Gut microbiota and butyrate contribute to nonalcoholic fatty liver disease in premenopause due to estrogen deficiency

Abstract Background：The incidence of nonalcoholic fatty liver disease (NAFLD) in postmenopausal women has increased significantly. NAFLD can be effectively inhibited by estrogen, but the severe side effects, especially the increased risk of malignant tumors, limit its application. Thus, it is of great clinical significance to explore the mechanism by which estrogen inhibits NAFLD. Gut microbiota and its metabolites short chain fatty acids (SCFA) have been shown to play important roles in the development of NAFLD.Objective：In this study, we investigated the impact of estrogen deficiency on the gut microbiome and SCFA in both NAFLD patients and an experimental NAFLD model in premenopause.Methods：The levels of estrogen，insulin and leptin was measured using ELISA. Gut microbiota was analyzed by 16S rRNA gene sequence analysis. Tissue sections were stained with hematoxylin and eosin. SCFAs were determined with Agilent 6890 N gas chromatography (GC). We quantified mRNA levels of genes in our study by quantitative real time-PCR. Additionally, Western Blotting was used to validate protein expression.Results：We showed that female NAFLD patients had much lower estrogen levels. Estrogen deficient mice, due to ovariectomy (OVX), suffered more severe liver steatosis with an elevated body weight, abdominal fat weight, and serum triglycerides with deterioration in histological hepatic steatosis. Altered gut microbiota composition and decreased butyrate content were found in patients with NAFLD and in OVX mice. Furthermore, fecal microbiota transplantation (FMT) or supplementing with butyrate markedly alleviated NAFLD in OVX mice. The production of antimicrobial peptides (AMP) RegIIIg, β-defensins 1, 3 and the expression of intestinal epithelial tight junction, including ZO-1 and occludin5, were decreased in the OVX mice compared to control mice. Upregulation of PPAR-ɣ and VLDLR and downregulation of PPAR-ɑ indicated that OVX mice suffered from abnormal lipid metabolism.Conclusions：These data indicate that changes in the gut microbiota and SCFA caused by estrogen reduction, together with a disorder in AMP production and lipid metabolism, promote NAFLD, thus provide microbiota derived SCFAs as new therapeutic targets for the clinical prevention and treatment of NAFLD.

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Nutrition and Nonalcoholic Fatty Liver Disease: The Significance of Cholesterol

International Journal of Hepatology ◽

10.1155/2012/925807 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 24

Author(s):

Munechika Enjoji ◽

Kenichiro Yasutake ◽

Motoyuki Kohjima ◽

Makoto Nakamuta

Keyword(s):

Fatty Acids ◽

Lipid Metabolism ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Cholesterol Metabolism ◽

Hepatic Lipid Metabolism ◽

Nonalcoholic Fatty Liver ◽

The Impact

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that ranges in severity from simple steatosis to cirrhosis. NAFLD is considered to be associated with hepatic metabolic disorders, resulting in overaccumulation of fatty acids/triglycerides and cholesterol. The pathogenesis and progression of NAFLD are generally explained by the “two-hit theory.” Most studies of lipid metabolism in the NAFLD liver have focused on the metabolism of fatty acids/triglycerides; therefore, the impact of cholesterol metabolism is still ambiguous. In this paper, we review recent studies on NAFLD from the viewpoint of hepatic lipid metabolism-associated factors and discuss the impact of disordered cholesterol metabolism in the etiology of NAFLD. The clinical significance of managing cholesterol metabolism, an option for the treatment of NAFLD, is also discussed.

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Structural and Functional Modulation of Gut Microbiota by Jiangzhi Granules during the Amelioration of Nonalcoholic Fatty Liver Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/2234695 ◽

2021 ◽

Vol 2021 ◽

pp. 1-18

Author(s):

Rui-rui Wang ◽

Lin-fang Zhang ◽

Lu-ping Chen ◽

Jian-ying Wang ◽

Lei Zhang ◽

...

Keyword(s):

Lipid Metabolism ◽

Liver Disease ◽

Gut Microbiota ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Relative Abundance ◽

Fatty Liver Disease ◽

Dose Effect ◽

Nonalcoholic Fatty Liver ◽

Hepatic Lipid

Recently, accumulating evidence revealed that nonalcoholic fatty liver disease (NAFLD) is highly associated with the dysbiosis of gut microbiota. Jiang Zhi Granule (JZG), which is composed of five widely used Chinese herbs, has shown hypolipidemic effect, while whether such effect is mediated by gut microbiota is still unclear. Here, we found that both low and high doses of JZG (LJZ and HJZ) could improve hepatic steatosis and function, as well as insulin resistance in NAFLD mice. 16S rRNA gene sequencing revealed that JZG treatment could reverse the dysbiosis of intestinal flora in NAFLD mice, exhibiting a dose-dependent effect. Notably, HJZ could significantly reduce the relative abundance of Desulfovibrionaceae, while increasing the relative abundance of such as S24_7 and Lachnospiraceae. PICRUSt analysis showed that HJZ could significantly alter the functional profile of gut microbiota, including the reduction of the lipopolysaccharide biosynthesis and sulfur metabolism pathway, which is verified by the decreased levels of fecal hydrogen sulfide (H2S) and serum lipopolysaccharide binding protein (LBP). In addition, hepatic mRNA sequencing further indicated that the HJZ group can regulate the peroxisome proliferator-activated receptor (PPAR) pathway and inflammatory signaling pathway, as validated by RT-PCR and Western blot. We also found that different doses of JZG may regulate lipid metabolism through differentiated pathways, as LJZ mainly through the promotion of hepatic lipid hydrolysis, while HJZ mainly through the improvement of hepatic lipid oxidation. Taken together, JZG could modulate gut dysbiosis with dose-effect, alleviate inflammation level, and regulate hepatic lipid metabolism, which may subsequently contribute to the improvement of NAFLD. Our study revealed the underlying mechanisms in the improvement of NAFLD by a Chinese herbal compound, providing future guidance for clinical usage.

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Peroxisome Proliferator-Activated Receptor Genetic Polymorphisms and Nonalcoholic Fatty Liver Disease: Any Role in Disease Susceptibility?

PPAR Research ◽

10.1155/2013/452061 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 15

Author(s):

Paola Dongiovanni ◽

Luca Valenti

Keyword(s):

Metabolic Syndrome ◽

Lipid Metabolism ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Peroxisome Proliferator ◽

Nonalcoholic Fatty Liver ◽

The Metabolic Syndrome ◽

The Impact

Nonalcoholic fatty liver disease (NAFLD) defines a wide spectrum of liver diseases that extend from simple steatosis, that is, increased hepatic lipid content, to nonalcoholic steatohepatitis (NASH), a condition that may progress to cirrhosis with its associated complications. Nuclear hormone receptors act as intracellular lipid sensors that coordinate genetic networks regulating lipid metabolism and energy utilization. This family of transcription factors, in particular peroxisome proliferator-activated receptors (PPARs), represents attractive drug targets for the management of NAFLD and NASH, as well as related conditions such as type 2 diabetes and the metabolic syndrome. The impact on the regulation of lipid metabolism observed for PPARs has led to the hypothesis that genetic variants within the human PPARs genes may be associated with human disease such as NAFLD, the metabolic syndrome, and/or coronary heart disease. Here we review the available evidence on the association between PPARs genetic polymorphism and the susceptibility to NAFLD and NASH, and we provide a meta-analysis of the available evidence. The impact of PPAR variants on the susceptibility to NASH in specific subgroup of patients, and in particular on the response to therapies, especially those targeting PPARs, represents promising new areas of investigation.

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Ginsenosides Improve Nonalcoholic Fatty Liver Disease via Integrated Regulation of Gut Microbiota, Inflammation and Energy Homeostasis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.622841 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wenyi Liang ◽

Kun Zhou ◽

Ping Jian ◽

Zihao Chang ◽

Qiunan Zhang ◽

...

Keyword(s):

Liver Disease ◽

Gut Microbiota ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Mrna Levels ◽

Dependent Manner ◽

Nonalcoholic Fatty Liver ◽

Gut Barrier Function ◽

Anti Inflammatory

Ginseng, the root and rhizome of Panax ginseng C. A. Mey., is a famous herbal medicine, and its major ginsenosides exert beneficial effects on nonalcoholic fatty liver disease (NAFLD). Due to the multicomponent and multitarget features of ginsenosides, their detailed mechanisms remain unclear. This study aimed to explore the role of ginsenosides on NAFLD and the potential mechanisms mediated by the gut microbiota and related molecular processes. C57BL/6J mice were fed a high-fat diet (HFD) supplemented or not supplemented with ginsenoside extract (GE) for 12 weeks. A strategy that integrates bacterial gene sequencing, serum pharmacochemistry and network pharmacology was applied. The results showed that GE significantly alleviated HFD-induced NAFLD symptoms in a dose-dependent manner. Furthermore, GE treatment modulated the HFD-induced imbalance in the gut microbiota and alleviated dysbiosis-mediated gut leakage and metabolic endotoxemia. Additionally, 20 components were identified in the mouse plasma after the oral administration of GE, and they interacted with 82 NAFLD-related targets. A network analysis revealed that anti-inflammatory effects and regulation of the metabolic balance might be responsible for the effects of GE on NAFLD. A validation experiment was then conducted, and the results suggested that GE suppressed NF-κB/IκB signaling activation and decreased the release and mRNA levels of proinflammatory factors (TNF-α, IL-1β and IL-6). Additionally, GE promoted hepatic lipolytic genes (CPT-1a), inhibited lipogenic genes (SREBP-1c, FAS, ACC-1) and improved leptin resistance. These findings imply that the benefits of GE are involved in modulating the gut microbiota, enhancing the gut barrier function, restoring the energy balance, and alleviating metabolic inflammation. Moreover, GE might serve as a potential agent for the prevention of NAFLD through the integration of prebiotic, anti-inflammatory and energy-regulatory effects.

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Nonalcoholic fatty liver disease and the risk of atrial fibrillation stratified by body mass index: a nationwide population-based study

Scientific Reports ◽

10.1038/s41598-021-83367-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

So-Ryoung Lee ◽

Kyung-Do Han ◽

Eue-Keun Choi ◽

Seil Oh ◽

Gregory Y. H. Lip

Keyword(s):

Atrial Fibrillation ◽

Body Mass Index ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Body Mass ◽

Fatty Liver Disease ◽

Nonalcoholic Fatty Liver ◽

Increased Risk ◽

The Impact

AbstractWe evaluated the association between nonalcoholic fatty liver disease (NAFLD) and incident atrial fibrillation (AF) and analyzed the impact of NAFLD on AF risk in relation to body mass index (BMI). A total of 8,048,055 subjects without significant liver disease who were available fatty liver index (FLI) values were included. Subjects were categorized into 3 groups based on FLI: < 30, 30 to < 60, and ≥ 60. During a median 8-year of follow-up, 534,442 subjects were newly diagnosed as AF (8.27 per 1000 person-years). Higher FLI was associated with an increased risk of AF (hazard ratio [HR] 1.053, 95% confidence interval [CI] 1.046–1.060 in 30 ≤ FLI < 60, and HR 1.115, 95% CI 1.106–1.125 in FLI ≥ 60). In underweight subjects (BMI < 18.5 kg/m2), higher FLI raised the risk of AF (by 1.6-fold in 30 ≤ FLI < 60 and by twofold in FLI ≥ 60). In normal- and overweight subjects, higher FLI was associated with an increased risk of AF, but the HRs were attenuated. In obese subjects, higher FLI was not associated with higher risk of AF. NAFLD as assessed by FLI was independently associated with an increased risk of AF in nonobese subjects with BMI < 25 kg/m2. The impact of NAFLD on AF risk was accentuated in lean subjects with underweight.

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Doxepin Exacerbates Renal Damage, Glucose Intolerance, Nonalcoholic Fatty Liver Disease and Urinary Chromium Loss in Obese Mice

Pharmaceuticals ◽

10.3390/ph14030267 ◽

2021 ◽

Vol 14 (3) ◽

pp. 267

Author(s):

Geng-Ruei Chang ◽

Po-Hsun Hou ◽

Wei-Cheng Yang ◽

Chao-Min Wang ◽

Pei-Shan Fan ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Glucose Intolerance ◽

Fatty Liver Disease ◽

Renal Damage ◽

Liver Lipid ◽

Interleukin 1 ◽

Mrna Levels ◽

Nonalcoholic Fatty Liver

Doxepin is commonly prescribed for depression and anxiety treatment. Doxepin-related disruptions to metabolism and renal/hepatic adverse effects remain unclear; thus, the underlying mechanism of action warrants further research. Here, we investigated how doxepin affects lipid change, glucose homeostasis, chromium (Cr) distribution, renal impairment, liver damage, and fatty liver scores in C57BL6/J mice subjected to a high-fat diet and 5 mg/kg/day doxepin treatment for eight weeks. We noted that the treated mice had higher body, kidney, liver, retroperitoneal, and epididymal white adipose tissue weights; serum and liver triglyceride, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and creatinine levels; daily food efficiency; and liver lipid regulation marker expression. They also demonstrated exacerbated insulin resistance and glucose intolerance with lower Akt phosphorylation, GLUT4 expression, and renal damage as well as higher reactive oxygen species and interleukin 1 and lower catalase, superoxide dismutase, and glutathione peroxidase levels. The treated mice had a net-negative Cr balance due to increased urinary excretion, leading to Cr mobilization, delaying hyperglycemia recovery. Furthermore, they had considerably increased fatty liver scores, paralleling increases in adiponectin, FASN, PNPLA3, FABP4 mRNA, and SREBP1 mRNA levels. In conclusion, doxepin administration potentially worsens renal injury, nonalcoholic fatty liver disease, and diabetes.

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Lycium barbarum polysaccharide combined with aerobic exercise ameliorated nonalcoholic fatty liver disease through restoring gut microbiota, intestinal barrier and inhibiting hepatic inflammation

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2021.05.066 ◽

2021 ◽

Author(s):

Lu-Lu Gao ◽

Jia-Min Ma ◽

Yan-Na Fan ◽

Yan-Nan Zhang ◽

Rui Ge ◽

...

Keyword(s):

Liver Disease ◽

Gut Microbiota ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Intestinal Barrier ◽

Hepatic Inflammation ◽

Lycium Barbarum ◽

Nonalcoholic Fatty Liver ◽

Lycium Barbarum Polysaccharide

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SGL 121 Attenuates Nonalcoholic Fatty Liver Disease through Adjusting Lipid Metabolism Through AMPK Signaling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms21124534 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4534

Author(s):

Da Eun Kim ◽

Bo Yoon Chang ◽

Byeong Min Jeon ◽

Jong In Baek ◽

Sun Chang Kim ◽

...

Keyword(s):

Lipid Metabolism ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Signaling Pathway ◽

Hepg2 Cells ◽

Fatty Liver Disease ◽

Fatty Acid Synthase ◽

Density Lipoprotein ◽

Nonalcoholic Fatty Liver

A ginsenoside F2-enhanced mixture (SGL 121) increases the content of ginsenoside F2 by biotransformation. In the present study, we investigated the effect of SGL 121 on nonalcoholic fatty liver disease (NAFLD) in vitro and in vivo. High-fat, high-carbohydrate-diet (HFHC)-fed mice were administered SGL 121 for 12 weeks to assess its effect on improving NAFLD. In HepG2 cells, SGL 121 acted as an antioxidant, a hepatoprotectant, and had an anti-lipogenic effect. In NAFLD mice, SGL 121 significantly improved body fat mass; levels of hepatic triglyceride (TG), hepatic malondialdehyde (MDA), serum total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL); and activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In HepG2 cells, induced by oxidative stress, SGL 121 increased cytoprotection, inhibited reactive oxygen species (ROS) production, and increased antioxidant enzyme activity. SGL 121 activated the Nrf2/HO-1 signaling pathway and improved lipid accumulation induced by free fatty acids (FFA). Sterol regulatory element-binding protein-1 (SREBP-1) and fatty acid synthase (FAS) expression was significantly reduced in NAFLD-induced liver and HepG2 cells treated with SGL 121. Moreover, SGL 121 activated adenosine monophosphate-activated protein kinase (AMPK), which plays an important role in the regulation of lipid metabolism. The effect of SGL 121 on the improvement of NAFLD seems to be related to its antioxidant effects and activation of AMPK. In conclusion, SGL 121 can be potentially used for the treatment of NAFLD.

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