Fisetin Protects Against Hepatic Steatosis Through Regulation of the Sirt1/AMPK and Fatty Acid β-Oxidation Signaling Pathway in High-Fat Diet-Induced Obese Mice (original) (raw)
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Effects of fisetin on mouse lipid metabolism in vitro and in vivo
Objective: The aim of this study was to investigate the anti-obesity effects of the polyphenol fisetin in 3T3-L1 preadipocytes and C57BL/6 female mice that were fed a high-fat diet (HFD). Background: Polyphenols, such as sakuranetin, hesperetin, tea catechin, and quercetin, reportedly regulate adipocyte differentiation in 3T3-L1 cells. Furthermore, green tea, apple, and molokheiya polyphenols exhibit anti-obesity activities in HFD-treated obese rats or mice. Fisetin is abundant in plants, fruits, and vegetables and exhibits multiple biological activities, such as the inhibition of prostate cancer growth, neuroprotection, and protection against osteoporosis. In addition, fisetin regulates obesity by targeting mammalian target of rapamycin complex 1 signaling, which is a central mediator of lipid biosynthesis. Materials and methods: (1) in vitro experiments; we investigated the effects of fisetin on intracellular lipid accumulation and glycerol-3-phosphate activity during the differentiation of 3T3-L1 cells. We monitored expression of adipogenetic related-genes in 3T3-L1 cells by real-time polymerase-chain-reaction. (2) in vivo experiments; we examined the effects of fisetin on anti-obesity activities in C57BL/6 female mice that were fed a HFD. Results: Fisetin inhibited intracellular lipid accumulation and glycerol-3-phosphate activity during the differentiation of 3T3-L1 cells in a dose-dependent manner (50-75 M). In addition, real-time polymerase-chain-reaction revealed that this compound suppressed the expression of peroxisome proliferator-activated receptor γ (PPARγ), adipocyte protein 2, and perilipin mRNAs in 3T3-L1 cells. In contrast, anti-obesity activities, such as reduction of body weight and fat tissue, and improvements in obesity-related blood biochemical parameters and fatty liver, were not observed in HFD-induced mice treated with fisetin (20 mg/kg body weight) by intraperitoneal injections twice per week for 8 weeks. Conclusions: Fisetin exerted anti-adipogenic activities by inhibiting the expression of PPARγ mRNA in 3T3-L1 preadipocytes. However, fisetin (20 mg/kg body weight) did not affect HFD-induced obesity. Our findings indicated that fisetin could be used as an effective remedy in the treatment of the symptoms of obesity.
The Potential of Flavonoids in the Treatment of Non-alcoholic Fatty Liver Disease
Critical reviews in food science and nutrition, 2015
The contemporary pathophysiological model of non-alcoholic fatty liver disease (NAFLD) consists of 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.
Biochimica et biophysica acta, 2018
Non-alcoholic fatty liver disease (NAFLD) affects 25% of adults and at present no licensed medication has been approved. Despite its complex patho-physiology, dietary strategies aiming at delaying or preventing NAFLD have taken a reductionist approach, examining the impact of single components. Accumulating evidence suggests that n-3 LC-PUFAs are efficacious in regulating lipogenesis and fatty acid oxidation. In addition, plant derived flavonoids are also emerging as a dietary strategy for NAFLD prevention, with efficacy attributed to their insulin sensitising and indirect antioxidant effects. Based on knowledge of their complementary molecular targets, we aimed to demonstrate that the combination of n-3 LC-PUFA (n-3) and flavan-3-ols (FLAV) prevents NAFLD. In a high-fat high-fructose (HF/HFr) fed C57Bl/6J mouse model, the independent and interactive impact of n-3 and FLAV on histologically defined NAFLD, insulin sensitivity, weight gain, intestinal and hepatic gene expression, inte...
Journal of Functional Foods, 2016
Hepatic steatosis and insulin resistance are highly prevalent and play a vital role in the development of nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). The present study examined the protective effects of naturally occurring flaxseed lignan secoisolariciresinol diglucoside (SDG) on these metabolic disorders resulting from high fat diet (HFD). SDG (0.05%, w/w) supplementation for 16 weeks attenuated body weight gain, hyperlipidaemia and hepatic steatosis in HFD (60% kcal from fat)-challenged C57BL/6J mice. Moreover, SDG lowered fasting serum glucose and insulin, and improved homeostasis model assessment of insulin resistance (HOMA-IR) index, glucose tolerance, and insulin response in HFD-fed mice. Furthermore, SDG prevented HFD-induced inhibition of protein kinase B, insulin receptor substrate-1 and AMP-activated protein kinase activation in the liver of HFDfed mice. These findings indicate that SDG supplementation alleviates hepatic steatosis and insulin resistance, at least in part, by enhancing insulin signalling and AMPK activation.
Food and Chemical Toxicology, 2008
Propose Obesity is a fast growing epidemic worldwide. During obesity, the increase in adipose tissue mass arise from two different mechanisms, namely, hyperplasia and hypertrophy. Hyperplasia which is the increase in adipocyte number is characteristic of severe obese patients. Recently, there has been much interest in targeting adipogenesis as therapeutic strategy against obesity. Flavonoids have been shown to regulate several pathways and affect a number of molecular targets during specific stages of adipocyte development. Methods Presently, we provide a review of key studies evaluating the effects of dietary flavonoids in different stages of adipocyte development with a particular emphasis on the investigations that explore the underlying mechanisms of action of these compounds in human or animal cell lines as well as animal models. Results Flavonoids have been shown to regulate several pathways and affect a number of molecular targets during specific stages of adipocyte development. Although most of the studies reveal anti-adipogenic effect of flavonoids, some flavonoids demonstrated proadipogenic effect in mesenchymal stem cells or preadipocytes. Conclusion The anti-adipogenic effect of flavonoids is mainly via their effect on regulation of several pathways such as induction of apoptosis, suppression of key adipogenic transcription factors, activation of AMPK and Wnt pathways, inhibition of clonal expansion, and cell-cycle arrest. Keywords Adipogenesis • Flavonoids • Obesity • Hyperplasia • Adipocyte Abbreviations FABP4 Fatty acid-binding protein 4 hBM-MSCs Human bone marrow mesenchymal stem cells LPL Lipoprotein lipase ChREBP Carbohydrate response element-binding protein EGCG Epigallocatechin gallate FASN Fatty acid synthase GPDH Glycerol-3-phosphate dehydrogenase
Marine Drugs
Non-alcoholic fatty liver disease (NAFLD) is the emerging cause of chronic liver disease globally and lack of approved therapies. Here, we investigated the feasibility of combinatorial effects of low molecular weight fucoidan and high stability fucoxanthin (LMF-HSFx) as a therapeutic approach against NAFLD. We evaluated the inhibitory effects of LMF-HSFx or placebo in 42 NAFLD patients for 24 weeks and related mechanism in high fat diet (HFD) mice model and HepaRGTM cell line. We found that LMF-HSFx reduces the relative values of alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglyceride, fasting blood glucose and hemoglobin A1c in NAFLD patients. For lipid metabolism, LMF-HSFx reduces the scores of controlled attenuation parameter (CAP) and increases adiponectin and leptin expression. Interestingly, it reduces liver fibrosis in NAFLD patients, either. The proinflammatory cytokines interleukin (IL)-6 and interferon-γ are reduced in LMF-HSFx group. In HFD m...
Oxidative Medicine and Cellular Longevity, 2021
Fatty liver disease (FLD), including nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD), is a serious chronic metabolic disease that affects a wide range of people. Lipid accumulation accompanied by oxidative stress and inflammation in the liver is the most important pathogenesis of FLD. The plant-based, high-fiber, and low-fat diet has been recommended to manage FLD for a long time. This review discusses the current state of the art into the effects, mechanisms, and clinical application of plant-based foods in NAFLD and AFLD, with highlighting related molecular mechanisms. Epidemiological evidence revealed that the consumption of several plant-based foods was beneficial to alleviating FLD. Further experimental studies found out that fruits, spices, teas, coffee, and other plants, as well as their bioactive compounds, such as resveratrol, anthocyanin, curcumin, and tea polyphenols, could alleviate FLD by ameliorating hepatic steatosis, oxidative stress...
2014
Dietary flavonoids may protect against cardiovascular diseases (CVD). Increased circulating lipid levels and hepatic lipid accumulation are known risk factors for CVD. The aim of this study was to investigate the effects and underlying molecular mechanisms of the flavonoid quercetin on hepatic lipid metabolism in mice with high-fat diet induced body weight gain and hepatic lipid accumulation. Adult male mice received a 40 energy% high-fat diet without or with supplementation of 0.33 % (w/w) quercetin for 12 weeks. Body weight gain was 29 % lower in quercetin fed mice (p \ 0.01), while the energy intake was not significantly different. Quercetin supplementation lowered hepatic lipid accumulation to 29 % of the amount present in the control mice (p \ 0.01). 1 H nuclear magnetic resonance serum lipid profiling revealed that the supplementation significantly lowered serum lipid levels. Global gene expression profiling of liver showed that cytochrome P450 2b (Cyp2b) genes, key target genes of the transcription factor constitutive androstane receptor (Car; official symbol Nr1i3), were downregulated. Quercetin decreased high-fat diet induced body weight gain, hepatic lipid accumulation and serum lipid levels. This was accompanied by regulation of cytochrome P450 2b genes in liver, which are possibly under transcriptional control of CAR. The quercetin effects are likely dependent on the fat content of the diet. Keywords Bioactive food component Á Flavonoid Á Gene expression profiling Á Hepatic lipid accumulation Á Lipid metabolism Abbreviations Acot3 Acyl-CoA thioesterase 3 B2m Beta-2 microglobulin Car Constitutive androstane receptor Csad Cysteine sulphinic acid decarboxylase CVD Cardiovascular diseases Cyp Cytochrome P450 En% Energy% Fabp5 Fatty acid binding protein 5 FA Fatty acids Hao2 Hydroxyacid oxidase 2 HOMA-IR Homoeostasis model assessment-insulin resistance Hprt1 Hypoxanthine phosphoribosyltransferase 1 Por Cytochrome P450 oxidoreductase RT-qPCR Real-time quantitative polymerase chain reaction Electronic supplementary material The online version of this article (
PharmaNutrition
Background: Lycopene (lyc) supplementation was shown to efficiently prevent multiple hepatic injuries. This study was assembled to examine lyc protective effects against non-alcoholic fatty liver disease (NAFLD) experimentally-induced in rats. Methods: The experiment was completed in eight weeks. Rats were indiscriminately distributed into four main groups: the control group and the high fat diet (HFD) fed group, received 1 mL/kg corn oil orally 3 times per week. Lyc only-treated group and HFD/lyc fed group, received 4 mg/kg of lyc orally 3 times per week. Results: Lyc significantly renovated liver enzymes and alleviated histopathological abrasions induced by HFD. Moreover, lyc significantly enhanced insulin receptor substrate 2 (IRS 2) expression by 25 % and ameliorated oxidative stress injury through restoring GSH level by 218 % and Nrf 2 expression by 56 %. Additionally, lyc significantly reduced pro-inflammatory cytokines production; interleukin-6; IL-6 and tumor necrosis factoralpha; TNF-α by 52 % and 57 % respectively, and inhibited nuclear factor-κB (NF-κB) by 52 %. Finally, lyc significantly reduced transforming growth factor-β (TGF-β) expression by 52 % and α-smooth muscle actin (α-SMA) expression by 53 % as well as collagen accumulation. Conclusion: According to these findings, lyc may be recommended as a promising dietary agent in the management of NAFLD. ω-oxidation of long chain fatty acids in the endoplasmic reticulum as a consequence of hepatic lipid burden [9]. The involvement of hepatic cellular oxidative stress along with the direct uptake of FFAs in Kupffer