Role of FXR in Liver Inflammation During Nonalcoholic Steatohepatitis

Armstrong, Laura E.; Guo, Grace L.

doi:10.1007/s40495-017-0085-2

Cited by 80 publications

(72 citation statements)

References 65 publications

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“…41 Interestingly, the expression of FXR is downregulated during the development of liver diseases. 42 On the basis of this background, we proposed that the decrease of BSH abundance in patients with liver diseases is associated with the host FXR expression level; however, further experiments need to be performed to elucidate the related underlying mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Metagenomic analysis of the human microbiome reveals the association between the abundance of gut bile salt hydrolases and host health

et al. 2020

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Bile acid metabolism by the gut microbiome exerts both beneficial and harmful effects on host health. Microbial bile salt hydrolases (BSHs), which initiate bile acid metabolism, exhibit both positive and negative effects on host physiology. In this study, 5,790 BSH homologs were collected and classified into seven clusters based on a sequence similarity network. Next, the abundance and distribution of BSH in 380 metagenomes from healthy participants were analyzed. It was observed that different clusters occupied diverse ecological niches in the human microbiome and that the clusters with signal peptides were relatively abundant in the gut. Then, the association between BSH clusters and 12 human diseases was analyzed by comparing the abundances of BSH genes in patients (n = 1,605) and healthy controls (n = 1,540). The analysis identified a significant association between BSH gene abundance and 10 human diseases, including gastrointestinal diseases, obesity, type 2 diabetes, liver diseases, cardiovascular diseases, and neurological diseases. The associations were further validated by separate cohorts with inflammatory bowel diseases and colorectal cancer. These large-scale studies of enzyme sequences combined with metagenomic data provide a reproducible assessment of the association between gut BSHs and human diseases. This information can contribute to future diagnostic and therapeutic applications of BSH-active bacteria for improving human health.

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Section: Discussionmentioning

confidence: 99%

Metagenomic analysis of the human microbiome reveals the association between the abundance of gut bile salt hydrolases and host health

et al. 2020

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“…However, it has been verified that TMAO exacerbates hepatic steatosis by blocking the farnesoid X receptor (FXR) signaling activated by bile acid [49]. By contrast, the activation of FXR signaling have shown a protective effect against NAFLD including liver steatosis and inflammation [50,51]. It should be mentioned that N,N,N-trimethyl-5-aminovaleric acid (TMAVA), a newly identified gut microbiota metabolite, appears as a key molecule exacerbating high-fat diet-induced liver steatosis through the inhibition of carnitine synthesis accompanied by a reduction in mitochondrial fatty acid β-oxidation in hepatic tissue [52].…”

Section: Gut Microbiota-derived Components and Metabolites That Accelmentioning

confidence: 99%

The Molecular and Mechanistic Insights Based on Gut–Liver Axis: Nutritional Target for Non-Alcoholic Fatty Liver Disease (NAFLD) Improvement

Yin

Sun

et al. 2020

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is recognized as the most frequent classification of liver disease around the globe. Along with the sequencing technologies, gut microbiota has been regarded as a vital factor for the maintenance of human and animal health and the mediation of multiple diseases. The modulation of gut microbiota as a mechanism affecting the pathogenesis of NAFLD is becoming a growing area of concern. Recent advances in the communication between gut and hepatic tissue pave novel ways to better explain the molecular mechanisms regarding the pathological physiology of NAFLD. In this review, we recapitulate the current knowledge of the mechanisms correlated with the development and progression of NAFLD regulated by the gut microbiome and gut–liver axis, which may provide crucial therapeutic strategies for NAFLD. These mechanisms predominantly involve: (1) the alteration in gut microbiome profile; (2) the effects of components and metabolites from gut bacteria (e.g., lipopolysaccharides (LPS), trimethylamine-N-oxide (TMAO), and N,N,N-trimethyl-5-aminovaleric acid (TMAVA)); and (3) the impairment of intestinal barrier function and bile acid homeostasis. In particular, the prevention and therapy of NAFLD assisted by nutritional strategies are highlighted, including probiotics, functional oligosaccharides, dietary fibers, ω-3 polyunsaturated fatty acids, functional amino acids (L-tryptophan and L-glutamine), carotenoids, and polyphenols, based on the targets excavated from the gut–liver axis.

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“…The next two associated pathways, LXR/RXR activation and FXR/RXR activation, are mechanistically linked via heterodimerization of the nuclear receptors farnesoid X receptor (FXR) and retinoid X receptor (RXR) [ 41 ]. FXR is highly expressed in the liver and is involved in several key metabolic processes including bile acid synthesis, glucose and lipid metabolism, and regulation of inflammatory pathways [ 42 ]. Administration of the synthetic bile acid derivative and FXR agonist, obeticholic acid, has been shown to reduce the histological NAFLD fibrosis score in a multicenter, randomized, double blind, placebo-controlled study [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Differentially methylated loci in NAFLD cirrhosis are associated with key signaling pathways

Gerhard¹,

Malenica²,

Llaci³

et al. 2018

Clin Epigenet

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Altered DNA methylation events contribute to the pathogenesis and progression of metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). Investigations of global DNA methylation patterns in liver biopsies representing severe NAFLD fibrosis have been limited. We used the HumanMethylation 450K BeadChip to analyze genome-wide methylation in patients with biopsy-proven grade 3/4 NAFLD fibrosis/cirrhosis (N = 14) and age- and sex-matched controls with normal histology (N = 15). We identified 208 CpG islands (CGIs), including 99 hypomethylated and 109 hypermethylated CGIs, showing statistically significant evidence (adjusted P value < 0.05) for differential methylation between cirrhotic and normal samples. Comparison of β values for each CGI to the read count of its corresponding gene obtained from RNA-sequencing analysis revealed negative correlation (adjusted P value < 0.05) for 34 transcripts. These findings provide supporting evidence for a role for CpG methylation in the pathogenesis of NAFLD-related cirrhosis, including confirmation of previously reported differentially methylated CGIs, and contribute new insight into the molecular mechanisms underlying the initiation and progression of liver fibrosis and cirrhosis.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0525-9) contains supplementary material, which is available to authorized users.

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Role of FXR in Liver Inflammation During Nonalcoholic Steatohepatitis

Cited by 80 publications

References 65 publications

Metagenomic analysis of the human microbiome reveals the association between the abundance of gut bile salt hydrolases and host health

Metagenomic analysis of the human microbiome reveals the association between the abundance of gut bile salt hydrolases and host health

The Molecular and Mechanistic Insights Based on Gut–Liver Axis: Nutritional Target for Non-Alcoholic Fatty Liver Disease (NAFLD) Improvement

Differentially methylated loci in NAFLD cirrhosis are associated with key signaling pathways

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