All-Trans-Retinoic Acid Improves Cholestasis inα-Naphthylisothiocyanate–Treated Rats andMdr2−/−Mice

Cai, Shi‐Ying; Mennone, Albert; Soroka, Carol J.; Boyer, James L.

doi:10.1124/jpet.113.209353

Cited by 34 publications

(26 citation statements)

References 11 publications

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“…In accordance with pre-clinical findings in animal models of cholestasis 6,7 , we observed inhibition of bile acid synthesis after ATRA and UDCA combination therapy. Specifically, the median serum level of the bile acid intermediate C4 significantly decreased after 12 weeks (9.8±19 vs. 7.6±11 ng/mL, p=.03), Figure 3B .…”

Section: Resultssupporting

confidence: 90%

“…Interestingly, the most beneficial effects in the BDL injury model were found with the combination of ATRA and UDCA. Similar, albeit less dramatic, findings were observed in the other two animal models 7 .…”

Section: Introductionsupporting

confidence: 81%

“…Studies in HepG2 cells and isolated human hepatocytes demonstrated that ATRA inhibited CYP7A1 mRNA expression, the rate-limiting enzyme in bile acid synthesis from cholesterol 5 . Based on these findings, several cholestatic animal models, including bile-duct ligation (BDL) and alpha-napthyl isothiocyanate (ANIT) treatment in rats, and the Mdr2−/− mouse model that mimics sclerosing cholangitis, were treated with ATRA with and without ursodeoxycholic acid (UDCA) and compared with untreated cholestatic animals 6,7 . The most striking findings were observed in the two-week bile duct obstruction model 6 .…”

Section: Introductionmentioning

confidence: 99%

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Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis

Abdelghany

Cai

Gossard

et al. 2017

Journal of Clinical Gastroenterology

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GOALS To perform an exploratory pilot study of all-trans retinoic acid (ATRA) combined with ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC). BACKGROUND PSC is a progressive disorder for which there is no accepted therapy. Studies in human hepatocyte cultures and in animal models of cholestasis indicate that ATRA might have beneficial effects in cholestatic disorders. STUDY ATRA (45 mg/m2/day, divided and given twice daily) was combined with moderate-dose UDCA in patients with PSC who had incomplete response to UDCA monotherapy. The combination was administered for 12 weeks, followed by a 12-week washout in which patients returned to UDCA monotherapy. We measured alkaline phosphatase (ALP), alanine aminotransferase (ALT), bilirubin, cholesterol, bile acids, and the bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) at baseline, week 12, and after washout. RESULTS Fifteen patients completed 12 weeks of therapy. The addition of ATRA to UDCA reduced the median serum ALP levels (277±211 to 243±225 U/L; P=.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32 U/L; P=.001) and C4 (9.8±19 to 7.9±11 ng/mL; P=.03) levels significantly decreased. After washout, ALP and C4 levels non-significantly increased while ALT levels significantly increased (46±32 to 74±74; p=0.0006), returning to baseline. CONCLUSIONS In this human pilot study, the combination of ATRA and UDCA did not achieve the primary endpoint (ALP), however it significantly reduced ALT and the bile acid intermediate C4. ATRA appears to inhibit bile acid synthesis and reduce markers of inflammation, making it a potential candidate for further study in PSC. NCT01456468.

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Section: Resultssupporting

confidence: 90%

Section: Introductionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

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Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis

Abdelghany

Cai

Gossard

et al. 2017

Journal of Clinical Gastroenterology

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“…This repression of bile acids synthesis enzyme by ATRA was potentiated by UDCA co-treatment [159] , suggesting that the combination therapy may be a superior to monotherapy. In line, recent studies in bile duct-ligated rats and Mdr2 (Abcb4) -/-mice demonstrated that ATRA has complemented UDCA effects in diminishing biliary fibrosis, bile duct proliferation and hepatic inflammation [157,160] . Based on these beneficial effects, the combination therapy of ATRA and UDCA is currently tested in an open label clinical trial in PSC patients (trial number NCT01456468).…”

Section: Bile Acids Receptors and Other (Nuclear Hormone) Receptorsmentioning

confidence: 60%

Therapy of Primary Sclerosing Cholangitis - Today and Tomorrow

Halilbasic

Fuchs

Hofer

et al. 2015

Dig Dis

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Primary sclerosing cholangitis (PSC) represents a fibro-obliterative bile duct disease with unpredictable individual clinical course that may progress to liver cirrhosis and malignancy. Due to our incomplete understanding of the etiology and pathogenesis of this disease, the therapeutic options are still rather limited. Bile acids play a key role in mediating cholangiocellular and hepatocellular injury in cholangiopathies such as PSC. Therefore, strategies targeting bile composition and homeostasis are valid approaches in PSC. Ursodeoxycholic acid (UDCA) is the paradigm therapeutic bile acid and its role in medical therapy of PSC is still under debate. Promising novel bile acid-based therapeutic options include 24-norursodeoxycholic acid (norUDCA), a side chain-shortened C₂₃ homologue of UDCA, and bile acid receptor/farnesoid X receptor agonists (e.g. obeticholic acid). Other nuclear receptors such as fatty acid-activated peroxisome proliferator-activated receptors, vitamin D receptor and vitamin A receptors (retinoic acid receptor, retinoid X receptor) are also of potential interest and can be targeted by already available drugs. Furthermore, drugs targeting the gut-liver axis (e.g. intregrin blockers such as vedolizumab, antibiotics) appear promising, based on the close link of PSC to inflammatory bowel disease and the emerging relevance of the gut microbiome for the development of PSC. Finally, fibrosis represents a valid therapeutic target for anti-fibrotic drugs (e.g. simtuzumab) in PSC as paradigm fibro-obliterative disease. This review summarizes the current status and recent progress in the development of targeted therapeutic approaches based on increasing knowledge about the pathogenesis of this disease.

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“…ATRA treatment repressed CYP7A1 promotor activity [39], which was potentiated by UDCA co-treatment [40]. In line, recent studies in bile duct-ligated rats and Mdr2 knockout mice demonstrated that the combination therapy with UDCA-reduced biliary fibrosis, bile duct proliferation and hepatic inflammation [38,41]. Based on these beneficial effects, the combination therapy of ATRA and UDCA is currently tested in an open label clinical trial in PSC patients (trial number NCT01456468).…”

Section: Fxr (And Other Future Therapies) In Treatment Of Cholestaticmentioning

confidence: 96%

Farnesoid X Receptor Agonists and Other Bile Acid Signaling Strategies for Treatment of Liver Disease

Halilbasic

Fuchs

Traussnigg

et al. 2016

Dig Dis

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The intracellular nuclear receptor farnesoid X receptor (FXR) and the transmembrane G protein-coupled receptor 5 (TGR5) respond to bile acids (BAs) by activating transcriptional networks and/or signaling cascades. These cascades affect the expression of a great number of target genes relevant for BA, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. FXR activation in the liver tissue and beyond, such as the gut-liver axis, kidney and adipose tissue, plays a role in metabolic diseases. These BA receptors activators hold promise to become a new class of drugs to be used in the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This review discusses the relevant BA receptors, the new drugs that target BA transport and signaling and their possible applications.

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All-Trans-Retinoic Acid Improves Cholestasis inα-Naphthylisothiocyanate–Treated Rats andMdr2^−/−Mice

Cited by 34 publications

References 11 publications

Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis

Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis

Therapy of Primary Sclerosing Cholangitis - Today and Tomorrow

Farnesoid X Receptor Agonists and Other Bile Acid Signaling Strategies for Treatment of Liver Disease

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