All-Trans-Retinoic Acid Improves Cholestasis in α-Naphthylisothiocyanate–Treated Rats and Mdr2−/− Mice
Open accessAbstract
Chronic cholestasis results in liver injury and eventually liver failure. Although ursodeoxycholic acid (UDCA) showed limited benefits in primary biliary cirrhosis, there is an urgent need to develop alternative therapy for chronic cholestatic disorders. Previous studies from our laboratory demonstrated that all-trans-retinoic acid (atRA) is a potent suppressor of CYP7A1, the rate-limiting enzyme in bile acid synthesis. atRA also repressed the expression of tumor growth factor-β and collagen 1A1 in activated primary human stellate cells and LX2 cells. When administered together with UDCA to bile duct-ligated rats, this combined therapy significantly reduced the bile acid pool size and improved liver conditions. To further examine whether atRA alone or in combination with UDCA has greater beneficial effects than UDCA treatment alone, we assessed this treatment in two additional chronic cholestatic rodent models: α-naphthylisothiocyanate (ANIT)-treated rats and the Mdr2(-/-) (Abcb4(-/-)) knockout mouse. atRA alone significantly reduced bile duct proliferation, inflammation, and hydroxyproline levels in ANIT-treated rats, whereas the combination of atRA and UDCA significantly reduced plasma bile salt level compared with UDCA treatment. atRA alone or in combination with UDCA significantly reduced plasma levels of alkaline phosphatase and bile salts in 12-week-old Mdr2(-/-) mice. Reduced bile duct proliferation and inflammation were also observed in the livers of these mice. Together, atRA alone or in combination with UDCA significantly reduced the severity of liver injury in these two animal models, further supporting the combination treatment of atRA and UDCA as a potential new therapy for patients with chronic cholestatic liver disease who have not responded fully to UDCA.
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Administration of atRAs in vitro to HSCs and in vivo in cholestatic animal models is linked to inhibition of pro-fibrotic gene expression such as TGF-β, col1α1, αSMA and MMP-2, and to protective properties regarding ECM accumulation.
“the administration of atRAs in vitro to HSCs and in vivo in cholestatic animal models was linked to an inhibition of pro-fibrotic gene expression (TGF-β, col1α1, αSMA, and MMP-2) [179][180][181][182] and showed protective properties in regard to ECM accumulation.[183][184][185]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [181]
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Königshofer, P., Brusilovskaya, K., Petrenko, O., Hofer, B. S., Schwabl, P., Trauner, M., & Reiberger, T. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2021.166235 · Cited by 45 · see citing works
- Authors
- Cai, S.-Y., Mennone, A., Soroka, C. J., & Boyer, J. L.
- Affiliations
- Yale University (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 349
- Issue
- 1
- Pages
- 94-98
- ISSN
- 0022-3565 (ISSN-L)
- PMC
- PMC3965885
- OpenAlex
- W2157121141
- Cited by
- 36
- References
- 12
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 4 · 2019: 4 · 2018: 7 · 2017: 3 · 2016: 5 · 2015: 3
- FWCI
- 2.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK 34989, R37 DK-25636, R37DK025636, P30DK034989)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- all-trans retinoic acid, chronic cholestasis, ursodeoxycholic acid, alpha-naphthylisothiocyanate, Mdr2 knockout mice, bile acid synthesis, CYP7A1, bile duct proliferation, liver injury, combination therapy, primary biliary cirrhosis
- MeSH terms
- ATP-Binding Cassette Sub-Family B Member 4, Animals, Bile Acids and Salts, Cholagogues and Choleretics, Cholestasis, Chronic Disease, Disease Models, Animal, Drug Therapy, Combination, Liver, Male, Tretinoin, Ursodeoxycholic Acid, 1-Naphthylisothiocyanate, Rats, Sprague-Dawley, Mice, Knockout, ATP Binding Cassette Transporter, Subfamily B, Cell Proliferation, Mice, Rats
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