Latest and Emerging Therapies for Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis

Zein, Claudia O.; Lindor, Keith D.

doi:10.1007/s11894-009-0079-2

Cited by 23 publications

(25 citation statements)

References 81 publications

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“…Chronic cholestasis causes liver fibrosis, cirrhosis, liver failure, hepatocellular carcinoma, and cholangiocarcinoma. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are two common types of progressive chronic cholestasis diagnosed in humans [48, 49]. The etiologies of PBC and PSC are not fully clear but involve genetic, immune, and environmental factors.…”

Section: Bile Acids As Therapeutic Agentsmentioning

confidence: 99%

Bile acid metabolism and signaling in liver disease and therapy

2017

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Bile acids play a critical role in the regulation of glucose, lipid, and energy metabolism through activation of the nuclear bile acid receptor farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (Gpbar-1, aka TGR5). Agonist activation of FXR and TGR5 improves insulin and glucose sensitivity and stimulates energy metabolism to prevent diabetes, obesity, and non-alcoholic fatty liver disease (NAFLD). Bile acids have both pro- and anti-inflammatory actions through FXR and TGR5 in the intestine and liver. In the intestine, bile acids activate FXR and TGR5 to stimulate stimulate fibroblast growth factor 15 and glucagon-like peptide-1 secretion. FXR and TGR5 agonists may have therapeutic potential for treating liver-related metabolic diseases, such as diabetes and NAFLD.

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Section: Bile Acids As Therapeutic Agentsmentioning

confidence: 99%

Bile acid metabolism and signaling in liver disease and therapy

2017

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“…This study revealed an elaborate regulatory cascade, tightly controlled by SHP, for regulating both the maintenance of bile acid production and detoxification in the liver [59]. A better understanding of these mechanisms may aid the development of better agents to decrease serum bile acids in chronic cholestatic liver diseases such as primary biliary cirrhosis and sclerosing cholangitis [144, 145]. …”

Section: Shp In Metabolismmentioning

confidence: 99%

Role of nuclear receptor SHP in metabolism and cancer

Zhang

Hagedorn

Wang

2011

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

220

205

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Small heterodimer partner (SHP, NR0B2) is a unique member of the nuclear receptor (NR) superfamily that contains the dimerization and ligand-binding domain found in other family members, but lacks the conserved DNA binding domain. The ability of SHP to bind directly to multiple NRs is crucial for its physiological function as a transcriptional inhibitor of gene expression. A wide variety of interacting partners for SHP have been identified, indicating the potential for SHP to regulate an array of genes in different biological pathways. In this review, we summarize studies concerning the structure and target genes of SHP and discuss recent progress in understanding the function of SHP in bile acid, cholesterol, triglyceride, glucose, and drug metabolism. In addition, we review the regulatory role of SHP in microRNA (miRNA) regulation, liver fibrosis and cancer progression. The fact that SHP controls a complex set of genes in multiple metabolic pathways suggests the intriguing possibility of developing new therapeutics for metabolic diseases, including fatty liver, dyslipidemia and obesity, by regulating SHP with small molecules. To achieve this goal, more progress regarding SHP ligands and protein structure will be required. Besides its metabolic regulatory function, studies by us and other groups provide strong evidence that SHP plays a critical role in the development of cancer, particularly liver and breast cancer. An increased understanding of the fundamental mechanisms by which SHP regulates the development of cancers will be critical in applying knowledge of SHP in diagnostic, therapeutic or preventive strategies for specific cancers.

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“…Alternative therapies, including combinations of UDCA with immunomodulating drugs, have been tried but have not been successful according to limited clinical trials 4. Thus, there is an urgent need to develop alternative beneficial treatments for these chronic cholestatic diseases 5, 6…”

mentioning

confidence: 99%

Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct-ligated rats and human hepatic cells

Mennone

Boyer

et al. 2010

Hepatology

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Cholestasis leads to liver cell death, fibrosis, cirrhosis, and eventually liver failure. Despite limited benefits, ursodeoxycholic acid (UDCA) is the only Food and Drug Administration–approved treatment for cholestatic disorders. Retinoic acid (RA) is a ligand for nuclear receptors that modulate bile salt homeostasis. RA also possesses immunomodulatory effects and is used to treat acute promyelocytic leukemia and inflammatory disorders such as psoriasis, acne, and rheumatoid arthritis. To test whether the supplementation of RA with UDCA is superior to UDCA alone for treating cholestasis, male Sprague‐Dawley rats underwent common bile duct ligation (BDL) for 14 days and were treated with phosphate‐buffered saline (PBS), UDCA, all‐trans retinoic acid (atRA), or UDCA and atRA by gavage. Treatment with UDCA and atRA substantially improved animal growth rates, significantly reduced liver fibrosis and bile duct proliferation, and nearly eliminated liver necrosis after BDL. Reductions in the bile salt pool size and liver hydroxyproline content were also seen with treatment with atRA or atRA and UDCA versus PBS and UDCA. Furthermore, atRA and UDCA significantly reduced liver messenger RNA and/or protein expression of transforming growth factor β1 (Tgf‐β1), collagen 1a1 (Col1A1), matrix metalloproteinase 2 (Mmp2), cytokeratin 19, α‐smooth muscle actin (α‐SMA), cytochrome P450 7A1 (Cyp7a1), tumor necrosis factor α, and interleukin‐β1. The molecular mechanisms of this treatment were also assessed in human hepatocytes, hepatic stellate cells, and LX‐2 cells. atRA alone or in combination with UDCA greatly repressed CYP7A1 expression in human hepatocytes and significantly inhibited COL1A1, MMP2, and α‐SMA expression and/or activity in primary human hepatic stellate cells and LX‐2 cells. Furthermore, atRA reduced TGF‐β1–induced Smad2 phosphorylation in LX‐2 cells. Conclusion: Our findings indicate that the addition of RA to UDCA reduces the bile salt pool size and liver fibrosis and might be an effective supplemental therapy with UDCA for cholestatic diseases. (HEPATOLOGY 2011;53:548‐557.)

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Latest and Emerging Therapies for Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis

Cited by 23 publications

References 81 publications

Bile acid metabolism and signaling in liver disease and therapy

Bile acid metabolism and signaling in liver disease and therapy

Role of nuclear receptor SHP in metabolism and cancer

Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct-ligated rats and human hepatic cells

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