is an important means of prevention and treatment of AS. In this study, by combining interaction technology (surface plasmon resonance, SPR) of small molecule compounds with membrane receptor proteins, cell experiments, and in vivo experiments, it is proved for the first time that 20(S)-protopanaxadiol (PPD), as a hydrolytic product of Panax notoginseng saponins in the intestinal tract, can bind to the extracellular domain of LDLR and inhibit the role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in mediating LDLR degradation. The results showed that PPD significantly reduced aortic plaques and hepatic steatosis in HFD-fed ApoE KO mice. LDLR protein levels were elevated in the liver tissues isolated from PPD-treated HFD-fed ApoE KO mice and PPD-treated HepG2 cells. Our findings demonstrated that PPD significantly increased LDLR levels and reduced AS in the HFD-fed ApoE KO mice on account of LDLR degradation being inhibited by PPD inhibiting the interaction between PCSK9 and LDLR.