Figure 2 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Schematic diagram of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter ABCB4 that is encoded by the ABCB4 gene and is located on Chromosome 7 (q21.1) in humans and on Chromosome 5 (3.43 cM) in mice, consisting of 27 coding exons and spanning approximately 74 kilobases (kb) in length. The orange cylinders symbolize the transmembrane domains (TMD) of the ABCB4 protein. TMD1 and TMD2 represent the two symmetrical regions that contain the transmembrane domains 1-6 and 7-12, respectively. Two TMDs are connected by six intracellular segments 1-6 and by six extracellular loops 1-6 (not shown). The ABCB4 gene promoter harbors a CpG island that is usually unmethylated in the hepatocytes. The Walker A (A) and Walker (B) motifs and the signature (S) in the nucleotide binding domains (NBD) are indicated. NBD1 and NBD2 denote the nucleotide binding domains 1 and 2, respectively.
Source publication
Clinical studies have revealed that the ABCB4 gene encodes the phospholipid transporter on the canalicular membrane of hepatocytes, and its mutations and variants are the genetic basis of low phospholipid-associated cholelithiasis (LPAC), a rare type of gallstone disease caused by a single-gene mutation or variation. The main features of LPAC inclu...
Contexts in source publication
Context 1
... each repeat has two structural modules, a transmembrane domain composed of six transmembrane α-helices and a cytoplasmatic nucleotide-binding domain [73]. On the cytoplasmatic side of the protein, four small linker peptides, also referred to as intracellular domains, hook up the transmembrane helices, and on the extracellular side, six short loops attach transmembrane segments ( Figure 2). The two transmembrane domains contain specific sites for substrate binding and translocation, whereas the two nucleotide-binding domains, which display a high degree of sequence similarity with the equivalent domain of ABC transporters, couple the energy obtained from ATP hydrolysis for substrate transport [74]. ...
Context 2
... small linker peptides, also referred to as intracellular domains, hook up the transmembrane helices, and on the extracellular side, six short loops attach transmembrane segments (Figure 2). The two transmembrane domains contain specific sites for substrate binding and translocation, whereas the two nucleotide-binding domains, which display a high degree of sequence similarity with the equivalent domain of ABC transporters, couple the energy obtained from ATP hydrolysis for substrate transport [74]. ...
Context 3
... intracellular domains are deemed to be involved in mediating the coupling between the conformational changes of nucleotide-binding domain and the reorientation of transmembrane helices concomitant with substrate extrusion [75]. Figure 2. Schematic diagram of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter ABCB4 that is encoded by the ABCB4 gene and is located on Chromosome 7 (q21.1) in humans and on Chromosome 5 (3.43 cM) in mice, consisting of 27 coding exons and spanning approximately 74 kilobases (kb) in length. ...
Context 4
... are positioned at homologous sites within the coding regions, but only loosely match when N-and C-terminal halves are compared. Notably, ABCB4 consists of six intracellular domains and six extracellular loops separated by twelve transmembrane domains ( Figure 2). The ABCB4 protein contains two intracytoplasmic ATP-binding domains, also known as nucleotide binding domains, with characteristic motifs Walker A, Walker B, and ABC signature located upstream from the Walker B domain. ...
Citations
... Gene therapy employing human ABCB4 messenger ribonucleic acid (mRNA) has the potential to prevent this outcome, indicating a causal role and a potential therapeutic avenue for human patients. 5,28,29 The identification of LPAC in humans has become a pivotal focus in comprehending the pathogenesis of GS disease. 28 Diagnostic criteria for LPAC include the presence of cholesterol GSs, familial clustering, an early age of onset often before the age of 40, intrahepatic cholelithiasis, and disease recurrence despite cholecystectomy. ...
... 5,28,29 The identification of LPAC in humans has become a pivotal focus in comprehending the pathogenesis of GS disease. 28 Diagnostic criteria for LPAC include the presence of cholesterol GSs, familial clustering, an early age of onset often before the age of 40, intrahepatic cholelithiasis, and disease recurrence despite cholecystectomy. 28 In a recent study conducted in France, 60 patients with established LPAC and ABCB4 variants were compared to 65 matched controls who required magnetic resonance imaging of the liver at a tertiary center. ...
... 28 Diagnostic criteria for LPAC include the presence of cholesterol GSs, familial clustering, an early age of onset often before the age of 40, intrahepatic cholelithiasis, and disease recurrence despite cholecystectomy. 28 In a recent study conducted in France, 60 patients with established LPAC and ABCB4 variants were compared to 65 matched controls who required magnetic resonance imaging of the liver at a tertiary center. The study found that patients with mutant ABCB4 were at an increased risk for intrahepatic cholelithiasis, biliary duct dilatation, and signs of complications (e.g., liver parenchyma heterogeneity, biliary ductal stenosis, abscess, and contrast enhancement of bile duct walls). ...
Gallstone (GS) disease is common and arises from a combination of genetic and environmental factors. Although genetic abnormalities specifically leading to cholesterol GSs are rare, there are clinically significant gene variants associated with cholesterol GSs. In contrast, most bilirubin GSs can be attributed to genetic defects. The pathogenesis of cholesterol and bilirubin GSs differs greatly. Cholesterol GSs are notably influenced by genetic variants within the ABC protein superfamily, including ABCG8, ABCG5, ABCB4, and ABCB11, as well as genes from the apolipoprotein family such as ApoB100 and ApoE (especially the E3/E3 and E3/E4 variants), and members of the MUC family. Conversely, bilirubin GSs are associated with genetic variants in highly expressed hepatic genes, notably UGT1A1, ABCC2 (MRP2), ABCC3 (MRP3), CFTR, and MUC, alongside genetic defects linked to hemolytic anemias and conditions impacting erythropoiesis. While genetic cases constitute a small portion of GS disease, recognizing genetic predisposition is essential for proper diagnosis, treatment, and genetic counseling.
... We found that there were differences in bile secretion, linoleic acid metabolism, and the PPAR signaling pathway between the CGS and the control groups, whereas Chaihu Shugan was able to dose-dependently reverse the changes in ABC transporters, bile secretion, arachidonic acid metabolism, and sphingolipid metabolism, which is in agreement with metagenomics and metabolomics results, suggesting that Chaihu Shugan could improve lipid and bile acid metabolism and prevent CGS. It has been reported that ABC transporters are associated with multiple aspects of cholesterol metabolism, such as baseline cholesterol levels, cholesterol kinetics, hypercholesterolemia, individual responses to dietary and pharmaceutical interventions, and an increased risk of gallstones (Rudkowska and Jones, 2008;Wang et al., 2022b). Additionally, arachidonic acid (Demetz et al., 2014), linoleic acid (Azemi et al., 2022;Dumont et al., 2018;O'Reilly et al., 2020) and sphingolipid metabolism (Shin et al., 2009;Lee et al., 2010) are related to cholesterol metabolism; their pharmacological modulation could increase the hepatic expression of ABC Frontiers in Pharmacology frontiersin.org ...
Introduction: Cholesterol gallstone (CGS) is a biliary tract disorder requiring treatment in approximately 20% of patients. The efficacy of Chaihu Shugan in preventing CGS recurrence after successful treatment remains uncertain.
Methods: We examined the in vivo preventive efficacy of Chaihu Shugan using a CGS mouse model and used multi-omics to study the interplay between gut microbiota, metabolism, and gene expression.
Results: The intestinal microbiota was severely dysregulated during the formation of CGS, showing a marked decrease in the abundance of beneficial microbiota, especially Lactobacillus and Akkermansia . Chaihu Shugan prevented CGS formation by restoring the composition of the gut microbiota and reversing the metabolic disturbances caused by dysbiosis. This preventive effect of Chaihu Shugan was paralleled by changes in the expression of metabolism-related genes in the liver. A network pharmacology analysis of Chaihu Shugan revealed that obacunone may be the key active metabolite in regulating bile acid metabolism. Multi-omics and correlation analyses elucidated the interplay between gut microbiota, metabolism, and gene alterations in the dose-dependent effect of Chaihu Shugan.
Conclusion: Our data show that Chaihu Shugan can prevent CGS and indicate its mechanisms of action.
... Finally, it is probably irrelevant to compare the pathogenesis of classic gallbladder stones, especially in a context of hyperlipemia as described in NASH, with that of LPAC-associated canalicular and small bile duct microlithiasis, since the composition of native bile differs significantly from that of the gallbladder.Other drugs could be considered as potential candidates for second-line therapy of LPAC syndrome. Ezetimibe has been shown to reduce biliary cholesterol saturation and crystallisation in mice and humans and may therefore be suggested as a potential secondline drug in combination with UDCA.15,16 Fibrates may also be candidates, as they are known inducers of the MDR3 canalicular transporter and of phospholipid secretion into bile.17,18 ...
Background
Low phospholipid‐associated cholelithiasis (LPAC) syndrome is a rare genetic cause of hepatolithiasis. A pathogenic variant of the ABCB4 gene is reported in half of all patients. Ursodeoxycholic acid (UDCA) is the only drug approved. However, in some patients, UDCA fails to prevent recurrence of symptoms and complications. Experimental evidence suggests that agonists of the farnesoid‐X receptor (FXR), the main transcription factor regulating ABCB4, may be beneficial in this context.
Aim
To study the efficacy of obeticholic acid (OCA) in patients with LPAC syndrome with an inadequate response or intolerance to UDCA.
Methods
This was a retrospective study of patients with LPAC syndrome treated with OCA, a selective FXR agonist.
Results
We reviewed the records of five OCA‐treated patients (4 women; median age 29; ABCB4 variant in 4; no hepatic fibrosis). All patients received OCA at an initial dose of 5 mg daily and then 10 mg daily for a median period of 36 months in combination with UDCA (4 patients) or as a monotherapy (one patient). There were no adverse effects reported. Four patients had improvement in their symptoms ‐ three completely and one partially. One patient had no clinical benefit. Abnormalities of blood liver tests persisted in one patient despite resolution of symptoms. Radiological signs of hepatolithiasis persisted in three of the four patients who responded clinically to OCA.
Conclusions
These preliminary observations suggest that OCA may have the potential to effectively treat LPAC syndrome in patients with inadequate response or intolerance to UDCA. Larger studies are needed to confirm these data.
... Some patients progress to portal hypertension, liver cirrhosis, or even liver failure. Laboratory examination is characterized by persistent or repeated alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT) increase [1][2], and ursodeoxycholic acid is the main drug of choice [3]. ...
Background:
Gene mutations in ATP-binding cassette, subfamily B (ABCB4) lead to autosomal recessive disorders. Primary light amyloidosis is a rare and incurable disease. Here, we report a rare case of liver cirrhosis caused by ABCB4 gene mutation combined with primary light amyloidosis.
Case summary:
We report a case of a 25-year-old female who was hospitalized due to recurrent abdominal pain caused by calculous cholecystitis and underwent cholecystectomy. Pathological examination of the liver tissue suggested liver cirrhosis with bile duct injury. Exon analyses of the whole genome from the patient's peripheral blood revealed the presence of a heterozygous mutation in the ABCB4 gene. Bone marrow biopsy tissues, renal puncture examination, and liver mass spectrometry confirmed the diagnosis of a rare progressive familial intrahepatic cholestasis type 3 with systemic light chain type κ amyloidosis, which resulted in cirrhosis. Ursodeoxycholic acid and the cluster of differentiation 38 monoclonal antibody daretozumab were administered for treatment. Following treatment, the patient demonstrated significant improvement. Urinary protein became negative, peripheral blood-free light chain and urine-free light chain levels returned to normal, and the electrocardiogram showed no abnormalities. Additionally, the patient's lower limb numbness resolved, and her condition remained stable.
Conclusion:
This report presents the diagnosis and treatment of liver cirrhosis, a rare disease that is easily misdiagnosed or missed.
... GBD1 (LPAC syndrome) should be suspected in patients with symptomatic cholelithiasis and at least one of the following criteria: under 40 years of age at onset of symptoms; recurrence after cholecystectomy; intrahepatic sludge or microlithiasis with spindle-shaped dilatations of the intrahepatic bile ducts on cholangiography; familial history of cholelithiasis in first-degree relatives. Histologically, cholesterol crystal aggregates and small cholesterol stones are typically observed in bile ducts [46,48]. ...
The biliary system consists of intrahepatic and extrahepatic bile ducts lined by biliary epithelial cells (cholangiocytes). Bile ducts and cholangiocytes are affected by a variety of disorders called cholangiopathies, which differ in aetiology, pathogenesis, and morphology. Classification of cholangiopathies is complex and reflects pathogenic mechanisms (immune-mediated, genetic, drug- and toxin-induced, ischaemic, infectious, neoplastic), predominant morphological patterns of biliary injury (suppurative and non-suppurative cholangitis, cholangiopathy), and specific segments of the biliary tree affected by the disease process. While the involvement of large extrahepatic and intrahepatic bile ducts is typically visualised using radiology imaging, histopathological examination of liver tissue obtained by percutaneous liver biopsy still plays an important role in the diagnosis of cholangiopathies affecting the small intrahepatic bile ducts. To increase the diagnostic yield of a liver biopsy and determine the optimal therapeutic approach, the referring clinician is tasked with interpreting the results of histopathological examination. This requires knowledge and understanding of basic morphological patterns of hepatobiliary injury and an ability to correlate microscopic findings with results obtained by imaging and laboratory methods. This minireview describes the morphological aspects of small-duct cholangiopathies pertaining to the diagnostic process.
... In agreement with these proposed roles, ABCB4 mutations result in a broad spectrum of phenotypes ranging from progressive familial intrahepatic cholestasis type 3 (PFIC3) to ABCB4-related cholestatic liver disorders of varying manifestation and severity in adults [7]. Clinical studies revealed the strong association between ABCB4 gene mutations and low-phospholipid-associated cholelithiasis syndrome (LPAC), a rare type of gallstone disease [8,9]. ...
ABCB4 is almost exclusively expressed in the liver, where it plays an essential role in bile formation by transporting phospholipids into the bile. ABCB4 polymorphisms and deficiencies in humans are associated with a wide spectrum of hepatobiliary disorders, attesting to its crucial physiological function. Inhibition of ABCB4 by drugs may lead to cholestasis and drug-induced liver injury (DILI), although compared with other drug transporters, there are only a few identified substrates and inhibitors of ABCB4. Since ABCB4 shares up to 76% identity and 86% similarity in the amino acid sequence with ABCB1, also known to have common drug substrates and inhibitors, we aimed to develop an ABCB4 expressing Abcb1-knockout MDCKII cell line for transcellular transport assays. This in vitro system allows the screening of ABCB4-specific drug substrates and inhibitors independently of ABCB1 activity. Abcb1KO-MDCKII-ABCB4 cells constitute a reproducible, conclusive, and easy to use assay to study drug interactions with digoxin as a substrate. Screening a set of drugs with different DILI outcomes proved that this assay is applicable to test ABCB4 inhibitory potency. Our results are consistent with prior findings concerning hepatotoxicity causality and provide new insights for identifying drugs as potential ABCB4 inhibitors and substrates.
... The transport of phosphatidylcholine into the biliary tract is carried out by the ABC transporter ABCB4 [52]. The transport of cholesterol into the biliary tract is carried out by the ABC transporters ABCG5 and ABCG8 [53]. ...
Cholesterol gallstones are very common in hepatobiliary surgery and have been studied to a certain extent by doctors worldwide for decades. However, the mechanism of cholesterol gallstone formation is not fully understood, so there is currently no completely effective drug for the treatment and prevention of cholesterol gallstones. The formation and development of cholesterol gallstones are caused by a variety of genetic and environmental factors, among which genetic susceptibility, intestinal microflora disorders, impaired gallbladder motility, and immune disorders are important in the pathogenesis of cholesterol gallstones. This review focuses on recent advances in these mechanisms. We also discuss some new targets that may be effective in the treatment and prevention of cholesterol gallstones, which may be hot areas in the future.
Introduction: Cholelithiasis is etiopathogenetically very heterogeneous and, in terms of frequency, a rare disease in the period of growth and development. The aim of the study was to analyze risk factors for the occurrence of cholelithiasis in that period of life. Material and Methods: This retrospective study included 80 children and adolescents, 50 females and 30 males, aged 4-18 (14±5.55) years, with symptomatic cholelithiasis who were operated on at the University Children's Hospital in Belgrade in the period from 2000 to 2016. The diagnosis of the disease was based on ultrasound findings. Data on risk factors for the development of biliary calculosis were obtained from medical history. Results: Predisposing risk factors for cholelithiasis were verified in 46 (57.5 %) patients. One risk factor was identified in 34 patients, two risk factors were identified in 10 patients, three risk factors were found in two patients, while in others risk factors were not identified. Family predisposition to cholelithiasis was registered in 28 (35%) patients, obesity in 10 (12.5%), pre-obesity in nine, rapid weight loss in four, hereditary hemolytic disease in two, and premature birth combined with parenteral nutrition and sepsis as a complication were found in two patients. Apart from those who were born prematurely, another 10 patients had combined risk factors for cholelithiasis, six patients had family predisposition and obesity, and four patients had obesity and self-initiated rapid weight loss program. Conclusion: According to our research, the most common risk factors for cholelithiasis in children and adolescents are family predisposition and excess body weight. Most of the patients were adolescents and females.
Common bile duct stones, as a type of cholelithiasis, are a benign biliary obstruction that easily acute abdominalgia, and Endoscopic Retrograde Cholangiopancreatography (ERCP) is usually the first choice for clinical treatment. However, the increasing recurrence rate of patients after treatment is troubling clinicians and patients. For the prevention of recurrence after ERCP, there is no guideline to provide a clear drug regimen, traditional Chinese medicine however has achieved some result in the treatment of liver-related diseases based on the “gut-liver-bile acid axis”. On the basis of this, this article discusses the possibility of traditional Chinese medicine to prevent common bile duct stones (CBDS) after ERCP, and we expect that this article will provide new ideas for the prevention of recurrence of CBDS and for the treatment of cholelithiasis-related diseases with traditional Chinese medicine in future clinical and scientific research.
MDR3 (multidrug resistance 3) deficiency in humans (MDR2 in mice) causes progressive familial intrahepatic cholestasis type 3 (PFIC3). PFIC3 is a lethal disease characterized by an early onset of intrahepatic cholestasis progressing to liver cirrhosis, a preneoplastic condition, putting individuals at risk of hepatocellular carcinoma (HCC). Hepatocyte-like organoids from MDR2-deficient mice (MDR2KO) were used in this work to study the molecular alterations caused by the deficiency of this transporter. Proteomic analysis by mass spectrometry allowed characterization of 279 proteins that were differentially expressed in MDR2KO compared with wild-type organoids. Functional enrichment analysis indicated alterations in three main cellular functions: (1) interaction with the extracellular matrix, (2) remodeling intermediary metabolism, and (3) cell proliferation and differentiation. The affected cellular processes were validated by orthogonal molecular biology techniques. Our results point to molecular mechanisms associated with PFIC3 that may drive the progression to liver cirrhosis and HCC and suggest proteins and cellular processes that could be targeted for the development of early detection strategies for these severe liver diseases.
