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Potent and Pleiotropic Effects of Preussin B on Inhibition of Intestinal Cholesterol Absorption: Integrative Mechanisms of Action and Proteomic Analysis

ABSTRACT: Preussin (Asperidine B) has recently shown its lipid-lowering effects by inhibiting intestinal absorption in human colorectal adenocarcinoma (Caco-2) cells and ex vivo intestinal loop in rats. While statins are widely prescribed as the primary line drug of choice for lowering hyperlipidemia, ezetimibe is the only drug that reduces intestinal cholesterol absorption, and is also optional for statin-nonresponsive individuals. To gain more understanding of the mechanisms of action and lead compounds, the derivatives of preussin: TP3, TP4, TP5, TP6, and TP7 have recently been synthesized, and the structures were confirmed using 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. However, whether these derivatives exhibited inhibitory effects on cholesterol absorption is unknown. Thus, this study aims to investigate the most potent inhibitory effect of cholesterol absorption of preussin derivatives using fluorescent-micelle cholesterol transport in intestinal Caco-2 cells, confirmed by an in vivo cholesterol absorption assay. Possible targets of the lead compounds were identified using a protein binding assay and label-free quantification using proteomic analyses. Results showed that all tested preussin derivatives markedly inhibited cholesterol absorption in the intestinal Caco2 cells to a similar extent to preussin and ezetimibe. TP5 (preussin B) consistently displayed a significant reduction of plasma cholesterol, identical to preussin and ezetimibe, with the same potency in rats. In addition, the proteomic analysis found that substantial differentially expressed changes in six proteins are involved in the lipid metabolism pathway. Interestingly, GOT2, as one of these six proteins in the lipid transport pathway, consistently interacts with TP5. The molecular docking and dynamic prediction showed that TP5 coupled with GOT2 at a pocket comparable to its cofactor. These findings suggest that preussin B has therapeutic potential as a candidate for a cholesterol absorption inhibitor to treat hyperlipidemia.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Chutima S. Vaddhanaphuti

PROVIDER: PXD066787 | JPOST Repository | Thu Dec 04 00:00:00 GMT 2025

REPOSITORIES: jPOST

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			Action	DRS
	Control1_setTP5_IDA1.wiff.scan	Wiff
	Control1_setTP5_IDA2.wiff.scan	Wiff
	Control1_setTP5_SWATH1.wiff.scan	Wiff
	Control1_setTP5_SWATH2.wiff.scan	Wiff
	Control2_setTP5_IDA1.wiff.scan	Wiff

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Project description:McAuley2012 - Whole-body Cholesterol Metabolism Lipid metabolism has a key role to play in human longevity and healthy aging. A whole-body mathematical model of cholesterol metabolism that explores the changes in both the rate of intestinal cholesterol absorption and the hepatic rate of clearance of LDL-C from the plasma, has been presented here. The model showed that of these two mechanisms, changes to the rate of LDL-C removal from the plasma with age had the most significant effect on cholesterol metabolism. The original SBML model file was generated using MathSBML 2.5.1. This model is described in the article: A whole-body mathematical model of cholesterol metabolism and its age-associated dysregulation. Mc Auley MM, Wilkinson DJ, Jones JJ, Kirkwood TT. BMC Syst Biol. 2012 Oct 10;6(1):130. Abstract: BACKGROUND: Global demographic changes have stimulated marked interest in the process of ageing. There has been, and will continue to be, an unrelenting rise in the number of the oldest old ( >85 years of age). Together with an ageing population there comes an increase in the prevalence of age related disease. Of the diseases of ageing, cardiovascular disease (CVD) has by far the highest prevalence. It is regarded that a finely tuned lipid profile may help to prevent CVD as there is a long established relationship between alterations to lipid metabolism and CVD risk. In fact elevated plasma cholesterol, particularly Low Density Lipoprotein Cholesterol (LDL-C) has consistently stood out as a risk factor for having a cardiovascular event. Moreover it is widely acknowledged that LDL-C may rise with age in both sexes in a wide variety of groups. The aim of this work was to use a whole-body mathematical model to investigate why LDL-C rises with age, and to test the hypothesis that mechanistic changes to cholesterol absorption and LDL-C removal from the plasma are responsible for the rise. The whole-body mechanistic nature of the model differs from previous models of cholesterol metabolism which have either focused on intracellular cholesterol homeostasis or have concentrated on an isolated area of lipoprotein dynamics. The model integrates both current and previously published data relating to molecular biology, physiology, ageing and nutrition in an integrated fashion. RESULTS: The model was used to test the hypothesis that alterations to the rate of cholesterol absorption and changes to the rate of removal of LDL-C from the plasma are integral to understanding why LDL-C rises with age. The model demonstrates that increasing the rate of intestinal cholesterol absorption from 50% to 80% by age 65 years can result in an increase of LDL-C by as much as 34mg/dL in a hypothetical male subject. The model also shows that decreasing the rate of hepatic clearance of LDL-C gradually to 50% by age 65 years can result in an increase of LDL-C by as much as 116mg/dL. CONCLUSIONS: Our model clearly demonstrates that of the two putative mechanisms that have been implicated in the dysregulation of cholesterol metabolism with age, alterations to the removal rate of plasma LDL-C has the most significant impact on cholesterol metabolism and small changes to the number of hepatic LDL receptors can result in a significant rise in LDL-C. This first whole-body systems based model of cholesterol balance could potentially be used as a tool to further improve our understanding of whole-body cholesterol metabolism and its dysregulation with age. Furthermore, given further fine tuning the model may help to investigate potential dietary and lifestyle regimes that have the potential to mitigate the effects aging has on cholesterol metabolism. This model is hosted on BioModels Database and identified by: MODEL1206010000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Background: Resveratrol has been demonstrated to exert pleiotropic health beneficial effects. Among the various mechanisms of action antioxidant, anti-inflammatory, cardio- and cancer-protective outcomes have been reported. Particularly, an important function of this natural compound against atherosclerosis has been postulated and the action of resveratrol on lipids and lipoprotein levels seems to be of relevance in this pathology, but also for other metabolic diseases. Accordingly, taking into consideration the straight contact of resveratrol with the intestine, this study aimed to gain insights into the protective effects of trans-resveratrol on enterocyte physiology and metabolism in proinflammatory conditions. For this purpose, a DNA microarray analysis was conducted in Caco-2 cells where global gene expression profile at intestinal level was screened. Cells were pretreated with 50 Î¼Î? of trans-resveratrol and, subsequently, lipopolysaccharide (LPS) was added for 48 h. Results: The microarray analysis revealed 121 genes differentially expressed between resveratrol-treated and non-treated cells (B> 0). Four genes, inhibitor of DNA binding 1(ID1), histidine-rich glycoprotein (HRG), NADPH oxidase (NOX1) and sprouty homolog 1 (SPRY), were upregulated by LPS treatment, but significantly downregulated with trans-resveratrol pretreatment (padj< 0.05). Moreover, genes implicated in pathways related to lipid metabolism, such as synthesis of lipids (z-score= -1.195) and concentration of cholesterol (z-score= -0.109), were markedly downregulated by trans-resveratrol. Other genes implicated in lipid metabolism, but also in cell death and survival function, such as transcription factors KrÃ¼ppel-like factor 5 (KLF5) and amphiregulin (AREG), were also significantly inhibited by trans-resveratrol pretreatment. RT-qPCR-data confirmed the microarray results. Special mention deserves acyl-CoA synthetase long-chain family member 3 (ACSL3) and endothelial lipase (LIPG), which were downregulated by the stilbene and have been previously associated with fatty acid synthesis and obesity in other tissues. Conclusions: This study envisages that trans-resveratrol might exert important anti-lipogenic effect at intestinal level under proinflammatory conditions, which have not been previously described. The experiment was conducte in Caco-2 cells. There were three experimental groups (n=5), Caco-2 cells stimulated with lipopolysaccharides (LPS), Caco-2 cells stimulated with LPS and pre-treated with trans-resveratrol (LPS+RSV) and non-treated Caco-2 cells.

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Potent and Pleiotropic Effects of Preussin B on Inhibition of Intestinal Cholesterol Absorption: Integrative Mechanisms of Action and Proteomic Analysis

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