ArticleHepatology (Baltimore, Md.)2016
Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice.
Article in Hepatology (Baltimore, Md.), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers, 1 of them a synthesis that pooled it.
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Who cites it
70 citing papers in PubMed, 1 synthesis or guideline pooled it, 140 citations in OpenAlex.
- The burden of Alagille syndrome: uncovering the potential of emerging therapeutics - a comprehensive systematic literature review.Journal of comparative effectiveness research · 2025Pooled it
- Dietary vitamin A restricts intestinal tuft cell differentiation.Cell reports · 2026Article
- Enzymatic hydrolysis of conjugated bile acids during benchtop processing: a preanalytical pitfall in quantitative bioanalysis.Analytical and bioanalytical chemistry · 2026Article
- Gut microbiome and bile acid metabolism in liver disease: Mechanisms, clinical implications, and therapeutic opportunities.Pharmacological reviews · 2026Review
- Pediatric Cholestatic Diseases in the Era of Ileal Bile Acid Transporter (IBAT) Inhibitors.Pediatric reports · 2026Review
- Bile acids engage the SIPR-STAT3 signaling axis to modulate regulatory T cell responses in fibrosing cholangiopathies.Journal of hepatology · 2025Article
- Benefits and challenges to therapeutic targeting of bile acid circulation in cholestatic liver disease.Hepatology (Baltimore, Md.) · 2025Review
- Primary sclerosing cholangitis.Nature reviews. Disease primers · 2025Review
- Hepatic bile acid accretion correlates with cholestatic liver injury and therapeutic response inAmerican journal of physiology. Gastrointestinal and liver physiology · 2024Article
- Bile acid transport inhibitors in paediatric hepatology: more than just an itch.Nature reviews. Gastroenterology & hepatology · 2024Article
- The gut microbiota-bile acid axis in cholestatic liver disease.Molecular medicine (Cambridge, Mass.) · 2024Review
- Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets.Signal transduction and targeted therapy · 2024Review
- MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation.Asian journal of pharmaceutical sciences · 2024Article
- Therapeutic potential of berberine in attenuating cholestatic liver injury: insights from a PSC mouse model.Cell & bioscience · 2024Article
- Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis.JHEP reports : innovation in hepatology · 2023Article
- Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice.JCI insight · 2023Article
- Polygoni Multiflori Radix interferes with bile acid metabolism homeostasis by inhibitingFrontiers in pharmacology · 2023Article
- Farnesoid X receptor antagonizes macrophage-dependent licensing of effector T lymphocytes and progression of sclerosing cholangitis.Science translational medicine · 2022Article
- Bile acids and their receptors: modulators and therapeutic targets in liver inflammation.Seminars in immunopathology · 2022Review
- Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology.Nature reviews. Gastroenterology & hepatology · 2022Review
10 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
unlabelledDeficiency of multidrug resistance 2 (mdr2), a canalicular phospholipid floppase, leads to excretion of low-phospholipid "toxic" bile causing progressive cholestasis. We hypothesize that pharmacological inhibition of the ileal, apical sodium-dependent bile acid transporter (ASBT), blocks progression of sclerosing cholangitis in mdr2(-/-) mice. Thirty-day-old, female mdr2(-/-) mice were fed high-fat chow containing 0.006% SC-435, a minimally absorbed, potent inhibitor of ASBT, providing, on average, 11 mg/kg/day of compound. Bile acids (BAs) and phospholipids were measured by mass spectrometry. Compared with untreated mdr2(-/-) mice, SC-435 treatment for 14 days increased fecal BA excretion by 8-fold, lowered total BA concentration in liver by 65%, reduced total BA and individual hydrophobic BA concentrations in serum by >98%, and decreased plasma alanine aminotransferase, total bilirubin, and serum alkaline phosphatase levels by 86%, 93%, and 55%, respectively. Liver histology of sclerosing cholangitis improved, and extent of fibrosis decreased concomitant with reduction of hepatic profibrogenic gene expression. Biliary BA concentrations significantly decreased and phospholipids remained low and unchanged with treatment. The phosphatidylcholine (PC)/BA ratio in treated mice corrected toward a ratio of 0.28 found in wild-type mice, indicating decreased bile toxicity. Hepatic RNA sequencing studies revealed up-regulation of putative anti-inflammatory and antifibrogenic genes, including Ppara and Igf1, and down-regulation of several proinflammatory genes, including Ccl2 and Lcn2, implicated in leukocyte recruitment. Flow cytometric analysis revealed significant reduction of frequencies of hepatic CD11b(+) F4/80(+) Kupffer cells and CD11b(+) Gr1(+) neutrophils, accompanied by expansion of anti-inflammatory Ly6C(-) monocytes in treated mdr2(-/-) mice.
conclusionInhibition of ASBT reduces BA pool size and retention of hydrophobic BA, favorably alters the biliary PC/BA ratio, profoundly changes the hepatic transcriptome, attenuates recruitment of leukocytes, and abrogates progression of murine sclerosing cholangitis.
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