Extracts of Salvia-Nelumbinis Naturalis Ameliorate Nonalcoholic Steatohepatitis via Inhibiting Gut-Derived Endotoxin Mediated TLR4/NF-κB Activation

Nonalcoholic steatohepatitis (NASH) is featured by the presence of hepatic steatosis combined with inflammation and hepatocellular injury. Gut-derived endotoxin plays a crucial role in the pathogenesis of NASH. Salvia-Nelumbinis naturalis (SNN), a formula of Traditional Chinese Medicine, has been identified to be effective for NASH, but the mechanisms were not thoroughly explored. In the present study, a NASH model was generated using C57BL/6 mice fed a high fat diet (HFD) supplemented periodically with dextran sulfate sodium (DSS) in drinking water for 12 weeks. Mice fed HFD alone (without DSS) or chow diet were used as controls. The NASH mice were given the SNN extracts in the following 4 weeks, while control mice were provided with saline. Mice fed HFD developed steatosis, and DSS supplementation resulted in NASH. The SNN extracts significantly improved metabolic disorders including obesity, dyslipidemia, and liver steatosis and reduced hepatic inflammation, circulating tumor necrosis factor-α (TNF-α), and lipopolysaccharide (LPS) levels. The beneficial effect of the SNN extracts was associated with restoration of intestinal conditions (microbiota, integrity of intestinal barrier) and inhibition of TLR4/NF-κB activation. These results suggest that the SNN extracts ameliorate NASH progression, possibly through blocking endotoxin related TLR4/NF-κB activation.

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Diverse Effects of Different Akkermansia muciniphila Genotypes on Brown Adipose Tissue Inflammation and Whitening in a High-fat-diet Murine Model

10.21203/rs.2.12409/v1 ◽

2019 ◽

Author(s):

Lulu Deng ◽

Zihao Ou ◽

Dongquan Huang ◽

Chong Li ◽

Zhi Lu ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

High Fat Diet ◽

Liver Steatosis ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Chow Diet ◽

High Fat ◽

Akkermansia Muciniphila ◽

Brown Adipose

Abstract Background The study aimed to investigate the differences of different Akkermansia muciniphila (A.muciniphila) genotypes on metabolic protective effects in mice with high-fat diet and explore possible mechanisms. Methods Male C57BL/6 mice were randomly divided into 6 groups, including high-fat diet (HFD)+ A.muciniphila I/II/PBS group, normal chow diet (NCD)+A.muciniphila I/ II /PBS group, respectively. Dietary intervention and A.muciniphila gavage were performed simultaneously. Blood glucose and lipid metabolism, brown adipose morphology and activities, and intestinal barrier function were examined after the mice were sacrificed. Results A.muciniphila gavage improved the impaired glucose tolerance, hyperlipidemia and liver steatosis in HFD mice, and that A.muciniphila II was not as effective as A.muciniphila I. This phenomenon might be because A.muciniphila I intervention significantly inhibited brown adipose tissue whitening and inflammation induced by HFD, by repairing the intestinal barrier and relieving endotoxemia. A.muciniphila II did not display the same results as A.muciniphila I in HFD mice, but had stronger effects in the NCD mice. Conclusions This study mainly reveals the distinct functions of different A.muciniphila genotypes on diet-induced obesity, suggesting that different A.muciniphila genotypes may play inequitable roles in pathological conditions through distinct action pathways.

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Disruption of hepatic small heterodimer partner induces dissociation of steatosis and inflammation in experimental nonalcoholic steatohepatitis

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.010233 ◽

2019 ◽

Vol 295 (4) ◽

pp. 994-1008 ◽

Cited By ~ 2

Author(s):

Nancy Magee ◽

An Zou ◽

Priyanka Ghosh ◽

Forkan Ahamed ◽

Don Delker ◽

...

Keyword(s):

Nonalcoholic Steatohepatitis ◽

Molecular Mechanisms ◽

Liver Steatosis ◽

Chow Diet ◽

Peroxisome Proliferator ◽

Rna Seq ◽

Hepatic Inflammation ◽

Peroxisome Proliferator Activated Receptor ◽

Small Heterodimer Partner

Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease worldwide and is characterized by steatosis, inflammation, and fibrosis. The molecular mechanisms underlying NASH development remain obscure. The nuclear receptor small heterodimer partner (Shp) plays a complex role in lipid metabolism and inflammation. Here, we sought to determine SHP's role in regulating steatosis and inflammation in NASH. Shp deletion in murine hepatocytes (ShpHep−/−) resulted in massive infiltration of macrophages and CD4+ T cells in the liver. ShpHep−/− mice developed reduced steatosis, but surprisingly increased hepatic inflammation and fibrosis after being fed a high-fat, -cholesterol, and -fructose (HFCF) diet. RNA-Seq analysis revealed that pathways involved in inflammation and fibrosis are significantly activated in the liver of ShpHep−/− mice fed a chow diet. After having been fed the HFCF diet, WT mice displayed up-regulated peroxisome proliferator-activated receptor γ (Pparg) signaling in the liver; however, this response was completely abolished in the ShpHep−/− mice. In contrast, livers of ShpHep−/− mice had consistent NF-κB activation. To further characterize the role of Shp specifically in the transition of steatosis to NASH, mice were fed the HFCF diet for 4 weeks, followed by Shp deletion. Surprisingly, Shp deletion after steatosis development exacerbated hepatic inflammation and fibrosis without affecting liver steatosis. Together, our results indicate that, depending on NASH stage, hepatic Shp plays an opposing role in steatosis and inflammation. Mechanistically, Shp deletion in hepatocytes activated NF-κB and impaired Pparg activation, leading to the dissociation of steatosis, inflammation, and fibrosis in NASH development.

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Atorvastatin Modulates Bile Acid Homeostasis in Mice with Diet-Induced Nonalcoholic Steatohepatitis

International Journal of Molecular Sciences ◽

10.3390/ijms22126468 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6468

Author(s):

Hana Lastuvkova ◽

Fatemeh Alaei Faradonbeh ◽

Jolana Schreiberova ◽

Milos Hroch ◽

Jaroslav Mokry ◽

...

Keyword(s):

Bile Acid ◽

Nonalcoholic Steatohepatitis ◽

Plasma Concentrations ◽

Liver Steatosis ◽

Saturated Fat ◽

Cardiovascular Complications ◽

Biliary Secretion ◽

Fecal Excretion ◽

High Cholesterol Diet ◽

Chow Diet

Bile acids (BA) play a significant role in the pathophysiology of nonalcoholic steatohepatitis (NASH). The present study evaluates the modulation of bile acid metabolomics by atorvastatin, a cholesterol-lowering agent commonly used to treat cardiovascular complications accompanying NASH. NASH was induced in mice by 24 weeks of consuming a high–saturated fat, high-fructose, and high-cholesterol diet (F), with atorvastatin administered orally (20 mg/kg/day) during the last three weeks. Biochemical and histological analyses confirmed the effectiveness of the F diet in inducing NASH. Untreated NASH animals had significantly reduced biliary secretion of BA and increased fecal excretion of BA via decreased apical sodium-dependent bile salt transporter (Asbt)-mediated reabsorption. Atorvastatin decreased liver steatosis and inflammation in NASH animals consistently with a reduction in crucial lipogenic enzyme stearoyl–coenzyme A (CoA) desaturase-1 and nuclear factor kappa light chain enhancer of activated B-cell pro-inflammatory signaling, respectively. In this group, atorvastatin also uniformly enhanced plasma concentration, biliary secretion and fecal excretion of the secondary BA, deoxycholic acid (DCA). However, in the chow diet–fed animals, atorvastatin decreased plasma concentrations of BA, and reduced BA biliary secretions. These changes stemmed primarily from the increased fecal excretion of BA resulting from the reduced Asbt-mediated BA reabsorption in the ileum and suppression of synthesis in the liver. In conclusion, our results reveal that atorvastatin significantly modulates BA metabolomics by altering their intestinal processing and liver synthesis in control and NASH mice.

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Probiotic Bacillus cereus Alleviates Dextran Sulfate Sodium-Induced Colitis in Mice through Improvement of the Intestinal Barrier Function, Anti-Inflammation, and Gut Microbiota Modulation

Journal of Agricultural and Food Chemistry ◽

10.1021/acs.jafc.1c03375 ◽

2021 ◽

Author(s):

Kangliang Sheng ◽

Yifan Xu ◽

Xiaowei Kong ◽

Jingmin Wang ◽

Xiangdong Zha ◽

...

Keyword(s):

Gut Microbiota ◽

Bacillus Cereus ◽

Barrier Function ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Anti Inflammation

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Desmethylbellidifolin Attenuates Dextran Sulfate Sodium-Induced Colitis: Impact on Intestinal Barrier, Intestinal Inflammation and Gut Microbiota

Planta Medica ◽

10.1055/a-1506-3476 ◽

2021 ◽

Author(s):

Jiaqi Wu ◽

Yuzheng Wu ◽

Yue Chen ◽

Mengyang Liu ◽

Haiyang Yu ◽

...

Keyword(s):

Ulcerative Colitis ◽

Gut Microbiota ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Intestinal Inflammation ◽

Activity Index ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Function Evaluation ◽

Biological Drugs

AbstractUlcerative colitis has been recognized as a chronic inflammatory disease predominantly disturbing the colon and rectum. Clinically, the aminosalicylates, steroids, immunosuppressants, and biological drugs are generally used for the treatment of ulcerative colitis at different stages of disease progression. However, the therapeutic efficacy of these drugs does not satisfy the patients due to the frequent drug resistance. Herein, we reported the anti-ulcerative colitis activity of desmethylbellidifolin, a xanthone isolated from Gentianella acuta, in dextran sulfate sodium-induced colitis in mice. C57BL/6 mice were treated with 2% dextran sulfate sodium in drinking water to induce acute colitis. Desmethylbellidifolin or balsalazide sodium was orally administrated once a day. Biological samples were collected for immunohistological analysis, intestinal barrier function evaluation, cytokine measurement, and gut microbiota analysis. The results revealed that desmethylbellidifolin alleviated colon shortening and body weight loss in dextran sulfate sodium-induced mice. The disease activity index was also lowered by desmethylbellidifolin after 9 days of treatment. Furthermore, desmethylbellidifolin remarkably ameliorated colonic inflammation through suppressing the expression of interleukin-6 and tumor necrosis factor-α. The intestinal epithelial barrier was strengthened by desmethylbellidifolin through increasing levels of occludin, ZO-1, and claudins. In addition, desmethylbellidifolin modulated the gut dysbiosis induced by dextran sulfate sodium. These findings suggested that desmethylbellidifolin effectively improved experimental ulcerative colitis, at least partly, through maintaining intestinal barrier integrity, inhibiting proinflammatory cytokines, and modulating dysregulated gut microbiota.

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Imaging Fibrogenesis in a Diet-Induced Model of Nonalcoholic Steatohepatitis (NASH)

Contrast Media & Molecular Imaging ◽

10.1155/2019/6298128 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8

Author(s):

S. V. Hartimath ◽

R. Boominathan ◽

V. Soh ◽

P. Cheng ◽

X. Deng ◽

...

Keyword(s):

Extracellular Matrix ◽

Liver Fibrosis ◽

Early Detection ◽

Pet Imaging ◽

Nonalcoholic Steatohepatitis ◽

High Fat Diet ◽

Detection Sensitivity ◽

Chow Diet ◽

High Fat ◽

Standard Chow Diet

Purpose. Liver fibrosis is the hallmark of chronic nonalcoholic steatohepatitis (NASH) and is characterised by the excessive deposition of extracellular matrix proteins. Early detection and accurate staging of liver fibrosis is critically important for patient management. One of the earliest pathological markers in NASH is the activation of hepatic stellate cells (HSCs) which may be exploited as a marker of fibrogenesis. Activated HSCs secreting factors such as integrin αvβ3 propagate fibrosis. The purpose of the current study was to assess the utility of the integrin αvβ3 imaging agent [18F]FtRGD for the early detection of fibrosis in a diet-induced model of NASH longitudinally using PET imaging. Procedures. Mice were fed with either standard chow diet (SD), high-fat diet (HFD), or a choline-deficient, L-amino acid-defined high-fat fibrogenic diet (CDAHFD) to mimic the clinical pathology of liver disease and followed longitudinally for 10 weeks to assess the development of liver fibrosis using [18F]FtRGD positron emission tomography (PET) imaging. Standard blood biochemistry, histological measures, and qPCR were used to quantify integrin αvβ3, smooth muscle actin, and collagen types 1 and 6 to assess the extent of NASH pathology and accurately stage liver fibrosis. Results. The CDAHFD fibrogenic diet predictably developed hepatic inflammation and steatosis over the 10 weeks studied with little NASH pathology detected in high fat diet-treated animals. Stage 1 fibrosis was detected early by histology at day 21 and progressed to stage 2 by day 35 and stage 3 by day 56 in mice fed with CDAHFD diet only. Noninvasive imaging with [18F]FtRGD correlated well with integrin αvβ3 and was able to distinguish early mild stage 2 fibrosis in CDAHFD animals compared with standard chow diet-fed animals at day 35. When compared with high fat diet-fed animals, [18F]FtRGD was only able to distinguish later moderate stage 2 fibrosis in CDAHFD animals at day 49. Conclusions. The diet-induced progression of liver fibrosis was confirmed using histology and correlated well with the mRNA of integrin αvβ3 and extracellular matrix protein expression. [18F]FtRGD showed very good correlation between liver uptake and integrin αvβ3 expression and similar detection sensitivity to the current clinical gold standard modalities for staging of liver fibrosis.

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Dietary intake of Lycium ruthenicum Murray ethanol extract inhibits colonic inflammation in dextran sulfate sodium-induced murine experimental colitis

Food & Function ◽

10.1039/d0fo00172d ◽

2020 ◽

Vol 11 (4) ◽

pp. 2924-2937

Author(s):

Shuai Zong ◽

Liu Yang ◽

Hyun Jin Park ◽

Jinglei Li

Keyword(s):

Inflammatory Cell ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Intestinal Barrier ◽

Ethanol Extract ◽

Experimental Colitis ◽

Lycium Ruthenicum ◽

Intestinal Barrier Integrity ◽

And Oxidative Stress ◽

Pro Inflammatory Cytokines

Lycium ruthenicum Murray extract protected experimental colitis by inhibiting pro-inflammatory cytokines production, inflammatory cell infiltration, inflammatory mediators activation and oxidative stress, and restored intestinal barrier integrity.

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