Aloe-emodin exerts cholesterol-lowering effects by inhibiting proprotein convertase subtilisin/kexin type 9 in hyperlipidemic rats

Abstract

Hyperlipidemia (HPL) characterized by metabolic disorder of lipids and cholesterol is one of the important risk factors for cardiovascular diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent circulating regulator of LDL through its ability to induce degradation of the low-density lipoprotein cholesterol receptor (LDLR) in the lysosome of hepatocytes. Aloe-emodin (AE) is one of potentially bioactive components of Chinese traditional medicine Daming capsule. In this study we evaluated the HPL-lowering efficacy of AE in both in vivo and in vitro HPL models. High-fat diet-induced rats were treated with AE (100 mg/kg per day, ig) for 6 weeks. We found that AE administration significantly decreased the levels of total cholesterol (TC) and LDL in the serum and liver tissues. Moreover, AE administration ameliorated HPL-induced hepatic lipid aggregation. But AE administration did not significantly inhibit HMG-CoA reductase activity in the liver of HPL rats. A cellular model of HPL was established in human hepatoma (HepG2) cells treated with cholesterol (20 μg/mL) and 25-hydroxycholesterol (2 μg/mL), which exhibited markedly elevated cholesterol levels. The increased cholesterol levels could be reversed by subsequent treatment with AE (30 μM). In both the in vivo and in vitro HPL models, we revealed that AE selectively suppressed the sterol-regulatory element-binding protein-2 (SREBP-2) and hepatocyte nuclear factor (HNF)1α-mediated PCSK9 signaling, which in turn upregulated LDL receptor (LDLR) and promoted LDL uptake. This study demonstrates that AE reduces cholesterol content in HPL rats by inhibiting the hepatic PCSK9/LDLR pathway.

Naturally Occurring PCSK9 Inhibitors

“…Interestingly, aloe ameliorates the liver fat content, and in vitro studies on HepG2 cells show a negative effect on SREBP and HNF1α. As expected, the inhibition of both transcription factors determined a downregulation of PCSK9, associated with increased expression of LDLR and LDL uptake ( Figure 1 ) [ 187 ].…”

“…Interestingly, aloe ameliorates the liver fat content, and in vitro studies on HepG2 cells show a negative effect on SREBP and HNF1α. As expected, the inhibition of both transcription factors determined a downregulation of PCSK9, associated with increased expression of LDLR and LDL uptake (Figure 1) [187]. Not known In vitro Not known [191,192] 0.2% 20 20 Oxidation [191,192] Most of the individualized compounds have been shown to inhibit PCSK9 transcription factors, such as SREBP and HNF1α.…”

Network Pharmacology Integrated Molecular Docking Reveals the Mechanism of Zhongfeng Xingnao Formula against Intracerebral Hemorrhage

“…Several pharmacological properties on Mandenol have been reported including attenuating the expression of pro-in ammatory factors [41], Gudiya et al have shown that Myricanone was equipped with the biological functions of antioxidant, antiin ammatory, and anti-ischemia-reperfusion injury [42]. In addition, aloe-emodin is a widely existing anthraquinone in nature, which has been found to lower cholesterol by inhibiting PCSK9 [43].…”

LuHui Derivative, A Novel Compound That Inhibits the Fat Mass and Obesity-Associated (FTO), Alleviates the Inflammatory Response and Injury in Hyperlipidemia-Induced Cardiomyopathy

“…Fatty acid metabolism disorders and lipid accumulation in cardiomyocytes result in the release of various cytokines, especially promoting the secretion of leukocyte adhesion molecules and chemokines, culminating in cardiomyocyte damaged and impaired diastolic and systolic functions ( Schilling et al, 2012 ; Jia et al, 2016 ). Recent studies have examined the novel traditional Chinese medicines that may prevent the progression of hyperlipidemia ( Bian et al, 2020 ; Chen et al, 2020 ; Su et al, 2020 ).…”