Therapeutic Opportunities of GPBAR1 in Cholestatic Diseases

GPBAR1, a transmembrane G protein-coupled receptor for bile acids, is widely expressed in multiple tissues in humans and rodents. In recent years, GPBAR1 has been thought to play an important role in bile homeostasis, metabolism and inflammation. This review specifically focuses on the function of GPBAR1 in cholestatic liver disease and summarizes the various pathways through which GPBAR1 acts in cholestatic models. GPBAR1 mainly regulates cholestasis in a holistic system of liver-gallbladder-gut formation. In the state of cholestasis, the activation of GPBAR1 could regulate liver inflammation, induce cholangiocyte regeneration to maintain the integrity of the biliary tree, control the hydrophobicity of the bile acid pool and promote the secretion of bile HCO3−. All these functions of GPBAR1 might be clear ways to protect against cholestatic diseases and liver injury. However, the characteristic of GPBAR1-mediated proliferation increases the risk of proliferation of cholangiocarcinoma in malignant transformed cholangiocytes. This dichotomous function of GPBAR1 limits its use in cholestasis. During disease treatment, simultaneous activation of GPBAR1 and FXR receptors often results in improved outcomes, and this strategy may become a crucial direction in the development of bile acid-activated receptors in the future.

ADAM Metalloproteinase Domain 17 Regulates Cholestasis-Associated Liver Injury and Sickness Behavior Development in Mice

Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) is a ubiquitously expressed membrane-bound enzyme that mediates shedding of a wide variety of important regulators in inflammation including cytokines and adhesion molecules. Hepatic expression of numerous cytokines and adhesion molecules are increased in cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), however, the pathophysiological role of ADAM17 in regulating these conditions remains unknown. Therefore, we evaluated the role of ADAM17 in a mouse model of cholestatic liver injury due to bile duct ligation (BDL). We found that BDL enhanced hepatic ADAM17 protein expression, paralleled by increased ADAM17 bioactivity. Moreover, inhibition of ADAM17 bioactivity with the specific inhibitor DPC 333 significantly improved both biochemical and histological evidence of liver damage in BDL mice. Patients with cholestatic liver disease commonly experience adverse behavioral symptoms, termed sickness behaviors. Similarly, BDL in mice induces reproducible sickness behavior development, driven by the upregulated expression of cytokines and adhesion molecules that are in turn regulated by ADAM17 activity. Indeed, inhibition of ADAM17 activity significantly ameliorated BDL-associated sickness behavior development. In translational studies, we evaluated changes in ADAM17 protein expression in liver biopsies obtained from patients with PBC and PSC, compared to normal control livers. PSC and PBC patients demonstrated increased hepatic ADAM17 expression in hepatocytes, cholangiocytes and in association with liver-infiltrating immune cells compared to normal controls. In summary, cholestatic liver injury in mice and humans is associated with increased hepatic ADAM17 expression. Furthermore, inhibition of ADAM17 activity improves both cholestatic liver injury and associated sickness behavior development, suggesting that ADAM17 inhibition may represent a novel therapeutic approach for treating patients with PBC/PSC.

Nasobiliary drainage: an effective treatment for pruritus in cholestatic liver disease

IntroductionNasobiliary drains (NBDs) have been successfully used to manage intrahepatic cholestasis, bile leaks and obstructive cholangitis. It allows external drainage of bile, bypassing the ileum where bile salts are reabsorbed. We assessed the utility of placement with effect on markers of cholestasis and patient symptoms.MethodsConsecutive patients undergoing NBD over 12 years for the management of pruritus were retrospectively analysed. Recorded variables included patient demographics, procedural characteristics and response to therapy.ResultsTwenty-three patients (14, 61% male) underwent 30 episodes of NBD. The median age was 26 years old (range 2–67 years old). A single procedure was carried out in 20. One patient each had two, three and five episodes of NBD. The most common aetiologies were hereditary cholestatic disease (n=17, 74%) and drug-induced cholestasis (n=5, 22%),NBD remained in situ for a median of 8 days (range 1–45 days). Significant improvement in bilirubin was seen at 7 days post-NBD (p=0.0324), maintained at day 30 (335 μmol/L vs 302 µmol/L vs 167 µmol/L). There was symptomatic improvement in pruritus in 20 (67%, p=0.0494) episodes. One patient underwent NBD during the first trimester of pregnancy after medical therapy failure with a good symptomatic response. The catheters were well tolerated in 27 (90%) of cases. Mild pancreatitis occurred in 4 (13%) cases.ConclusionNBD can be used to provide symptomatic improvement to patients with pruritus associated with cholestasis. It is well tolerated by patients. They can be used in pregnancy where medical management has failed.

Changes in beta-catenin expression and activation during progression of primary sclerosing cholangitis predict disease recurrence

Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts. We have previously demonstrated the importance of Wnt/β-catenin signaling in mouse models of PSC. In this study, we wished to determine the clinical relevance of β-catenin localization in patient samples. In livers explanted from patients diagnosed with PSC, the majority (12/16; 75%) lacked β-catenin protein expression. Biopsies from patients post-transplant were classified as recurrent or non-recurrent based on pathology reports and then scored for β-catenin activation as a function of immunohistochemical localization. Despite lack of statistical significance, patients with recurrent primary disease (n = 11) had a greater percentage of samples with nuclear, transcriptionally active β-catenin (average 58.8%) than those with no recurrence (n = 10; 40.53%), while non-recurrence is correlated with β-catenin staining at the cell surface (average 52.63% for non-recurrent vs. 27.34% for recurrent), as determined by three different methods of analysis. β-catenin score and years-to-endpoint are both strongly associated with recurrence status (p = 0.017 and p = 0.00063, respectively). Finally, there was significant association between higher β-catenin score and increased alkaline phosphatase, a marker of biliary injury and disease progression. Thus, β-catenin expression and activation changes during the progression of PSC, and its localization may be a useful prognostic tool for predicting recurrence of this disease.

Eff ect of ursodeoxycholic acid in postcholecystectomy cholestatic hepatopathy verified by ultrasonography

Summary: Cholestasis syndrome is accompanied by a large number of diverse liver and biliary tract diseases. Many cholestatic changes are fully reversible in the fi rst phase. However, with long-term cholestasis, extensive hepatocyte dysfunction occurs, the disease progresses, and many cholestatic syndromes result in irreversible liver damage and failure. Cholestatic liver diseases represent an important group of liver diseases that are an indication for liver transplantation. Postcholecystectomy syndrome is an imprecisely defi ned term, which includes a set of ongoing or recurrent or new diffi culties of patients after gallbladder surgery. We distinguish between early postcholecystectomy syndrome immediately in the postoperative period, or late postcholecystectomy syndrome, which occurs months or even years later. Ultrasonography is the fi rst imaging examination method for diseases of the liver and hepatobiliary system. It is a non-invasive method, available, relatively cheap, easily repeatable, and it does not represent a burden for the patient. Common bile duct dilatation after cholecystectomy is a common accidental fi nding that is inconclusive in the absence of clinical symptomatology and with normal laboratory fi ndings. Ursodeoxycholic acid forms the basis of cholestasis therapy, the only treatment whose effi cacy in cholestatic liver disease has been demonstrated in randomized and long-term studies. A further positive is that many years of ursodeoxycholic acid administration are not accompanied by more serious side eff ects. This case report supports the concept of a prompt and at the same time deepening benefi cial eff ect of ursodeoxycholic acid treatment in patients with cholestatic hepatopathy verified by ultrasonography indicated for conservative treatment or refusing invasive treatment. Key words: cholestasis – postcholecystectomy syndrome – ultrasonography – ursodeoxycholic acid

Pterostilbene Alleviates Cholestasis by Promoting SIRT1 Activity in Hepatocytes and Macrophages

Background and purpose: FXR is a promising target for the treatment of human cholestatic liver disease (CLD). SIRT1 is a deacetylase which promotes FXR activity through deacetylating FXR. Pterostilbene (PTE) is an activator of SIRT1. However, the role of PTE in cholestasis has so far not been investigated. We examined whether PTE treatment alleviate liver injury in DDC or ANIT-induced experimental cholestasis, and explored the underlying mechanisms.Experimental approach: Mice with DDC- or ANIT-induced cholestasis were treated with different dose of PTE. Primary hepatocytes and bone marrow derived macrophages were used in vitro to assess the molecular mechanism by which PTE may improve CLD. Identical doses of UDCA or PTE were administered to DDC- or ANIT-induced cholestasis mice.Key results: PTE intervention attenuated DDC or ANIT-induced cholestasis. PTE inhibited macrophage infiltration and activation in mouse liver through the SIRT1-p53 signaling pathway, and it improved hepatic bile metabolism through the SIRT1-FXR signaling pathway. Compare with UDCA, the same doses of PTE was more effective in improving cholestatic liver injury caused by DDC or ANIT.Conclusion and implications: SIRT1 activation in macrophages may be an effective CLD treatment avenue. Using CLD models, we thus identified PTE as a novel clinical candidate compound for the treatment of CLD.

Biallelic Mutations in Ubiquitin-Specific Peptidase 53 (USP53) Causing Progressive Intrahepatic Cholestasis. Report of a Case With Review of Literature

Whole-exome sequencing studies have recently identified novel genes implicated in normal- or low-GGT pediatric cholestasis including ubiquitin-specific peptidase 53 ( USP53). We identified novel biallelic mutations in the USP53 gene in a 7-month-old infant with pruritus and progressive intrahepatic cholestasis. His liver biopsy showed portal and perivenular fibrosis with bland bilirubinostasis. His parents were asymptomatic heterozygous for the same mutation. He is currently on vitamin supplements and cholestyramine and his family has also been counseled for liver transplantation. Our report confirms that patients with biallelic mutation in USP53 develop cholestatic liver disease.