phytoestrogens and Non-alcoholic-Fatty-Liver-Disease

Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder, affecting around 25% of the population worldwide. It is a complex disease spectrum, closely linked with other conditions such as obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, which may increase liver-related mortality. In light of this, numerous efforts have been carried out in recent years in order to clarify its pathogenesis and create new prevention strategies. Currently, the essential role of environmental pollutants in NAFLD development is recognized. Particularly, endocrine-disrupting chemicals (EDCs) have a notable influence. EDCs can be classified as natural (phytoestrogens, genistein, and coumestrol) or synthetic, and the latter ones can be further subdivided into industrial (dioxins, polychlorinated biphenyls, and alkylphenols), agricultural (pesticides, insecticides, herbicides, and fungicides), residential (phthalates, polybrominated biphenyls, and bisphenol A), and pharmaceutical (parabens). Several experimental models have proposed a mechanism involving this group of substances with the disruption of hepatic metabolism, which promotes NAFLD. These include an imbalance between lipid influx/efflux in the liver, mitochondrial dysfunction, liver inflammation, and epigenetic reprogramming. It can be concluded that exposure to EDCs might play a crucial role in NAFLD initiation and evolution. However, further investigations supporting these effects in humans are required.

Topics: Benzhydryl Compounds; Coumestrol; Dioxins; Endocrine Disruptors; Environmental Pollutants; Genistein; Humans; Lipid Metabolism; Non-alcoholic Fatty Liver Disease; Phenols; Phytoestrogens; Polychlorinated Biphenyls

Nonalcoholic Fatty Liver Disease (NAFLD) includes a variety of changes including nonalcoholic fatty liver, cirrhosis and Hepatocellular Carcinoma (HCC), which are associated with metabolic disorders and cardiovascular diseases. The pathogenesis of NAFLD is complex and multifactorial. Many studies have shown that estrogen has a protective effect on premenopausal women with metabolic disorders and non-alcoholic fatty liver disease. Estrogen supplements may, at least in theory, prevent the development and progression of NAFLD. Phytoestrogen is extracted from plants, especially legumes, whose molecular structure and biological activity are similar to those of mammals estrogen, therefore it could replace the role of estrogen and prevent the occurrence of adverse reactions to estrogen. In this article, we review the published literature related to phytoestrogens and NAFLD as well as suggest the possible mechanisms that may underlie the association between phytoestrogens and NAFLD.

Topics: Animals; Humans; Molecular Structure; Non-alcoholic Fatty Liver Disease; Phytoestrogens; Protective Agents

Many studies have shown that estrogen has a protective effect on premenopausal women with metabolic disorders and non-alcoholic fatty liver disease. Estrogen supplements may, at least in theory, prevent the development and progression of NAFLD, while the possibility of inducing cancer limits its application in practice. Phytoestrogen is extracted from plants, whose molecular structure and biological activity are similar to those of mammals' estrogen, therefore, could replace the role of estrogen and prevent the occurrence of adverse reactions to estrogen. This article reviews the published literature related to phytoestrogens and NAFLD as well as suggest the possible mechanisms that may underlie the association between phytoestrogens and NAFLD. It is hoped to provide basis for the treatment of NAFLD with phytoestrogen.

Topics: Animals; Humans; Non-alcoholic Fatty Liver Disease; Phytoestrogens; Plant Extracts

Dietary phytoestrogens are bioactive compounds with estrogenic activity. With the growing popularity of plant-based diets, the intake of phytoestrogen-rich legumes (especially soy) and legume-derived foods has increased. Evidence from preclinical studies suggests these compounds may have an effect on hormones and health, although the results of human trials are unclear. The effects of dietary phytoestrogens depend on the exposure (phytoestrogen type, matrix, concentration, and bioavailability), ethnicity, hormone levels (related to age, sex, and physiological condition), and health status of the consumer. In this review, we have summarized the results of human studies on dietary phytoestrogens with the aim of assessing the possible hormone-dependent outcomes and health effects of their consumption throughout a lifespan, focusing on pregnancy, childhood, adulthood, and the premenopausal and postmenopausal stages. In pregnant women, an improvement of insulin metabolism has been reported in only one study. Sex hormone alterations have been found in the late stages of childhood, and goitrogenic effects in children with hypothyroidism. In premenopausal and postmenopausal women, the reported impacts on hormones are inconsistent, although beneficial goitrogenic effects and improved glycemic control and cardiovascular risk markers have been described in postmenopausal individuals. In adult men, different authors report goitrogenic effects and a reduction of insulin in non-alcoholic fatty liver patients. Further carefully designed studies are warranted to better elucidate the impact of phytoestrogen consumption on the endocrine system at different life stages.

Topics: Adult; Child; Diet; Female; Glycine max; Gonadal Steroid Hormones; Heart Disease Risk Factors; Hormones; Humans; Hypothyroidism; Isoflavones; Lignans; Longevity; Male; Non-alcoholic Fatty Liver Disease; Phytoestrogens; Postmenopause; Pregnancy; Premenopause; Vegetables

Equol is a metabolite of soy isoflavone and has estrogenic activity. The incidence of non-alcoholic fatty liver disease (NAFLD) increases after menopause in women, which is thought to result in a decrease in estrogen. This study aimed to evaluate the association between equol and NAFLD.. We evaluated 1185 women aged 50-69 years who underwent health check-ups at four health centers in Fukushima, Japan. Equol producers were defined by a urinary equol concentration of 1.0 μM or more. In addition to comparison between equol producers and non-producers, the association between equol and NAFLD was estimated using logistic regression analysis adjusting for fast walking and eating habits.. Of the 1185 participants, 345 (29.1%) women were equol producers. The proportions of women who had NAFLD (34.8% vs 45.2%) were significantly lower in the equol-producing group than in the non-producing group. Multivariable logistic regression analysis showed that equol production was significantly associated with NAFLD (odds ratio = 0.66, 95% confidence interval: 0.51-0.86).. Equol production was significantly associated with NAFLD in women in their 50s and 60s.

Topics: East Asian People; Equol; Female; Humans; Isoflavones; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Phytoestrogens; Postmenopause

Phytoestrogens can alleviate some pathological processes related to nonalcoholic fatty liver disease (NAFLD). However, there are limited and contradictory studies on the relationships between phytoestrogens (especially single phytoestrogen) and NAFLD. The purpose of this study was to explore the relationships between urinary phytoestrogen concentrations and NAFLD in American adults. This cross-sectional study used the data of the National Health and Nutrition Examination Survey from 1999 to 2010, and 2294 adults were finally enrolled in this study. The concentrations of phytoestrogens were measured in urine samples, and urinary phytoestrogens were divided into tertiles according to the concentration distributions. The diagnosis of NAFLD was determined by the United States fatty liver index. The main analysis used a multivariate logistic regression model. The fully adjusted models included gender, age, race, education, marriage, poverty, body mass index, waist circumference, smoking, diabetes, hypertension, total cholesterol, high-density lipoprotein cholesterol, triglycerides, and other five phytoestrogens. In the fully adjusted model, the urinary enterolactone (ENL) concentration was negatively correlated with NAFLD (OR of Tertile 3 : 0.48, 95% CI 0.25-0.94). When stratified by age and gender, the urinary ENL concentration was negatively correlated with NAFLD in males aged 40-59 years (OR of Tertile 3 : 0.08, 95% CI 0.01-0.82), while the urinary equol concentration was positively correlated with NAFLD in such population (OR of Tertile 3 : 4.27, 95% CI 1.02-17.85). In addition, a negative correlation between enterodiol (END) concentration and NAFLD was observed in males aged 60 years or over (OR of Tertile 2 : 0.18, 95% CI 0.05-0.69). Collectively, in middle-aged males, urinary ENL may be associated with a lower risk of NAFLD, while urinary equol may be related to a higher risk. In addition, urinary END has a possible relationship with a reduced risk of NAFLD in elder males. Definitely, clinical randomized controlled trials are needed to further verify the conclusions.

Topics: Adult; Aged; Cholesterol, HDL; Cross-Sectional Studies; Equol; Humans; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Nutrition Surveys; Phytoestrogens; United States

Oxidative stress and mitochondria dysfunction could be involved in the onset of non-alcoholic fatty liver disease (NAFLD) and in its progression to non-alcoholic steatohepatitis (NASH). Estrogens/phytoestrogens could counteract liver fat deposition with beneficial effects against NAFLD by unclear mechanisms. We aimed to analyze the protective effects elicited by genistein/estradiol in hepatocytes cultured in NAFLD-like medium on cell viability, triglycerides accumulation, mitochondrial function and oxidative stress and the role of NLRP3 inflammasome, toll like receptors 4 (TLR4), Akt and 5' AMP-activated protein kinase (AMPK)α1/2.. Human primary hepatocytes/hepatoma cell line (Huh7.5 cells) were incubated with a 2 mM mixture of oleate/palmitate in presence/absence of genistein/17β-estradiol. In some experiments, Huh7.5 cells were exposed to various inhibitors of the above pathways and estrogenic receptors (ERs) and G protein-coupled estrogen receptor (GPER) blockers, before genistein/17β-estradiol. Cell viability, mitochondrial membrane potential, reactive oxygen species and triglycerides content were examined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT), 5,51,6,61-tetrachloro-1,11,3,31 tetraethylbenzimidazolyl carbocyanine iodide (JC-1), 2,7-dichlorodihydrofluorescein diacetate (H2DCFDA) and the Triglyceride Colorimetric Assay. The expression/activation of kinases was analyzed by means of Western blot.. Genistein/17β-estradiol protected hepatocytes against NAFLD-like medium, by preventing the loss of cell viability and mitochondrial function, triglycerides accumulation and peroxidation. The blocking of kinases, ERs and GPER was able to reduce the above effects, which were potentiated by NLRP3 inflammasome.. Our findings suggest novel mechanisms underlying the protective effects elicited by phytoestrogens/estrogens against NAFLD/NASH and open novel therapeutic perspectives in the management of NAFLD in postmenopausal women.

Topics: AMP-Activated Protein Kinase Kinases; Cell Line; Cell Survival; Estradiol; Genistein; Hepatocytes; Humans; Inflammasomes; Membrane Potential, Mitochondrial; Mitochondria; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Phytoestrogens; Protein Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Receptors, Estrogen; Receptors, G-Protein-Coupled; Toll-Like Receptor 4; Triglycerides

Estrogen is involved in lipid metabolism. Menopausal women with low estrogen secretion usually gain weight and develop steatosis associated with abnormal lipid metabolism. A previous study showed that blackcurrant (

Topics: Adipocytes; Adiponectin; Alanine Transaminase; Animals; Aspartate Aminotransferases; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Dyslipidemias; Fatty Liver; Female; gamma-Glutamyltransferase; Intra-Abdominal Fat; Leptin; Lipid Metabolism; Liver; Menopause; Non-alcoholic Fatty Liver Disease; Ovariectomy; Phytoestrogens; Plant Extracts; Rats; Rats, Sprague-Dawley; Ribes; Triglycerides

Genistein, a kind of phytoestrogen abundant in soybeans, is beneficial for alleviating non-alcoholic fatty liver disease (NAFLD), but the specific mechanism was not clearly understood. This study was designed to determine the effect of genistein on NAFLD and explore the possible mechanism. 36 male Sprague-Dawley rats were divided into 4 groups: the control group, high fat-high sucrose diet (HFS) group, HFS with 4mg/kg body weight genistein, and HFS with 8mg/kg body weight genistein. 12 weeks later, serum and hepatic lipid profiles, liver histopathological examination were characterized. The protein levels of liver AMP-activated protein kinase (AMPK), phosphorylation of AMPK (p-AMPK), acetyl-CoA carboxylase (ACC), phosphorylation of ACC (p-ACC) and sterol regulatory element binding protein 1 (SREBP-1) were determined by western blot. mRNA expressions of fatty acid synthase gene (FAS) and glycerol-3-phosphate acyltransferase (GPAT), peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyl transfer enzyme-1 (CPT-1) and acyl-CoA oxidase (ACO) were measured by reverse transcription polymerase chain reaction (RT-PCR). Results showed that genistein effectively improved serum and hepatic lipid metabolism and diminished fat accumulation in liver. And the protein level of hepatic p-AMPK and p-ACC were increased, but SREBP-1 was decreased by genistein. Meanwhile, the mRNA levels of FAS and GPAT were lower, but PPARα, CPT-1, ACO were higher in rats treated with genistein compared with HFS group. Collectively, genistein can improve hepatic steatosis via activating AMPK, thus promoting fatty acid oxidation and inhibiting lipid synthesis in liver.

Topics: AMP-Activated Protein Kinases; Animals; Body Weight; Diet, High-Fat; Fatty Liver; Genistein; Lipid Metabolism; Liver; Male; Non-alcoholic Fatty Liver Disease; Oxidation-Reduction; Phytoestrogens; PPAR alpha; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Sucrose

Obesity emerged as the major risk factor for metabolic syndrome. Postmenopausal women are more prone to develop obesity than premenopausal women. The absence of safe and effective conventional treatments for postmenopausal obesity has changed the focus to natural products as alternative remedy. We investigated the molecular basis of the effect of soy isoflavones (SIFs) on hypertriglyceridemia and hepatic steatosis in an animal model of postmenopausal obesity. Ovariectomized (OVX) and sham-operated Wistar rats were fed with high-fat diet (HFD) and normal diet for 8 weeks with and without SIF extract (150mg/kg body weight/day). Both OVX and HFD per se and when combined caused hypertriglyceridemia, hypercholesterolemia and atherogenic lipid profile. Proteomic studies revealed that both OVX and HFD caused overexpression of hepatic lipogenic proteins, such as LXR, SREBP1, PPARγ, ACC and FAS, in association with reduced expression of lipolytic proteins, such as FXR, PPARα, insig2 and SHP. Histological analysis showed fat accumulation and morphological abnormalities in the liver of OVX and HFD rats. All these metabolic derangements were further augmented when OVX was followed by HFD. In conclusion, these findings suggest that there was a synergism in the development of deranged lipid metabolism with the coexistence of postmenopausal state and the intake of fat-rich diet. SIF extract markedly alleviated the derangement of lipid metabolism suggesting the use of this natural phytoestrogen as a strategy for relieving dyslipidemia and hepatic steatosis associated with the postmenopausal women.

Topics: Animals; Biomarkers; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Dyslipidemias; Female; Humans; Hypertriglyceridemia; Isoflavones; Lipid Metabolism; Liver; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Obesity; Organ Size; Osteoporosis, Postmenopausal; Ovariectomy; Phytoestrogens; Random Allocation; Rats, Wistar; Soy Foods

Tissue-selective estrogen complex (TSEC), which combines a selective estrogen receptor modulator (SERM) with one or more estrogens, is a novel approach to menopausal therapy. It has been demonstrated that the phytoestrogen genistein (GEN) exhibits mixed estrogen receptor agonist and antagonist activity, suggesting that GEN may have potential for use as a natural SERM. We evaluated, for the first time, the effects of GEN, conjugated estrogens (CE), and their pairing effects as a TSEC treatment on estrogen-induced endometrial hyperplasia and metabolic dysfunction in ovariectomized (OVX) mice fed a high-fat diet. CE replacement prevented fat accumulation in the adipose tissue and liver, improved glucose homeostasis, and induced endometrial hyperplasia in OVX mice. GEN at 100 mg/kg showed CE mimetic effects in preventing ovariectomy-induced metabolic dysfunctions without endometrial stimulation. Combination treatments with CE and GEN prevented metabolic dysfunctions more strongly than CE alone, but at both low and high doses, GEN did not reverse CE-induced endometrial hyperplasia. In addition, we found that in a TSEC regimen, a typical SERM raloxifene maintains the metabolic benefits of CE while simultaneously protecting the endometrium in OVX mice. These findings indicate that GEN acts as an estrogen agonist in metabolic regulation, but has no SERM function in the uteri of OVX mice.

Topics: Adiposity; Animals; Diet, High-Fat; Dietary Supplements; Endometrial Hyperplasia; Endometrium; Estrogen Replacement Therapy; Estrogens; Estrogens, Conjugated (USP); Female; Genistein; Glucose Intolerance; Liver; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Ovariectomy; Overweight; Phytoestrogens; Raloxifene Hydrochloride; Random Allocation; Selective Estrogen Receptor Modulators

Globally, non-alcoholic fatty liver disease (NAFLD) continues to rise and isoflavones exert antisteatotic effects by the regulation of hepatic lipogenesis/insulin resistance or adiposity/a variety of adipocytokines are related to hepatic steatosis. However, there is very little information regarding the potential effects of daidzein, the secondary abundant isoflavone, on NAFLD. Here, we have assessed the hepatic global transcription profiles, adipocytokines and adiposity in mice with high fat-induced NAFLD and their alteration by daidzein supplementation.. C57BL/6J mice were fed with normal fat (16% fat of total energy), high fat (HF; 36% fat of total energy) and HF supplemented with daidzein (0.1, 0.5, 1 and 2 g per kg diet) for 12 weeks.. Daidzein supplementation (≥ 0.5 g per kg diet) reduced hepatic lipid concentrations and alleviated hepatic steatosis. The hepatic microarray showed that daidzein supplementation (1 g per kg diet) downregulated carbohydrate responsive element binding protein, a determinant of de novo lipogenesis, its upstream gene liver X receptor β and its target genes encoding for lipogenic enzymes, thereby preventing hepatic steatosis and insulin resistance. These results were confirmed by lower insulin and blood glucose levels as well as homeostasis model assessment insulin resistance scores. In addition, daidzein supplementation inhibited adiposity by the upregulation of genes involved in fatty acid β-oxidation and the antiadipogeneis, and moreover augmented antisteatohepatitic leptin and adiponectin mRNA levels, whereas it reduced the mRNA or concentration of steatotic tumor necrosis factor α and ghrelin.. These findings show that daidzein might alleviate NAFLD through the direct regulation of hepatic de novo lipogenesis and insulin signaling, and the indirect control of adiposity and adipocytokines by the alteration of adipocyte metabolism.

Topics: Adipocytes; Adipokines; Adipose Tissue; Animals; Body Weight; Diet; Fatty Liver; Gene Expression Profiling; Insulin; Insulin Resistance; Isoflavones; Lipogenesis; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Phytoestrogens; Reverse Transcriptase Polymerase Chain Reaction

The high fructose-fed rat is widely used as a model of insulin resistance. Genistein, a soy isoflavone, has been shown to improve insulin sensitivity in this model. The present study investigated whether genistein could prevent fatty liver disease in this model.. Male Wistar rats were fed a diet containing starch (control) or 60% fructose (insulin-resistant model). Fifteen days later, rats in each dietary group were divided into two groups and were treated with either genistein (1 mg/kg per day) in dimethylsulfoxide (DMSO) or 30% DMSO alone. After 60 days, markers of liver injury, oxidative stress, interleukin (IL)-6, tumor necrosis factor (TNF)-α, lipids, lipoprotein profile, nitrite, and nitrosothiol in the plasma and liver were quantified. Liver sections were examined for 3-nitrotyrosine (3-NT) expression and pathological lesions.. Fructose-fed rats displayed hyperlipidemia, significant changes in plasma lipoprotein profile, and increases in IL-6 and TNF-α levels compared with control. In addition, the accumulation of lipids, liver injury, a decline in liver function, inactivation of the glyoxalase system, depletion of antioxidants, and increased 3-NT expression were observed in the fructose-fed group. Administration of genistein to fructose-fed rats significantly reduced these biochemical and histological abnormalities.. Genistein activates the antioxidant profile, decreases IL-6 and TNF-α concentrations, prevents oxidative damage, and ameliorates fatty liver in insulin-resistant rats.

Topics: Animals; Ascorbic Acid; Body Weight; Cholesterol; Fatty Liver; Genistein; Glutathione Peroxidase; Glutathione Reductase; Insulin; Insulin Resistance; Interleukin-6; Liver; Liver Function Tests; Male; Non-alcoholic Fatty Liver Disease; Organ Size; Phospholipids; Phytoestrogens; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Vitamin E