ABSTRACT
The contemporary pathophysiological model of non-alcoholic fatty liver disease (NAFLD) comprises multiple parallel pathways with a dynamic cross talk that cumulate in steatosis and inflammation, and ultimately fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma. So far, no pharmacological treatment has been approved. A major impediment of drugs, in general, is that they are intended to act on one single target in the pathology of a disease. However, the multitude of pathways involved in the pathogenesis of NAFLD underpins the need for treatments that address these various pathways. Interestingly, flavonoids have been found to have positive effects on lipid metabolism, insulin resistance, inflammation, and oxidative stress, the most important pathophysiological pathways in NAFLD. This puts flavonoids in the spotlight for the treatment of NAFLD and prompted us to review the existing evidence for the use of these food-derived compounds in the treatment of NAFLD.
Subject(s)
Flavonoids/therapeutic use , Non-alcoholic Fatty Liver Disease/drug therapy , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Flavonoids/chemistry , Humans , Molecular Structure , Non-alcoholic Fatty Liver Disease/etiology , Plants, Medicinal/chemistryABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease. An evidence-based pharmacological treatment for NAFLD is still lacking, but flavonoids have shown therapeutic potential. The present study was designed to investigate the effect of the flavonoid monoHER on the onset of NAFLD in Ldlr(-/-) mice on a high-fat and high-cholesterol diet. The focus was put on the effect on oxidative stress as well as the adaptive response. Wild type mice served as a control and the effect of monoHER was compared to that of a placebo. In the Ldlr(-/-) group, monoHER provided only a mild protection against oxidative stress. In the placebo Ldlr(-/-) group an adaptive response elicited by the NRF2 antioxidant defense system was observed, evidenced by a higher HO-1 and Gpx3 gene expression, as well as an increased redox status, evidenced by the higher GSH/GSSG ratio. In the monoHER treated Ldlr(-/-) group both the adaptive response as well as the increase in redox status tended to be higher, although this did not reach significance on a group level. Unexpectedly, a strong within animal relationship was found that links a high adaptive response to a low redox status in the monoHER Ldlr(-/-) group. This correlation was absent in the placebo and wild type group. The concept that emerges is that a thiol-reactive oxidation product of monoHER, formed during oxidative stress, selectively induces the NRF2 pathway and enforces the endogenous antioxidant shield, to provide protection against NAFLD.
Subject(s)
Flavonoids/pharmacology , Hydroxyethylrutoside/analogs & derivatives , Non-alcoholic Fatty Liver Disease/drug therapy , Oxidative Stress/drug effects , Receptors, LDL/genetics , Animals , Antioxidants/pharmacology , Female , Gene Expression Regulation , Glutathione Peroxidase/metabolism , Heme Oxygenase-1/metabolism , Hydroxyethylrutoside/pharmacology , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , NF-E2-Related Factor 2/metabolism , Oxidation-Reduction , Reactive Oxygen SpeciesABSTRACT
The flavonoid 7-mono-O-(ß-hydroxyethyl)-rutoside (monoHER) is an effective protector against doxorubicin induced toxicity which has been related to the antioxidant activity of monoHER. The present study examines the potential relevance of the direct scavenging activity of the flavonoid. The potency of the direct antioxidant effect was confirmed by its instantaneous protection against intracellular oxidative stress in human umbilical vein endothelial cells at therapeutically achievable concentrations (EC50=60 nM) underpinning the involvement of a direct scavenging activity. This direct effect of monoHER is substantiated by (i) its site specific scavenging effect, i.e. on a molecular level monoHER is positioned at the location of radical formation, (ii) its position in the antioxidant network, i.e. on a biochemical level oxidized monoHER quickly reacts with ascorbate or glutathione, (iii) its location in the vascular system, i.e. on a cellular level monoHER is localized in the endothelial and smooth muscle cells in the vascular wall. It is concluded that the flavonoid monoHER can display a physiologically important direct antioxidant effect.
Subject(s)
Antioxidants/pharmacology , Endothelial Cells/drug effects , Rutin/analogs & derivatives , Rutin/pharmacology , Animals , Carotid Arteries/drug effects , Cell Survival , Cells, Cultured , Humans , Hydroxyethylrutoside/analogs & derivatives , Hydroxyethylrutoside/pharmacology , Hydroxyl Radical , Mice , Mice, Inbred C57BL , Oxidative StressABSTRACT
Plasma citrate levels were found to be elevated in non-alcoholic fatty liver disease (NAFLD) patients. Cellular experiments indicated that increased citrate levels might originate from an excess of fatty acids. The impact of elevated citrate levels on oxidative stress was examined. It was found that citrate stimulated hydrogen peroxide induced intracellular oxidative stress in HepG2 cells. This was related to the promotion of iron mediated hydroxyl radical formation from hydrogen peroxide by citrate. The stimulating effect of citrate on the reactivity of iron promotes oxidative stress, a crucial process in the progression of NAFLD.