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Interleukin-13 drives cholestasis and compositional changes in the gut microbiome in Abcb4-deficient mice by compromising bile duct barrier integrity

ABSTRACT: The Th2 cytokine IL-13 has been described to be involved in biliary epithelial injury and liver fibrosis in patients as well as in animal models. IL-13 was found to reduce tight junction-associated barrier function of bile ducts, to promote cholangiocyte hyperplasia, and thus causing biliary epithelial injury. We generated Abcb4-/-- and IL-13-/- double-knockout mice on fibrosis susceptible genetic background BALB/c. Molecular and cellular mechanisms of hepatic and ileal pathology were investigated by mRNA microarray. Depletion of IL-13 in Abcb4-/--mice resulted in a tenfold decrease of total serum bile acid concentrations at the age of 8 weeks and lead to a recovery of intrahepatic bile duct integrity. The decrease of serum bile acid in 8 week old mice went along with relative enhancement of bile acid excretion and normalization of the composition of fecal bile excretion, correction of fecal microbiome, and improved ileal integrity. Liver integrity, measured by serum ALT, was ameliorated in younger mice and strongly correlated with the concentration of serum bile acids. 52 weeks old Abcb4-/-IL-13-/--mice exhibited significantly reduced hepatic fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE90995 | GEO | 2020/11/02

REPOSITORIES: GEO

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Abcb4 liver expression profiling

Project description:The multidrug resistance gene 2 (Mdr2 or Abcb4) encodes a P-glycoprotein (Pgp) - a phospholipid flippase - that is the murine orthologue of the MDR3 gene in humans. The MDR2 protein is principally expressed in the bile canalicular membrane of the liver. A homozygous disruption of Abcb4 causes absence of phospholipids from bile. This phospholipid deficiency results in liver injury. The Balb-Abcb4-/- mouse strain has been generated by introgressing the Abcb4 knockout from the fibrosis-resistant FVB/NJ (FVB.129P2-Abcb4tm1Bor/J) strain into the susceptible BALB/cJ background, by backcrossing FVB- Abcb4-/- mice in to fibrosis-susceptible BALB/cJ mice for 10 generations. cDNA expression profiling of mRNA from liver of four single male mutant mice against a pool of RNA from four wild type controls (n=8). For each mutant animal two technical replicates were performed including a dye swap experiment.

2011-07-31 | E-GEOD-26699 | biostudies-arrayexpress

Abcb4 liver expression profiling

2011-08-01 | GSE26699 | GEO

Hepatic Sel1L-Hrd1 ER-associated degradation deficiency leads to intrahepatic cholestasis in mice

Project description:The liver is the central organ critically regulating the balance of the metabolically potent yet toxic bile acids in the body. While genomic association studies have pointed to hepatic Sel1L – a critical component of mammalian Hrd1 ER-associated degradation (ERAD) machinery – as an influencer of serum bile acid levels, physiological relevance and mechanistic insights of ERAD in bile homeostasis remain unexplored. Using hepatocyte-specific Sel1L-deficient mouse models, we report that hepatic Sel1L-Hrd1 ERAD critically manages bile homeostasis in the body. Mice with hepatocyte-specific Sel1L developed intrahepatic cholestasis, with significant overload of bile acids in the liver and circulation under basal condition, and were hypersensitive to dietary bile acid challenge. By contrast, biliary bile acid and phosphatidylcholine levels were reduced, pointing to an export defect from hepatocytes. Unbiased proteomics analysis followed by biochemical assays revealed significant accumulation of the bile-stabilizing phosphatidylcholine exporter ATP-binding cassette 4 (Abcb4) in the ER of Sel1L-deficient livers, a gene associated with Progressive Familial Intrahepatic Cholestasis type III. Indeed, Abcb4 was a substrate of Sel1L-Hrd1 ERAD. Hence, hepatic Sel1L-Hrd1 ERAD maintains bile equilibrium via quality control of Abcb4 maturation in the ER.

2023-03-11 | PXD035243 | Pride

Gene expression profiles of sclerosing cholangitis activity in mice

Project description:Background. Abcb4 (-/-) mice secrete phosphatidylcholine-deficient bile and develop sclerosing cholangitis (SC). The cholangitis involves differential hepatic transcription of genes whose products govern inflammation, activation of hepatic stellate cells and fibrosis. This study was undertaken to test the hypothesis that several genes involved in regulation of tissue inflammation and fibrosis display transcription rates that reflect SC disease activity. Methods. Abcb4 (-/-) mice fed cholic acid (CA) display high SC activity and ursodeoxycholic acid (UDCA) fed mice display low SC activity. Differential hepatic transcription of genes was accordingly measured in abcb4 (-/-) mice maintained on CA- and UDCA-supplemented diets using cDNA microarrays. Abcb4 (+/+) mice served as controls. The differential transcription of selected genes was verified by real time polymerase chain reaction. Liver tissue pathology was quantified by histopathology scoring and immunohistochemistry to visualize bile duct cells and activated hepatic stellate cells. Results. Differential transcription of Ccl2, Ccl20, Cxcl10, Nfκb1, Nfκb2, Tgfβ1, Tgfβ2, Sparc, Ctgf, Lgals3, Elf3, Spp1, Pdgfa, Pdgfrb, Col1a1, Col1a2 and Col4a1 genes paralleled the differing SC activities of cholic acid- and UDCA-fed abcb4 (-/-) mice. Histopathology scores and immunohistochemistry showed greatly enhanced activation of hepatic stellate cells during high SC activity due to CA feeding. Conclusion. Differential transcription of several genes relating to tissue inflammation and hepatic stellate cell activation parallels SC activity in abcb4 (-/-) mice. Data on their differential transcription may be used to gauge SC disease activity.

2008-08-20 | GSE11507 | GEO

Mig-6 plays a critical role in the regulation of cholesterol homeostasis and bile acid synthesis.

Project description:The disruption of cholesterol homeostasis leads to an increase in cholesterol levels which results in the development of cardiovascular disease. Mitogen Inducible Gene 6 (Mig-6) is an immediate early response gene that can be induced by various mitogens, stresses, and hormones. To identify the metabolic role of Mig-6 in the liver, we conditionally ablated Mig-6 in the liver using the Albumin-Cre mouse model (Albcre/+Mig-6f/f; Mig-6d/d). Mig-6d/d mice exhibit hepatomegaly and fatty liver. Serum levels of total, LDL, and HDL cholesterol and hepatic lipid were significantly increased in the Mig-6d/d mice. The daily excretion of fecal bile acids was significantly decreased in the Mig-6d/d mice. DNA microarray analysis of mRNA isolated from the livers of these mice showed alterations in genes that regulate lipid metabolism, bile acid, and cholesterol synthesis, while the expression of genes that regulate biliary excretion of bile acid and triglyceride synthesis showed no difference in the Mig-6d/d mice compared to Mig-6f/f controls. These results indicate that Mig-6 plays an important role in cholesterol homeostasis and bile acid synthesis. Mice with liver specific conditional ablation of Mig-6 develop hepatomegaly and increased intrahepatic lipid and provide a novel model system to investigate the genetic and molecular events involved in the regulation of cholesterol homeostasis and bile acid synthesis. Defining the molecular mechanisms by which Mig-6 regulates cholesterol homeostasis will provide new insights into the development of more effective ways for the treatment and prevention of cardiovascular disease. Eight week old Mig-6f/f vs Mig-6d/d male mice after undergoing a 24 hour fast

2011-08-30 | E-GEOD-31752 | biostudies-arrayexpress

Molecular and metabolic effects of norUDCA in Abcb4 knockout mice

Project description:To identify (i) target genes relevant for the disease development (WT vs. Abcb4-/- mice) and (ii) to gain insights into mechanisms leading to the reversal of chronic cholestatic liver injury in Abcb4-/- mice treated with the side-chain modified bile acid "norUDCA" (Abcb4-/- mice vs. norUDCA treated Abcb4-/- mice).

2011-02-02 | GSE26547 | GEO

Transintestinal cholesterol transport is important in mice and humans and controls ezetimibe induced fecal neutral sterol excretion

Project description:Except for conversion to bile salts, there is no major cholesterol degradation pathway in mammals. Efficient excretion from the body is therefore a crucial element in cholesterol homeostasis. Yet, the existence and importance of these pathways in humans is a matter of debate. We quantified cholesterol fluxes in 15 male volunteers using a cholesterol balance approach. Ten participants repeated the protocol after 4-weeks treatment with ezetimibe, an inhibitor of intestinal and biliary cholesterol absorption. Under basal conditions, about 65% of daily fecal neutral sterol excretion was bile-derived, with the remainder being contributed by direct transintestinal cholesterol excretion (TICE). Surprisingly, ezetimibe induced a fourfold increase in cholesterol elimination via TICE. Mouse studies revealed that most of ezetimibe-induced TICE flux is mediated by the cholesterol transporter Abcg5/Abcg8. In conclusion, TICE is active in humans and may serve as a novel target to stimulate cholesterol elimination in patients at risk for cardiovascular disease.

2016-11-04 | GSE77236 | GEO

Mig-6 plays a critical role in the regulation of cholesterol homeostasis and bile acid synthesis.

2011-08-31 | GSE31752 | GEO

Gut microbiota ameliorates hepatic fibrosis through modulating intestinal bile acid metabolism and hepatocyte pyroptosis (Hepatic fibrosis feces)

Project description:Hepatic fibrosis decreased feces bile acid level. Hepatic fibrosis increased serum bile acid. This result showed that hepatic fibrosis inhibited the excretion of bile acid in clinical patients. This result provided phenotype for hepatic fibrosis patients. Bile acid was important indexes for liver injury. TCDCA was important, and it play toxicity effect through ferroptosis and apoptosis. The research for other bile acid such CA, UDCA, TUDCA, TDCA, LCA, TLCA would be important. Hepatic fibrosis feces (sample 2) analysis is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS6742' rel='noopener noreferrer' target='_blank'>MTBLS6742</a>.Hepatic fibrosis serum (sample 1) analysis is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS6732' rel='noopener noreferrer' target='_blank'>MTBLS6732</a>.Hepatic fibrosis serum+feces (sample 3) analysis is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS6728' rel='noopener noreferrer' target='_blank'>MTBLS6728</a>.

2023-03-17 | MTBLS6742 | MetaboLights

Gut microbiota ameliorates hepatic fibrosis through modulating intestinal bile acid metabolism and hepatocyte pyroptosis (Hepatic fibrosis serum)

Project description:Hepatic fibrosis decreased feces bile acid level. Hepatic fibrosis increased serum bile acid. This result showed that hepatic fibrosis inhibited the excretion of bile acid in clinical patients. This result provided phenotype for hepatic fibrosis patients. Bile acid was important indexes for liver injury. TCDCA was important, and it play toxicity effect through ferroptosis and apoptosis. The research for other bile acid such CA, UDCA, TUDCA, TDCA, LCA, TLCA would be important. Hepatic fibrosis serum (sample 1) analysis is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS6732' rel='noopener noreferrer' target='_blank'>MTBLS6732</a>.Hepatic fibrosis feces (sample 2) analysis is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS6742' rel='noopener noreferrer' target='_blank'>MTBLS6742</a>.Hepatic fibrosis serum+feces (sample 3) analysis is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS6728' rel='noopener noreferrer' target='_blank'>MTBLS6728</a>.

2023-03-17 | MTBLS6732 | MetaboLights

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