Intestine farnesoid X receptor agonist and the gut microbiota activate G‐protein bile acid receptor‐1 signaling to improve metabolism

Pathak, Preeti; Xie, Cen; Nichols, Robert G.; Ferrell, Jessica M.; Boehme, Shannon; Krausz, Kristopher W.; Patterson, Andrew D.; Gonzalez, Frank J.; Chiang, John Y.L.

doi:10.1002/hep.29857

Cited by 371 publications

(284 citation statements)

References 43 publications

(56 reference statements)

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“…Inhibition of FXR in the intestine via administration of glycine‐β‐muricholic acid or glycoursodeoxycholic acid has been reported to ameliorate obesity‐related metabolic dysfunction . In contrast, selective activation of intestinal FXR by fexaramine appears to improve liver function, as well as metabolic profiles, in mice fed a HFD . We and others observed that both hepatic FXR levels and hepatic bile acid signalling are suppressed in patients with NAFLD, and this was also true in the obese mice with NAFLD assessed in this study.…”

Section: Discussionsupporting

confidence: 58%

Farnesoid X receptor activation induces the degradation of hepatotoxic 1‐deoxysphingolipids in non‐alcoholic fatty liver disease

Gai

Gui

Alecu

et al. 2020

Liver International

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Background & Aims Patients with non‐alcoholic fatty liver disease (NAFLD) exhibit higher levels of plasma 1‐deoxysphingolipids than healthy individuals. The aim of this study was to investigate the role of farnesoid X receptor (FXR) in 1‐deoxysphingolipid de novo synthesis and degradation. Methods Mice were fed with a high‐fat diet (HFD) to induce obesity and NAFLD, and then treated with the FXR ligand obeticholic acid (OCA). Histology and gene expression analysis were performed on liver tissue. Sphingolipid patterns from NAFLD patients and mouse models were assessed by liquid chromatography‐mass spectrometry. The molecular mechanism underlying the effect of FXR activation on sphingolipid metabolism was studied in Huh7 cells and primary cultured hepatocytes, as well as in a 1‐deoxysphinganine‐treated mouse model. Results 1‐deoxysphingolipids were increased in both NAFLD patients and mouse models. FXR activation by OCA protected the liver against oxidative stress, apoptosis, and reduced 1‐deoxysphingolipid levels, both in a HFD‐induced mouse model of obesity and in 1‐deoxysphinganine‐treated mice. In vitro, FXR activation lowered intracellular 1‐deoxysphingolipid levels by inducing Cyp4f‐mediated degradation, but not by inhibiting de novo synthesis, thereby protecting hepatocytes against doxSA‐induced cytotoxicity, mitochondrial damage, and apoptosis. Overexpression of Cyp4f13 in cells was sufficient to ameliorate doxSA‐induced cytotoxicity. Treatment with the Cyp4f pan‐inhibitor HET0016 or FXR knock‐down fully abolished the protective effect of OCA, indicating that OCA‐mediated 1‐deoxysphingolipid degradation is FXR and Cyp4f dependent. Conclusions Our study identifies FXR‐Cyp4f as a novel regulatory pathway for 1‐deoxysphingolipid metabolism. FXR activation represents a promising therapeutic strategy for patients with metabolic syndrome and NAFLD.

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Section: Discussionsupporting

confidence: 58%

Farnesoid X receptor activation induces the degradation of hepatotoxic 1‐deoxysphingolipids in non‐alcoholic fatty liver disease

Gai

Gui

Alecu

et al. 2020

Liver International

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“…More and more studies have confirmed that TGR5 is also involved in energy metabolism regulation, such as glucose metabolism and lipid metabolism. Another study shows that gut‐specific FXR agonists could improve insulin resistance and abnormal glycolipid metabolism by activating TGR5, which in turn stimulated glucagon‐like peptide‐1 secretion (Pathak et al, ). All of these studies indicate that FXR/TGR5 pathway is involved in the regulation of lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Quercetin improves nonalcoholic fatty liver by ameliorating inflammation, oxidative stress, and lipid metabolism in db/db mice

Yang

Cai

et al. 2019

Phytotherapy Research

142

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Multiphase pathological processes involve in Type 2 diabetes (T2DM)‐induced nonalcoholic fatty liver disease (NAFLD). However, the therapies are quite limited. In the present study, the hepatoprotective effects and underlying mechanisms of quercetin in T2DM‐induced NAFLD were investigated. T2DM‐induced NAFLD and quercetin treatment models were established in vivo and in vitro. The results revealed that quercetin alleviated serum transaminase levels and markedly reduced T2DM‐induced histological alterations of livers. Additionally, quercetin restored superoxide dismutase, catalase, and glutathione content in livers. Not only that, quercetin markedly attenuated T2DM‐induced production of interleukin 1 beta, interleukin 6, and TNF‐α. Accompanied by the restoration of the increased serum total bile acid (p = .0001) and the decreased liver total bile acid (p = .0005), quercetin could reduce lipid accumulation in the liver of db/db mice. Further mechanism studies showed that farnesoid X receptor 1/Takeda G‐protein‐coupled receptor 5 signaling pathways was involved in quercetin regulation of lipid metabolism in T2DM‐induced NAFLD. In high D‐glucose and free fatty acid cocultured HepG2 cells model, quercetin eliminated lipid droplets and restored the upregulated total cholesterol and triglyceride levels. Similar to the findings in mice, quercetin could also activate farnesoid X receptor 1/Takeda G‐protein‐coupled receptor 5 signaling pathway. These findings suggested that quercetin might be a potentially effective drug for the treatment of T2DM‐induced NAFLD.

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“…LCA and DCA activate TGR5, which is expressed in intestinal cells, cholangiocytes, Kupffer cells, and other epithelial cells and tissues but not in hepatocytes . Activation of TGR5 stimulates glucagon‐like peptide 1 (GLP‐1) secretion from intestinal L cells to improve hepatic glucose and insulin sensitivity . A dual FXR and TGR5 agonist induced TGR5 expression and FXR and TGR5 crosstalk to stimulate GLP‐1 secretion and adipose tissue browning, improving hepatic metabolism and metabolic disorders .…”

mentioning

confidence: 99%

Deficiency of Both Farnesoid X Receptor and Takeda G Protein–Coupled Receptor 5 Exacerbated Liver Fibrosis in Mice

et al. 2019

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Activation of the nuclear bile acid receptor farnesoid X receptor (FXR) protects against hepatic inflammation and injury, while Takeda G protein–coupled receptor 5 (TGR5) promotes adipose tissue browning and energy metabolism. Here, we examined the physiological and metabolic effects of the deficiency of these two bile acid receptors on hepatic metabolism and injury in mice. Fxr/Tgr5 double knockout mice (DKO) were generated for metabolic phenotyping. Male DKO mice fed a chow diet had reduced liver lipid levels but increased serum cholesterol levels. Liver cholesterol 7α‐hydroxylase (Cyp7a1) activity and sterol 12α‐hydroxylase mRNA levels were induced, while ileum FXR target genes were suppressed in DKO mice compared to wild‐type (WT) mice. Bile acid pool size was increased in DKO mice, with increased taurocholic acid and decreased tauromuricholic acids. RNA sequencing analysis of the liver transcriptome revealed that bile acid synthesis and fibrosis gene expression levels are increased in chow‐fed DKO mice compared to WT mice and that the top regulated pathways are involved in steroid/cholesterol biosynthesis, liver cirrhosis, and connective tissue disease. Cholestyramine treatment further induced Cyp7a1 mRNA and protein in DKO mice and increased bile acid pool size, while cholic acid also induced Cyp7a1 in DKO mice, suggesting impaired bile acid feedback regulation. A Western diet containing 0.2% cholesterol increased oxidative stress and markers of liver fibrosis but not hepatic steatosis in DKO mice. Conclusion: FXR and TGR5 play critical roles in protecting the liver from inflammation and fibrosis, and deficiency of both of these bile acid receptors in mice increased cholic acid synthesis and the bile acid pool, liver fibrosis, and inflammation; FXR and TGR5 DKO mice may be a model for liver fibrosis.

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Intestine farnesoid X receptor agonist and the gut microbiota activate G‐protein bile acid receptor‐1 signaling to improve metabolism

Cited by 371 publications

References 43 publications

Farnesoid X receptor activation induces the degradation of hepatotoxic 1‐deoxysphingolipids in non‐alcoholic fatty liver disease

Farnesoid X receptor activation induces the degradation of hepatotoxic 1‐deoxysphingolipids in non‐alcoholic fatty liver disease

Quercetin improves nonalcoholic fatty liver by ameliorating inflammation, oxidative stress, and lipid metabolism in db/db mice

Deficiency of Both Farnesoid X Receptor and Takeda G Protein–Coupled Receptor 5 Exacerbated Liver Fibrosis in Mice

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