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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??g/mL) and 25-hydroxycholesterol (2??g/mL), which exhibited markedly elevated cholesterol levels. The increased cholesterol levels could be reversed by subsequent treatment with AE (30??M). 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)1?-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.

SUBMITTER: Su ZL

PROVIDER: S-EPMC7470781 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Su Zhen-Li ZL Hang Peng-Zhou PZ Hu Juan J Zheng Yu-Yang YY Sun Han-Qi HQ Guo Jing J Liu Ke-Yu KY Du Zhi-Min ZM

Acta pharmacologica Sinica 20200318 8

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 w ...[more]

PMID: 32203084

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Project description:Alirocumab undergoes target-mediated clearance via binding of proprotein convertase subtilisin/kexin type 9 (PCSK9). Statins increase PCSK9 levels; the effects of nonstatin lipid-lowering therapies are unclear. Every-4-weeks dosing of alirocumab may be appropriate for some patients in absence of background statin but is not yet approved. Low-density lipoprotein cholesterol (LDL-C), PCSK9, and alirocumab levels were assessed in subjects (LDL-C >130 mg/dL, n=24/group) after a 4-week run-in taking oral ezetimibe, fenofibrate, or ezetimibe placebo, when alirocumab 150 mg every 4 weeks (days 1, 29, and 57) was added. Maximal mean LDL-C reductions from day -1 baseline (prealirocumab) occurred on day 71 in all groups: alirocumab plus placebo, 47.4%; alirocumab plus ezetimibe, 56.6%; and alirocumab plus fenofibrate, 54.3%. LDL-C reductions were sustained through day 85 with alirocumab plus placebo (47.0%); the duration of effect was slightly diminished at day 85 versus day 71 with ezetimibe (49.6%) or fenofibrate combinations (43.2%). Free PCSK9 concentrations were lowest at day 71 in all groups, then increased over time; by day 85, free PCSK9 concentrations were higher, and alirocumab levels lower, with alirocumab plus fenofibrate, and to a lesser extent alirocumab plus ezetimibe, versus alirocumab plus placebo. Alirocumab 150 mg every 4 weeks produced maximal LDL-C reductions of 47% in combination with placebo and 54% to 57% in combination with ezetimibe or fenofibrate. The oral lipid-lowering therapies appear to increase PCSK9 levels, leading to increased alirocumab clearance. Although the duration of effect was modestly diminished with alirocumab plus ezetimibe/fenofibrate versus placebo, the effect was less than observed in trials with background statins, and it would not preclude the use of alirocumab every 4 weeks in patients taking these nonstatin lipid-lowering therapies concomitantly. URL: http://www.Clinicaltrials.gov. Unique identifier: NCT01723735.

Dataset Information

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

Publications

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

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