Modulation of hepatic lipoprotein metabolism by dietary procyanidins
INTRODUCTION<br/>During the past decade, Nutrition research has been subjected to a shift of focus, from epidemiology and physiology to the comprensión of the molecular basis of nutrients actions.<br/>Thus, the new "-omics" disciplines transcriptomics, proteomics or metabolomic...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2007 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/8662 |
| Acceso en línea: | http://www.tdx.cat/TDX-1205107-143046 http://hdl.handle.net/10803/8662 |
| Access Level: | acceso abierto |
| Palabra clave: | SREBP SHP FXR liver lipoproteins cholesterol triglycerides flavonoids Procyanidins 663/664 |
| Sumario: | INTRODUCTION<br/>During the past decade, Nutrition research has been subjected to a shift of focus, from epidemiology and physiology to the comprensión of the molecular basis of nutrients actions.<br/>Thus, the new "-omics" disciplines transcriptomics, proteomics or metabolomics, provide the tools to understand the molecular mechanisms involved in the modulation of gene expression by nutrients. The study of the beneficial properties of wine procyanidins has not avoided this shift of focus. Thus, from the initial studies which defined the "French paradox", to nowadays, a wide array of studies have been focused in defining the properties of the non-alcoholic components of red wine, mainly flavonoids, a family of polyphenolic compounds. The objectives of this thesis have been to define the molecular mechanisms by which grape procyanidins modulate the hepatic metabolism of lipoproteins, reducing the risk of cardiovascular disease and other pathologies which basis is found in the dysregulation of the lipoprotein metabolism.<br/>SUMMARY<br/>In the present thesis, the effect of procyanidins in the hepatic lipoprotein metabolism has been studied. With this objective, HepG2, HeLa and CV-1 cells have been used as invitro models. In vivo studies have been performed in Wistar rats and C57BL6 mice, wild-type and transgenic mice lacking SHP (NR0B2) and FXR (NR5H1).<br/>RESULTS<br/>1. Procyanidins improve plasma lipid profile in the postprandial phase in rats. A single oral dose of procyanidins decreases plasma triglycerides and ApoB levels to 50% of control values. In addition LDL-Cholesterol is significantly reduced, thus improving the atherosclerotic risk index.<br/>2. Procyanidins display a triglyceride-lowering effect both in vivo and in vitro. In rat and mouse, procyanidin treatment triggers a hypotriglyceridemic response. In HepG2 cultures, procyanidins down-regulate the secretion of triglycerides and ApoB, thus showing that these flavonoids act directly on hepatic cells. This fact strongly suggests that, in vivo, a direct action of procyanidins on the liver contributes to their hypotriglyceridemic response.<br/>3. Nuclear receptor Small Heterodimer Partner (SHP) is a target of procyanidins in hepatic cells. Procyanidins modulate the expression of SHP, rapidly increasing its expression in rat liver as well as in HepG2 cultured cells.<br/>4. SHP mediates the triglyceride-lowering activity of procyanidins in vitro and in vivo. When SHP expression is silenced in HepG2 or abolished in SHP-null mice, procyanidins lose their hypotriglyceridemic activity. In contrast, in SHP-silenced HepG2 cells, procyanidins are still able to reduce apoB secretion. Hence, procyanidins reduce triglyceride via a SHP-dependent mechanism, whereas they reduce apoB in a SHPindependent manner.<br/>5. Nuclear receptor Farnesoid X Receptor (FXR) is an essential mediator of the hypotriglyceridemic action of procyanidins upstream SHP. Oral gavage of procyanidins to FXR-null mice have not a hypotriglyceridemic effect. Moreover, luciferase based in vitro assays showed that procyanidins increase the transcriptional activity of FXR. Thus, FXR is an essential component of the signalling pathway used by procyanidins to elicit the triglyceride lowering effect.<br/>6. Key genes of the inflammation process are targets of procyanidins in liver, in the postprandial phase. Oral administration of procyanidins to rats rapidly downregulates the expression, in liver, of transcription factor Egr1, a mediator of the hepatic inflammatory response, and several acute-phase proteins, namely haptoglobin, fibrinogen B and alpha-1 antitrypsin. In addition, expression of DUSP6, a component of the ERK1/2 subfamily of MAPK, is repressed by this treatment. Nfkbia, a repressor of NF-kB activity, is overexpressed upon procyanidin treatment. This expression pattern strongly suggests that procyanidins attenuate the pro-inflammatory state associated to the postprandial phase. |
|---|