A narrative review of genes associated with liver fibrosis in biliary atresia

Introduction

Biliary atresia (BA) is characterized by progressive obliterative cholangiopathy of the intra- and extrahepatic bile ducts. The pathogenesis mainly starts in the embryonic or perinatal period and often leads to severe and persistent neonatal jaundice (1). BA has an incidence of 1 in 10,000–15,000 live births in the United States (2,3), and an incidence of 1 in 16,700 in the British Isles (4,5). BA is more common in the East Asia, with an incidence up to 1 in 5,000 (6). The cause of BA in most infants is not fully understood and it is postulated that the disease is multifactorial with interaction between genetics and exogenous stimuli. As BA is a disease related to genetic anomalies, gene therapy for fibrosis of BA patients may be a potential new direction. In this review, we performed a review on BA related genes and their role in fibrosis, with a hope to bring an insight to new therapy in clinical practice. We present this article in accordance with the Narrative Review reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-24-94/rc).

Methods

MalaCards leverages disease associated genes, Gene Cards and Gene Analytics. Each “card” contains a variety of detailed sections. The Gene Cards Knowledgebase integrates more than 190 data sources to provide a gene-centric, disease-centric, pathway-centric, compound-centric database with associated interconnections and rich annotations. This data is available for research purposes, via an academic collaboration agreement, or through commercial licenses through Life Map Sciences. We conducted an in-depth analysis of the following genes according to their correlation with fibrosis of BA according to MalaCards disease database using search strategy shown in Table 1. The genes list is composed by: (I) the Gene Cards search mechanism; (II) genetic testing resources supplying specific genetic tests for the disease; (III) genetic variations resources supplying specific causative variations in genes for the disease; (IV) resources that manually curate the association of the disease with genes. A prioritizing algorithm is applied to generate the genes list. Table 2 shows gene symbols, descriptions, relevance scores, and the context according to which the gene is related to the disease. The relevance score is provided by Elasticsearch and computed by factoring the importance of the different resources to get the association of one gene with one disease. Theory behind relevance score uses the Boolean model to find matching documents and a formula called the practical scoring function to calculate relevance. Thirty-one genes that are associated with BA according to the disease relevance score were reviewed by two authors (F.L. and P.H.Y.C.). After further evaluations by all the authors, 11 genes [glutamic-pyruvic transaminase (GPT), nuclear receptor subfamily 1 group H member 4 (NR1H4), transforming growth factor beta 1 (TGF-B1), matrix metallopeptidase 7 (MMP7), cellular communication network factor 2 (CCN2), TIMP metallopeptidase inhibitor 1 (TIMP1), secreted phosphoprotein 1 (SPP1), adducin 3 (ADD3), keratin 7 (KRT7), ADD3 antisense RNA 1 (ADD3-AS1), SRY-box transcription factor 9 (SOX9)] that were found to have a closer association with liver fibrosis, were selected for detailed review.

Gene related to liver fibrosis in BA

GPT gene

GPT, also named as alanine aminotransferase (ALT), catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate. GPT participates in cellular nitrogen metabolism and involves in liver gluconeogenesis starting with precursors transported from skeletal muscles by similarity. GPT belongs to the class-I pyridoxal-phosphate-dependent aminotransferase family and belongs to ALT subfamily.

BA infants have a significantly higher ALT expression than those suffering from hepatitis and choledochal cyst (7,8). Some researchers used gamma-glutamyl transferase (GGT)/ALT ratio to differentiate biliary obstruction from neonatal hepatitis (9). Among BA patients after Kasai operation, those with persistent cholestasis have a higher ALT expression than those who can achieve jaundice clearance (10). After intervention with certain drugs, such as: herbal medicine Inchinko-to, it has been found that low expression levels of GPT are associated with better prognosis and treatment outcomes. Liver function test at puberty for low expression levels of GPT is a good prognostic point for BA children (11,12). Serum GPT level as liver fibrosis marker could also indicate drug effect and liver injury for postoperative BA patients (13,14).

NR1H4 gene

NR1H4 promotes transcriptional activation of target genes ABCB11/BSEP, NR0B2/SHP, SLC51B/OSTB and FABP6/IBAP. NR1H4 belongs to the nuclear hormone receptor family and NR1 subfamily. NR1H4 participates in hepatocyte glucose and lipid metabolism. By modulating gene expression, it influences the balance of glucose production, utilization and storage within hepatocytes. Proper glucose metabolism is essential for maintaining blood sugar levels and preventing conditions like diabetes. Additionally, NR1H4 helps regulate lipid metabolism, impacting processes such as fatty acid synthesis, cholesterol homeostasis, and bile acid synthesis (15). The affected glucose and lipid metabolism of hepatocyte in turn inhibit fibrosis, inflammation, and apoptosis.

NR1H4 gene expression is low in BA patients in the Gene Expression Omnibus database (15). Protein and mRNA level experiments also validate the bioanalysis result that there’s lower NR1H4 gene expression in BA patients than in non-BA control group (15). Low NR1H4 gene expression group have higher immunologically infiltration levels (15). As NR1H4 has been found to play an important role in modulating hepatocellular transport, bile acid homeostasis as well as metabolic functions, some scholars questioned the differential expression of NR1H4 in early and late stages of BA. In a study of BA infants with early- and late-stage disease, NR1H4 expression level was downregulated at early-stage cholestasis, bile salt export pump (BSEP) expression level was similar with its upstream regulator NR1H4. At late-stage cholestasis, NR1H4 and BSEP gene expression level returned to normal (16).

TGF-B1 gene

TGF-B1 is multifunctional protein that controls proliferation, differentiation and other functions in many cell types. Many cells synthesize TGF-B1 and have specific receptors for its interaction with other growth factors. This gene encodes a secreted ligand of the TGF-beta superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. SMADs are composed of structurally similar families of proteins that are major signaling sensors for TGF-beta superfamily receptors, which are critical for regulating cell development and growth.

A previous study that evaluated TGF-B1 divided the cohort into three groups: BA before and after liver transplant as well healthy controls (17). It was revealed that BA patients who were indicated for liver transplant had the lowest plasma TGF-B1 concentrations and the highest plasma hepatocyte growth factor (HGF)/TGF-B1 ratios (17), which suggested that low TGF-B1 expression may represent a worse prognosis. TGF-B1 expression could be found in activated hepatic stellate cells (HSCs), hepatocytes and bile duct epithelial cells, which also indicated proximity to fibrosis (18). TGF-B1 regulates proliferation and replication of liver cell that is associated with hepatic fibrosis. TGF-B1 activates HSCs that is also involved in fibrogenesis (19). TGF-B1 expressed in both biliary epithelial cells and hepatocytes in the congenital BA group infants and the expression levels of which increased gradually with fibrosis progression (20). In a 3-year follow-up study of patients with successful Kasai portoenterostomy, hepatic TGF-B1 expression level was significantly decreased, but TGF-B2 expression level was found to increase (21). This phenomenon signified the potential interaction of TGF-beta family after Kasai portoenterostomy among BA patients (22).

MMP7 gene

MMP7 degrades casein, gelatins of types I, III, IV, and V, and fibronectin, also activates procollagens, belongs to M10 matrix metallopeptidases (MMPs). Proteins in this family are involved in the breakdown of extracellular matrix (ECM) in normal physiological processes. The encoded preproprotein is proteolytically processed to generate the mature protease. This secreted protease breaks down proteoglycans, fibronectin, elastin and casein and differs from most MMP family members in that it lacks a conserved C-terminal hemopexin domain. The gene is part of a cluster of MMP genes on chromosome 11.

A previous study divided BA patients into three different groups: early-stage BA group at the time of Kasai portoenterostomy, late-stage BA group at the time of liver transplantation with advanced fibrosis and control group without liver fibrosis. MMP7 expression levels were significantly different between control group and liver transplantation group, which indicated that MMP7 is associated with disease progression. MMP7 expression level had a progressive increase from the time at Kasai portoenterostomy to liver transplantation (23). Besides, MMP7 is mainly expressed in hepatocytes, Kupffer cells and bile ductular epithelial cells of liver. The comparison among different MMPs such as MMP2, MMP7, MMP9 and MMP13 indicated that MMP7 is the MMP with a prominent expression (24), especially in late-stage BA group at the time of liver transplantation with advanced fibrosis. Experiment using mouse model also showed that MMP7 expressed more in mice with fibrosis, which indicates that MMP7 is a mediator of hepatic fibrosis between sick BA mice and spontaneously recovered BA mice (25). Many researchers have studied the relation of MMP7 and BA fibrosis and cirrhosis. MMP7 plays an important role in BA fibrosis of young patients (24,26-30). MMP7 express location was in biliary epithelium having ductular proliferation (31). MMP7 gene is upregulated in BA patients in contrast with control patients (32). MMP7 may be involved in the pathophysiological process of BA occurrence and development. On the one hand, MMP7 can promote the migration and activation of macrophages and neutrophils by cutting target proteins such as TNF-α and syndecan-1, thus aggravating inflammation and bile duct injury. On the other hand, MMP7 can activate FAS receptors and destroy adhesion molecules between bile duct epithelial cells, thereby mediating cell apoptosis (33). MMP7 is of great importance both as a prognostic factor and a diagnostic tool for BA.

CCN2 gene

CCN2 is hypertrophic chondrocyte-specific protein 24 that belongs to the CCN family. It is a mitoattractant of connective tissue and secreted by vascular endothelial cells. CCN2 promotes proliferation and differentiation of chondrocytes and mediates heparin- and divalent cation-dependent cell adhesion in many cell types including fibroblasts, myofibroblasts, endothelial and epithelial cells. It also enhances fibroblast growth factor-induced DNA synthesis. CCN2 is related to cell matrix induction, mitosis and chemotaxis, which is specifically induced in by TGF-beta in fibroblast cell.

CCN2 serum expression level was associated with fibrosis in BA. This result indicated that CCN2 is a potential indicator to monitor fibrosis in BA patients (34). One study evaluated the expression of CCN2 mRNA in BA patients and normal controls. It was reported that BA patients had significantly higher CCN2 and collagen type IV expression than normal control group. CCN2 expression also positive associated with collagen type IV expression. As collagen type IV is used as an indicator of fibrosis severity, this study concluded that CCN2 may affect BA pathogenesis and fibrosis progression (35). CCN2 expression is mainly observed in biliary epithelial cells and vascular endothelial cells of BA patients and related to biliary epithelial cell fibrogenesis (36). Thirty-six infants with BA and neonatal hepatitis were divided into two different disease groups and their CCN2, TGF-B1 expression levels and liver fibrosis were compared. The result showed that BA patients have a higher expression of CCN2 and TGF-B1 expression as well as fibrosis than patients suffering from hepatitis. Hepatic CCN2 expression level was significantly decreased in a 3 years’ follow-up study of successful Kasai portoenterostomy patients. In addition, taking into consideration of CCN2 role in fibroblasts senescence, it can be expected that cholangiocyte senescence-associated secretory phenotype paracrine communication plays an essential role in the prognosis of BA (37).

TIMP1 gene

TIMP1 is a metalloproteinase inhibitor that functions by forming one to one complex with target metalloproteinases, such as collagenases, and irreversibly inactivates them by binding to their catalytic zinc cofactor. It also functions as a growth factor that regulates cell differentiation, migration and cell death, and activates cellular signaling cascades via CD63 and ITGB1. This gene belongs to the TIMP gene family. The proteins encoded by this gene family are natural inhibitors of the MMPs. In addition to its inhibitory role against most of the known MMPs, the encoded protein is able to promote cell proliferation in a wide range of cell types and may also have an anti-apoptotic function. Transcription of this gene is highly inducible in response to many cytokines and hormones. In addition, the expression from some but not all inactive X chromosomes suggests that this gene inactivation is polymorphic in human females. This gene is located within intron 6 of the synapsin I gene and is transcribed in the opposite direction.

In the process of liver fibrosis, activated HSC are a key source of collagen production. At the same time, the activated HSC secretes a large amount of TGF-B1, which upregulates the gene expression of TIMP1 and downregulates the expression of MMPs. This leads to an imbalance of MMPs/TIMPs, which in turn leads to an imbalance of ECM synthesis and degradation, which promotes liver fibrosis (38). The imbalance of TIMP1 activity is an important factor leading to the progression of liver fibrosis. One study found that the positive expression of TIMP1 protein in liver fibrosis tissues increased with the aggravation of fibrosis degree, while the positive expression of MMP1 protein did not change significantly (39). This further supports the role of TIMP1 in liver fibrosis. Many studies have revealed that TIMP1 is associated with liver fibrosis in BA (23,25,40-42). Some studies found that vitamin D deficiency could increase the expression of TIMP1, which in turn promote hepatic fibrosis in BA children (43). Furthermore, TIMP1 expression is associated with persistent jaundice and portal hypertension among patients among Kasai operation (10).

SPP1 gene

SPP1 is also known as osteopontin (OPN). Among the related pathways of SPP1 are integrin pathway and ERK signaling. Gene Ontology (GO) annotations related to this gene include cytokine activity and ECM binding.

Compared with other cholestatic diseases, the expression levels of osteopontin mRNA and protein in the liver of BA patients are significantly increased, and the expression of osteopontin is limited to the proliferating biliary epithelium/bile duct blockade epithelium. Osteopontin expression was not found in the portal biliary tract of normal liver. According to previous study, the expression of osteopontin in biliary epithelial cells is related to the expression of IL-2 and TNF-α, and the increased expression of osteopontin in biliary interlobular epithelium in BA patients is related to portal fibrosis and biliary hyperplasia, suggesting the role of osteopontin in the mechanism of BA (44).

Another study found that osteopontin was expressed in BA intrahepatic bile duct epithelial cells, but only in small amounts in normal intrahepatic bile duct epithelial cells. The expression of osteopontin in BA liver tissue is positively correlated with the degree of liver fibrosis. In the process of forming fibrosis in BA, MMP7 and osteopontin can form a positive feedback loop, whereby MMP7 amplifies fibrosis and inflammation through osteopontin and TNF-α (45). The expression level of osteopontin was positively correlated with the degree of BA fibrosis and the hardness of BA liver (46). Plasma osteopontin level is not only positively correlated with serum ALT and serum total bilirubin level, but also can be used as a biomarker to predict portal hypertension and liver dysfunction (47).

ADD3 gene

Adducins are heteromeric proteins composed of different subunits referred to as adducin alpha, beta and gamma. The three subunits are encoded by distinct genes and belong to a family of membrane skeletal proteins involved in the assembly of spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues. Structurally, each subunit is comprised of two distinct domains. ADD3 is membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network and regulates expression of profibrotic markers MMP2, MMP9, TGF-B1, tubular tight junction protein E-cadherin, and mesenchymal markers vimentin and alpha-SMA.

ADD3 gene is associated with cell damage repair, cycle and apoptosis in patients with BA. Single nucleotide polymorphisms in ADD3 were associated with BA, with the strongest association detected for rs17095355, which was associated with BA susceptibility in Asians and Caucasians (48,49). In addition, many other studies have confirmed the link between the function/mutation of ADD3 gene and the occurrence of BA (49-51). Deletion of ADD3 gene can cause excessive deposition of actin and myosin, resulting in biliary fibrosis (52). Long non-coding RNA (lncRNA) ADD3-AS1 is involved in the occurrence of liver fibrosis in BA children and can be used as a potential biomarker for the diagnosis of liver fibrosis in BA patients (53). Studies using zebrafish as experimental subjects found that ADD3 affects the occurrence of BA through Hedgehog signaling pathway (54).

KRT7 gene

The protein encoded by KRT7 gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains co-expressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in the simple epithelia lining the cavities of the internal organs and in the gland ducts and blood vessels. The genes encoding the type II cytokeratins are clustered in a region of chromosome 12q12–q13. Alternative splicing may result in several transcript variants; however, not all variants have been fully described.

The positive percentage of KRT7 has been reported to be useful as a marker for liver fibrosis and cirrhosis (55). Increased KRT7 immunopositivity in periportal hepatocytes after jaundice clearance can predict hepatic fibrosis during follow-up (56,57). KRT7 is associated with epithelial mesenchymal transformation and is localized in intrahepatic biliary duct epithelial cells (58). The absence of interlobular biliary ducts in BA patients results in abnormal expression of KRT7 in hepatocytes, which represents phenotypic changes in stem cells due to loss of contact with the biliary tree (59).

ADD3-AS1 gene

ADD3-AS1 is an RNA gene and is affiliated with the lncRNA class. Diseases associated with ADD3-AS1 include BA. This gene increases susceptibility to BA, plays a role in the mechanism of liver fibrosis in BA patients, and can be used as an important indicator to monitor liver fibrosis in BA patients (53,60).

Although the specific mechanism of action of ADD3-AS1 in liver fibrosis in BA patients is unclear, several molecular pathways related to ADD3-AS1 may play a key role in the development of liver fibrosis in BA patients, which are listed as follows. MicroRNAs (miRNAs) are a class of small RNA molecules that have been shown to play an important role in liver fibrosis caused by various chronic liver diseases. They can interfere with the development of liver fibrosis by regulating the expression of genes related to liver fibrosis. Chitinase-3-like protein 1 (CHI3L1) is a protein that plays a role in the interaction between liver macrophages and myofibroblasts, which further activates HSCs, forming a cascade that leads to liver fibrosis. Intrahepatic cell and epithelial mesenchymal transformation may also play an important role in liver fibrosis in BA patients. Persistent inflammatory factors, such as infiltration of inflammatory cells and mediators, may damage bile duct epithelial cells and cause the occurrence of BA liver fibrosis.

SOX9 gene

SOX9 is a protein coding gene. Among its related pathways are gene expression (transcription) and mammalian disorder of sexual development. GO annotations related to this gene include DNA-binding transcription factor activity and protein kinase activity. An important paralog of this gene is SOX10. The protein encoded by this gene recognizes the sequence CCTTGAG along with other members of the high mobility group (HMG)-box class DNA-binding proteins. It acts during chondrocyte differentiation and, with steroidogenic factor 1, regulates transcription of the anti-Muellerian hormone (AMH) gene. In addition to the role in cartilage development, SOX9 also acts as a regulator of proliferation and differentiation in epithelial stem/progenitor cells. Furthermore, SOX9 has vital role in Hirschsprung disease as well, not specific with only liver fibrosis.

SOX9 is mainly expressed in the fibrotic bridge and portal vein space, regulating liver fibrosis, bile duct development and liver regeneration process. In BA patients, SOX9 is mainly expressed in reactive ductal epithelium, and the expression pattern is significantly different from that of normal people, SOX9 may play a role in BA diagnosis (61). Other studies have also found an association between abnormal expression of SOX9 in ductular reaction form and liver fibrosis in BA patients (62,63). SOX9 may play a role in BA mechanisms by affecting reactive duct cells and hepatocytes (64). SOX9 plays a protective role in the progression of catheter response and can be used as a prognostic indicator to predict natural liver survival in BA patients after Kasai surgery, and patients with high SOX9 expression of BA have a better prognosis (65).

Discussion

Based on our work, we believe that by regulating certain genes can potentially suppress or even reverse liver fibrosis in BA (66). This study discussed 11 genes correlated to liver fibrosis in BA, with an aim to provide a new treatment strategy to BA related liver fibrosis. The roles of each gene in alleviating or aggravating BA liver fibrosis have been discussed in detail. Even though the modulating process of some genes are uncertain, these findings can still demonstrate their ability in reversing liver fibrosis and improving the treatment outcome. According to MalaCards, we can identify many pathways that are mostly associated with each fibrosis related gene in BA. The limitations of this study include a lack of detailed literature on some genes and their influence on liver fibrosis cannot be fully determined.

Conclusions

According to detailed literature search, we found 11 genes that are closely related to liver fibrosis in BA. Increased expression of GPT, TGF-B1, MMP7, CCN2, TIMP1, SPP1, ADD3, KRT7 and ADD3-AS1 maybe associated with the development of liver fibrosis in BA patients, while the expression of NR1H4 and SOX9 are more likely to suppress liver fibrosis. Future works that explore gene therapy is recommended for its potential in alleviating fibrosis in BA. Drugs targeting fibrosis related genes can be a new research area in BA.

Acknowledgments

Funding: This study was supported by the Theme-based Research Scheme, Research Grant Council, Hong Kong (Project code: T12-712/21-R ‘Translating Disease-Mechanism Discoveries to Improve Treatment of Biliary Atresia, an Intractable Newborn Liver Disease’).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-24-94/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-94/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-94/coif). P.H.Y.C. serves as an unpaid editorial board member of Translational Pediatrics from August 2022 to July 2024. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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