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Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 30748

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Dr. Jinghua Wang

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Institute of Bioscience & Integrative Medicine, Daejeon University, 75, Daedeok-aero 176, Seo-gu, Daejeon 35235, Republic of Korea
Interests: chronic liver hepatitis; acute liver injury; NAFLD/MAFLD; hepatic fibrosis/cirrhosis; hepatic carcinoma; liver cancer metastasis; herbal medicine; gut microbiome; metagenomics; bile acid metabolite; oxidative stress; lipid metabolism; biomarkers
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Dear Colleagues,

In mammals, the hepatic and biliary system comprises serval essential organs, including the liver, bile duct, and gallbladder, for participating in the metabolism of both diets and drugs. In recent decades, the burden of hepatobiliary disease has been heavy, and the overall trend is gradually upwards worldwide. Specifically, around two million patients die annually in the world due to liver cirrhosis, viral hepatitis, and hepatic carcinoma. Nevertheless, a feasible therapeutic strategy is still not available because of the heterogeneity of pathophysiologic mechanisms. Recently, with the rapid improvement of cutting-edge technology, e.g., OMICs, more and more evidence has demonstrated that symbiotic bacteria, as a hidden “organ” in the holobiont, can disrupt the normal function of the hepatic and biliary system. For instance, gut-microbiota-derived PAMPs (pathogen-associated molecular patterns) and bile acid metabolites affect liver cancer progression and metastasis through immune-regulation, such as NKT cells and cytotoxic T cells. Further, many studies have shown that commensal microbes play a crucial role in non-alcoholic fatty liver disease. However, the causality and corresponding mechanisms are still indistinct. Beyond that, many explicit molecular mechanisms and pathological factors regarding other hepatobiliary diseases are still to be discovered. Therefore, this Special Issue, titled “Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases”, welcomes the submission of original research and review articles to address hepatobiliary disorders concerning novel insights into pathogenesis and therapeutic strategies. We look forward to your contributions.

Dr. Jinghua Wang
Guest Editor

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Keywords

acute/chronic liver diseases
NAFLD/MAFLD
viral hepatitis
cholestatic liver diseases
cholangitis
gallbladder diseases
metabolic disorders
bile acid metabolite
gut microbiota
precision medicine

Published Papers (12 papers)

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Editorial

Jump to: Research, Review

3 pages, 210 KiB

Open AccessEditorial

Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases

by Jing-Hua Wang

Biomedicines 2023, 11(4), 1140; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11041140 - 10 Apr 2023

Viewed by 1257

Abstract

The hepatobiliary system, comprising the liver, gallbladder, and bile ducts, performs a diverse array of functions that are essential to maintaining homeostasis [...] Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases)

Research

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10 pages, 246 KiB

Open AccessArticle

Comorbidities and Outcomes among Females with Non-Alcoholic Fatty Liver Disease Compared to Males

by Naim Abu-Freha, Bracha Cohen, Sarah Weissmann, Reut Hizkiya, Reem Abu-Hammad, Gadeer Taha and Michal Gordon

Biomedicines 2022, 10(11), 2908; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10112908 - 12 Nov 2022

Cited by 6 | Viewed by 1442

Abstract

Sex-based medicine is an important emerging discipline within medicine. We investigated the clinical characteristics, complications, and outcomes of Nonalcoholic Fatty Liver Disease (NAFLD) in females compared to males. Demographics, comorbidities, malignancy, complications, outcomes, and all-cause mortality of NAFLD patients older than 18 years were analyzed. The data were extracted using the MDClone platform from “Clalit” in Israel. A total of 111,993 (52.8%) of the study subjects were females with an average age of 44.4 ± 14.7 years compared to 39.62 ± 14.9 years in males, p < 0.001. Significantly higher rates of hypertension, diabetes mellitus, obesity, dementia, and thyroid cancer and lower rates of ischemic heart disease (22.3% vs. 27.3%, p < 0.001) were found among females. Females had a higher rate of cirrhosis, 2.3% vs. 1.9%, p < 0.001, and a lower rate of hepatocellular carcinoma, 0.4% vs. 0.5%, p < 0.001. In the multivariate analysis, a relationship between age, diabetes mellitus, and cirrhosis development were found among males and females. A lower age-adjusted mortality rate was found among females, 94.5/1000 vs. 116/1000 among males. In conclusion, older age at diagnosis, higher rates of hypertension, diabetes mellitus, obesity, cirrhosis, and a lower age-adjusted all-cause mortality rate were found among females with NAFLD. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases)

11 pages, 979 KiB

Open AccessArticle

Baseline Circulating miR-125b Levels Predict a High FIB-4 Index Score in Chronic Hepatitis B Patients after Nucleos(t)ide Analog Treatment

by Jyun-Yi Wu, Yi-Shan Tsai, Chia-Chen Li, Ming-Lun Yeh, Ching-I Huang, Chung-Feng Huang, Jia-Ning Hsu, Meng-Hsuan Hsieh, Yo-Chia Chen, Ta-Wei Liu, Yi-Hung Lin, Po-Cheng Liang, Zu-Yau Lin, Wan-Long Chuang, Ming-Lung Yu and Chia-Yen Dai

Biomedicines 2022, 10(11), 2824; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10112824 - 05 Nov 2022

Cited by 1 | Viewed by 4084

Abstract

The regulatory role of microRNAs (miRNAs) in HBV-associated HCC pathogenesis has been reported previously. This study aimed to investigate the association between serum miR-125b and liver fibrosis progression in chronic hepatitis B (CHB) patients after nucleos(t)ide analog (NA) treatment. Baseline serum miR-125b levels and other relevant laboratory data were measured for 124 patients who underwent 12-month NA therapy. Post-12-month NA therapy, serum miR-125, platelet, AST, and ALT levels were measured again for post-treatment FIB-4 index calculation. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for a higher post-treatment FIB-4 index. Results showed that baseline miR-125b levels were inversely correlated with the post-treatment FIB-4 index (ρ = −0.2130, p = 0.0082). In logistic regression analyses, age (OR = 1.17, p < 0.0001), baseline platelet level (OR = 0.98, p = 0.0032), and ALT level (OR = 1.00, p = 0.0241) were independent predictors of FIB-index > 2.9 post-12-month treatment. The baseline miR-125b level was not significantly associated with a higher post-treatment FIB-4 index (p = 0.8992). In 59 patients receiving entecavir (ETV) monotherapy, the alternation of serum miR-125b in 12 months and age were substantially associated with a higher post-treatment FIB-4 index (>2.9), suggesting that miR-125b is a reliable biomarker for detecting early liver fibrosis under specific anti-HBV NA treatments (e.g., ETV). Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases)

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7 pages, 259 KiB

Open AccessArticle

Long-Term Persistence of Mitochondrial DNA Instability among HCV-Cured People Who Inject Drugs

by Mélusine Durand, Nicolas Nagot, Quynh Bach Thi Nhu, Amélie Vizeneux, Linh Le Thi Thuy, Huong Thi Duong, Binh Nguyen Thanh, Delphine Rapoud, Roselyne Vallo, Catherine Quillet, Hong Thi Tran, Laurent Michel, Thanh Nham Thi Tuyet, Oanh Khuat Thi Hai, Vinh Vu Hai, Jonathan Feelemyer, Philippe Vande Perre, Don Des Jarlais, Khue Pham Minh, Didier Laureillard and Jean-Pierre Molès Show full author list Hide full author list

Biomedicines 2022, 10(10), 2541; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10102541 - 12 Oct 2022

Cited by 1 | Viewed by 1271

Abstract

People who inject drugs (PWID) are a population exposed to many genotoxicants and with a high prevalence of HCV infection. Direct-acting antiviral (DAA) regimens are now widely used to treat chronic HCV infection. Although side effects to treatment are currently rare, the long-term effects such as suspicions of de novo hepatocellular carcinoma (HCC) occurrence or HCC recurrence and cardiac defects are still up for debate. Given the structure of DAAs, the molecules have a potential mitochondrial DNA (mtDNA) genotoxicity. We have previously reported acute mtDNA toxicity of three DAA regimens among PWID with a strong impact on the rate of mtDNA deletion, less on the quantity of mtDNA copy per cell at sustained viral response at 12 weeks (SVR12). Herein, we report the mtDNA parameters nine months after drug discontinuation. We observed that the percentage of the deleted mtDNA genome increased over time. No exposure to any other genotoxicants during this period was associated with a high deletion percentage, suggesting that the replicative advantage of the deleted molecules outweighed their elimination processes. Such observation calls for longer-term follow-up and may contribute to the molecular basis of subclinical side effects of DAA treatments. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases)

10 pages, 1155 KiB

Open AccessArticle

Comparable Outcomes in Early Hepatocellular Carcinomas Treated with Trans-Arterial Chemoembolization and Radiofrequency Ablation

by Benjamin Wei Rong Tay, Daniel Q. Huang, Muthiah Mark, Neo Wee Thong, Lee Guan Huei, Lim Seng Gee, Low How Cheng, Lee Yin Mei, Prem Thurairajah, Lim Jia Chen, Cheng Han Ng, Wen Hui Lim, Darren Jun Hao Tan, Da Costa Maureen, Kow Wei Chieh Alfred, Iyer Shridar Ganpathi, Tan Poh Seng and Dan Yock Young

Biomedicines 2022, 10(10), 2361; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10102361 - 22 Sep 2022

Cited by 4 | Viewed by 1442

Abstract

The guidelines recommend radiofrequency ablation (RFA) for early hepatocellular carcinomas that are less than 3 cm and trans-arterial chemoembolization (TACE) for intermediate-stage tumors. Real-world patient and tumor factors commonly limit strict adherence to the guidelines. We aimed to compare the clinical outcomes for TACE and RFA in early HCC. All consecutive patients from 2010 to 2014 that were treated with locoregional therapy at our institution were enrolled. The decision for TACE or RFA was based on tumor location, stage and technical accessibility for ablation. A subgroup analysis was performed for patients with tumors less than 3 cm. A total of 168 patients underwent TACE while 56 patients underwent RFA. Patients treated with TACE and RFA had 1- and 5-year survival rates of 84.7% and 39.8% versus 91.5% and 51.5%, respectively (p = 0.28). In tumors less than 3 cm, there was no significant difference in overall survival (p = 0.69), time to progression (p = 0.55), or number of treatment sessions required (p = 0.12). Radiofrequency ablation had a significantly higher chance of a complete response (p = 0.004). In conclusion, TACE may be selectively considered for early-stage hepatocellular carcinoma in patients unsuitable for other modalities. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases)

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21 pages, 2341 KiB

Open AccessArticle

Identification of the Potential Molecular Mechanisms Linking RUNX1 Activity with Nonalcoholic Fatty Liver Disease, by Means of Systems Biology

by Laia Bertran, Ailende Eigbefoh-Addeh, Marta Portillo-Carrasquer, Andrea Barrientos-Riosalido, Jessica Binetti, Carmen Aguilar, Javier Ugarte Chicote, Helena Bartra, Laura Artigas, Mireia Coma, Cristóbal Richart and Teresa Auguet

Biomedicines 2022, 10(6), 1315; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061315 - 03 Jun 2022

Cited by 4 | Viewed by 2491

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic hepatic disease; nevertheless, no definitive diagnostic method exists yet, apart from invasive liver biopsy, and nor is there a specific approved treatment. Runt-related transcription factor 1 (RUNX1) plays a major role in angiogenesis and inflammation; however, its link with NAFLD is unclear as controversial results have been reported. Thus, the objective of this work was to determine the proteins involved in the molecular mechanisms between RUNX1 and NAFLD, by means of systems biology. First, a mathematical model that simulates NAFLD pathophysiology was generated by analyzing Anaxomics databases and reviewing available scientific literature. Artificial neural networks established NAFLD pathophysiological processes functionally related to RUNX1: hepatic insulin resistance, lipotoxicity, and hepatic injury-liver fibrosis. Our study indicated that RUNX1 might have a high relationship with hepatic injury-liver fibrosis, and a medium relationship with lipotoxicity and insulin resistance motives. Additionally, we found five RUNX1-regulated proteins with a direct involvement in NAFLD motives, which were NFκB1, NFκB2, TNF, ADIPOQ, and IL-6. In conclusion, we suggested a relationship between RUNX1 and NAFLD since RUNX1 seems to regulate NAFLD molecular pathways, posing it as a potential therapeutic target of NAFLD, although more studies in this field are needed. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases)

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18 pages, 1029 KiB

Open AccessArticle

Hepatitis B Virus Variants with Multiple Insertions and/or Deletions in the X Open Reading Frame 3′ End: Common Members of Viral Quasispecies in Chronic Hepatitis B Patients

by Selene García-García, Andrea Caballero-Garralda, David Tabernero, Maria Francesca Cortese, Josep Gregori, Francisco Rodriguez-Algarra, Josep Quer, Mar Riveiro-Barciela, Maria Homs, Ariadna Rando-Segura, Beatriz Pacin-Ruiz, Marta Vila, Roser Ferrer-Costa, Tomas Pumarola, Maria Buti and Francisco Rodriguez-Frias

Biomedicines 2022, 10(5), 1194; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10051194 - 21 May 2022

Cited by 1 | Viewed by 2449

Abstract

Deletions in the 3′ end region of the hepatitis B virus (HBV) X open reading frame (HBX) may affect the core promoter (Cp) and have been frequently associated with hepatocellular carcinoma (HCC). The aim of this study was to investigate the presence of variants with deletions and/or insertions (Indels) in this region in the quasispecies of 50 chronic hepatitis B (CHB) patients without HCC. We identified 103 different Indels in 47 (94%) patients, in a median of 3.4% of their reads (IQR, 1.3–8.4%), and 25% (IQR, 13.1–40.7%) of unique sequences identified in each quasispecies (haplotypes). Of those Indels, 101 (98.1%) caused 44 different altered stop codons, the most commonly observed were at positions 128, 129, 135, and 362 (putative position). Moreover, 39 (37.9%) Indels altered the TATA-like box (TA) sequences of Cp; the most commonly observed caused TA2 + TA3 fusion, creating a new putative canonical TATA box. Four (8%) patients developed negative clinical outcomes after a median follow-up of 9.4 (8.7–12) years. In conclusion, we observed variants with Indels in the HBX 3′ end in the vast majority of our CHB patients, some of them encoding alternative versions of HBx with potential functional roles, and/or alterations in the regulation of transcription. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases)

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18 pages, 2931 KiB

Open AccessArticle

Diagnostic and Clinical Value of Specific Autoantibodies against Kelch-like 12 Peptide and Nuclear Envelope Proteins in Patients with Primary Biliary Cholangitis

by Alicja Bauer, Andrzej Habior and Damian Gawel

Biomedicines 2022, 10(4), 801; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10040801 - 29 Mar 2022

Cited by 6 | Viewed by 1754

Abstract

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by the presence of antimitochondrial and antinuclear antibodies in patients’ serum. Here, we analyzed the reactivity of autoantibodies against a novel autoantigen, kelch-like 12 (KLHL12) protein, in a cohort of 138 PBC and 90 non-PBC patients. Additionally, we compared the reactivity of KLHL12 with antinuclear envelope antibodies: anti-gp210, anti-p62, and anti-LBR. Commercially available kits and an ‘in-house’ ELISA were used in the studies. Antinuclear envelope antibodies were detected in 65% of PBC patients and the presence of these antibodies was observed more frequently in patients diagnosed with later stages (III/IV) of PBC, according to Ludwig’s classification (p < 0.05) and were found to correlate with a higher concentration of bilirubin. Overall, anti-KLHL12 antibodies were found more frequently in PBC patients than in non-PBC controls (p < 0.001). Anti-KLHL12 antibodies were detected in 36% of the tested PBC cohort, including PBC patients negative for antimitochondrial antibodies. Presence of anti-KLHL12 was also associated with a higher concentration of bilirubin and correlated with fibrosis (p < 0.05). Anti-KLHL12 antibodies were detected in 30% of PBC individuals positive for antinuclear envelope antibodies, while anti-KLHL12 and antinuclear envelope antibodies were found in 17% of all PBC cases. Concluding, our data confirm that antibodies against the KLHL12 protein are highly specific for PBC and when used in combination with other markers, may significantly increase the diagnosis of PBC. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases)

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Review

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11 pages, 570 KiB

Open AccessReview

Obeticholic Acid for Primary Biliary Cholangitis

by Annarosa Floreani, Daniela Gabbia and Sara De Martin

Biomedicines 2022, 10(10), 2464; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10102464 - 02 Oct 2022

Cited by 10 | Viewed by 2668

Abstract

Primary biliary cholangitis (PBC) is a rare autoimmune cholestatic liver disease that may progress to fibrosis and/or cirrhosis. Treatment options are currently limited. The first-line therapy for this disease is the drug ursodeoxycholic acid (UDCA), which has been proven to normalize serum markers of liver dysfunction, halt histologic disease progression, and lead to a prolongation of transplant-free survival. However, 30–40% of patients unfortunately do not respond to this first-line therapy. Obeticholic acid (OCA) is the only registered agent for second-line treatment in UDCA-non responders. In this review, we focus on the pharmacological features of OCA, describing its mechanism of action of and its tolerability and efficacy in PBC patients. We also highlight current perspectives on future therapies for this condition. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases)

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27 pages, 782 KiB

Open AccessReview

Ultrasound-Based Hepatic Elastography in Non-Alcoholic Fatty Liver Disease: Focus on Patients with Type 2 Diabetes

by Georgiana-Diana Cazac, Cristina-Mihaela Lăcătușu, Cătălina Mihai, Elena-Daniela Grigorescu, Alina Onofriescu and Bogdan-Mircea Mihai

Biomedicines 2022, 10(10), 2375; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10102375 - 23 Sep 2022

Cited by 4 | Viewed by 2117

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease and is the hepatic expression of metabolic syndrome. The development of non-invasive methods for the diagnosis of hepatic steatosis and advanced fibrosis in high-risk patients, especially those with type 2 diabetes mellitus, is highly needed to replace the invasive method of liver biopsy. Elastographic methods can bring significant added value to screening and diagnostic procedures for NAFLD in patients with diabetes, thus contributing to improved NAFLD management. Pharmacological development and forthcoming therapeutic measures that address NAFLD should also be based on new, non-invasive, and reliable tools that assess NAFLD in at-risk patients and be able to properly guide treatment in individuals with both diabetes and NAFLD. This is the first review aiming to outline and discuss recent studies on ultrasound-based hepatic elastography, focusing on NAFLD assessment in patients with diabetes. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases)

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17 pages, 662 KiB

Open AccessReview

Update on the Pharmacological Treatment of Primary Biliary Cholangitis

by Annarosa Floreani, Daniela Gabbia and Sara De Martin

Biomedicines 2022, 10(8), 2033; https://doi.org/10.3390/biomedicines10082033 - 20 Aug 2022

Cited by 5 | Viewed by 4306

Abstract

Ursodeoxycholic acid (UDCA) is the first-line therapy used for the treatment of PBC. In recent years, new pharmacological agents have been proposed for PBC therapy to cure UDCA-non-responders. Obeticholic acid (OCA) is registered in many countries for PBC, and fibrates also seem to be effective in ameliorating biochemistry alteration and symptoms typical of PBC. Moreover, a variety of new agents, acting with different mechanisms of action, are under clinical evaluation for PBC treatment, including PPAR agonists, anti-NOX agents, immunomodulators, and mesenchymal stem cell transplantation. Since an insufficient amount of data is currently available about the effect of these novel approaches on robust clinical endpoints, such as transplant-free survival, their clinical approval needs to be supported by the consistent improvement of these parameters. The intensive research in this field will hopefully lead to a novel treatment landscape for PBC in the near future, with innovative therapies based on the combination of multiple agents acting on different pathogenetic mechanisms. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases)

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20 pages, 1864 KiB

Open AccessReview

Gene Therapy for Acquired and Genetic Cholestasis

by Javier Martínez-García, Angie Molina, Gloria González-Aseguinolaza, Nicholas D. Weber and Cristian Smerdou

Biomedicines 2022, 10(6), 1238; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061238 - 26 May 2022

Cited by 4 | Viewed by 3399

Abstract

Cholestatic diseases can be caused by the dysfunction of transporters involved in hepatobiliary circulation. Although pharmacological treatments constitute the current standard of care for these diseases, none are curative, with liver transplantation being the only long-term solution for severe cholestasis, albeit with many disadvantages. Liver-directed gene therapy has shown promising results in clinical trials for genetic diseases, and it could constitute a potential new therapeutic approach for cholestatic diseases. Many preclinical gene therapy studies have shown positive results in animal models of both acquired and genetic cholestasis. The delivery of genes that reduce apoptosis or fibrosis or improve bile flow has shown therapeutic effects in rodents in which cholestasis was induced by drugs or bile duct ligation. Most studies targeting inherited cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), have focused on supplementing a correct version of a mutated gene to the liver using viral or non-viral vectors in order to achieve expression of the therapeutic protein. These strategies have generated promising results in treating PFIC3 in mouse models of the disease. However, important challenges remain in translating this therapy to the clinic, as well as in developing gene therapy strategies for other types of acquired and genetic cholestasis. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases)

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