Role of bile acids in inflammatory liver diseases

Evangelakos, Ioannis; Heeren, Joerg; Verkade, Esther; Kuipers, Folkert

doi:10.1007/s00281-021-00869-6

Cited by 68 publications

(57 citation statements)

References 108 publications

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“…Changes in bile acid and oxysterol levels contribute and/or occur during the establishment of metabolic abnormalities such as type 2 diabetes and MAFLD [19,38]. Therefore, unravelling the contribution of specific cytochrome P450 superfamily enzymes that mediate their biosynthetic pathways can shed light on their pathophysiological role.…”

Section: Discussionmentioning

confidence: 99%

“…Next to nuclear receptors, G protein-coupled bile acid receptors (such as TGR5) regulate immune cells in various organs. For instance, the TGR5 ligand LCA reduces pro-inflammatory signaling pathways in macrophages of the liver [19]. Notably, CYP7B1 influences concentrations of hydroxycholesterol and bile acid species, suggesting that the enzyme could affect immune cell abundance and plasticity in chronic inflammatory metabolic disorders such as NASH.…”

Section: Introductionmentioning

confidence: 99%

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Oxysterol 7-α Hydroxylase (CYP7B1) Attenuates Metabolic-Associated Fatty Liver Disease in Mice at Thermoneutrality

Evangelakos

Schwinge

Worthmann

et al. 2021

Cells

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Ambient temperature is an important determinant of both the alternative bile acid synthesis pathway controlled by oxysterol 7-α hydroxylase (CYP7B1) and the progression of metabolic-associated fatty liver disease (MAFLD). Here, we investigated whether CYP7B1 is involved in the etiology of MAFLD under conditions of low and high energy expenditure. For this, Cyp7b1−/− and wild type (WT) mice were fed a choline-deficient high-fat diet and housed either at 30 °C (thermoneutrality) or at 22 °C (mild cold). To study disease phenotype and underlying mechanisms, plasma and organ samples were analyzed to determine metabolic parameters, immune cell infiltration by immunohistology and flow cytometry, lipid species including hydroxycholesterols, bile acids and structural lipids. In WT and Cyp7b1−/− mice, thermoneutral housing promoted MAFLD, an effect that was more pronounced in CYP7B1-deficient mice. In these mice, we found higher plasma alanine aminotransferase activity, hyperlipidemia, hepatic accumulation of potentially harmful lipid species, aggravated liver fibrosis, increased inflammation and immune cell infiltration. Bile acids and hydroxycholesterols did not correlate with aggravated MAFLD in Cyp7b1−/− mice housed at thermoneutrality. Notably, an up-regulation of lipoprotein receptors was detected at 22 °C but not at 30 °C in livers of Cyp7b1−/− mice, suggesting that accelerated metabolism of lipoproteins carrying lipotoxic molecules counteracts MAFLD progression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oxysterol 7-α Hydroxylase (CYP7B1) Attenuates Metabolic-Associated Fatty Liver Disease in Mice at Thermoneutrality

Evangelakos

Schwinge

Worthmann

et al. 2021

Cells

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“…The ratio of these two primary bile acids is regulated by the sterol 12a-hydroxylase (CYP8B1), which is necessary for CA synthesis [62]. To enhance solubility, the newly synthesized bile acids are conjugated with hydrophilic molecules, such as taurine or glycine [63]. SLC6A9 and SLC6A6 genes encode a multi-pass membrane protein that transports glycine or taurine, respectively [64,65].…”

Section: Discussionmentioning

confidence: 99%

A Lard and Soybean Oil Mixture Alleviates Low-Fat–High-Carbohydrate Diet-Induced Nonalcoholic Fatty Liver Disease in Mice

Yan

Liu

et al. 2022

Nutrients

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Dietary habit is highly related to nonalcoholic fatty liver disease (NAFLD). Low-fat–high-carbohydrate (LFHC) diets could induce lean NAFLD in Asians. Previously, we found that a lard and soybean oil mixture reduced fat accumulation with a medium-fat diet; therefore, in this study, we evaluated the effect of a lard and soybean oil mixture (LFHC diet) on NAFLD and its underlying mechanisms. Mice in groups were fed with lard, soybean oil, or a lard and soybean oil mixture—an LFHC diet—separately. Our results showed that mixed oil significantly inhibited serum triglyceride, liver triglyceride, serum free fatty acids (FFAs), and liver FFAs compared with soybean oil or lard, and we found fewer inflammatory cells in mice fed with mixed oil. RNA-seq results indicate that mixed oil reduced FFAs transportation into the liver via decreasing liver fatty acid-binding protein 2 expression, inhibited oxidative phosphorylation via tumor necrosis factor receptor superfamily member 6 downregulation, and alleviated inflammation via downregulating inflammatory cytokine. The liquid chromatography–mass spectrometry results showed that the mixed oil promoted bile acid conjugated with taurine and glycine, thus activating G-protein-coupled bile acid receptor 1 for improved lipids metabolism. In conclusion, the lard and soybean oil mixture alleviated NAFLD.

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“…BA receptors became focus of interest for drug targets in cholestatic diseases. Especially, Farnesoid X receptor (FXR) as a nuclear receptor, and Takeda G protein coupled receptor 5 (TGR5) as a membrane bound receptor are extensively investigated [43]. It is possible that bile acids trigger ROS production and inflammasome activation after binding to FXR or TGR5 [44].…”

Section: Discussionmentioning

confidence: 99%

Bile Acids Activate NLRP3 Inflammasome, Promoting Murine Liver Inflammation or Fibrosis in a Cell Type-Specific Manner

Holtmann

Inzaugarat

Knorr

et al. 2021

Cells

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Bile acids (BA) as important signaling molecules are considered crucial in development of cholestatic liver injury, but there is limited understanding on the involved cell types and signaling pathways. The aim of this study was to evaluate the inflammatory and fibrotic potential of key BA and the role of distinct liver cell subsets focusing on the NLRP3 inflammasome. C57BL/6 wild-type (WT) and Nlrp3−/− mice were fed with a diet supplemented with cholic (CA), deoxycholic (DCA) or lithocholic acid (LCA) for 7 days. Additionally, primary hepatocytes, Kupffer cells (KC) and hepatic stellate cells (HSC) from WT and Nlrp3−/− mice were stimulated with aforementioned BA ex vivo. LCA feeding led to strong liver damage and activation of NLRP3 inflammasome. Ex vivo KC were the most affected cells by LCA, resulting in a pro-inflammatory phenotype. Liver damage and primary KC activation was both ameliorated in Nlrp3-deficient mice or cells. DCA feeding induced fibrotic alterations. Primary HSC upregulated the NLRP3 inflammasome and early fibrotic markers when stimulated with DCA, but not LCA. Pro-fibrogenic signals in liver and primary HSC were attenuated in Nlrp3−/− mice or cells. The data shows that distinct BA induce NLRP3 inflammasome activation in HSC or KC, promoting fibrosis or inflammation.

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Role of bile acids in inflammatory liver diseases

Cited by 68 publications

References 108 publications

Oxysterol 7-α Hydroxylase (CYP7B1) Attenuates Metabolic-Associated Fatty Liver Disease in Mice at Thermoneutrality

Oxysterol 7-α Hydroxylase (CYP7B1) Attenuates Metabolic-Associated Fatty Liver Disease in Mice at Thermoneutrality

A Lard and Soybean Oil Mixture Alleviates Low-Fat–High-Carbohydrate Diet-Induced Nonalcoholic Fatty Liver Disease in Mice

Bile Acids Activate NLRP3 Inflammasome, Promoting Murine Liver Inflammation or Fibrosis in a Cell Type-Specific Manner

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