scholarly journals Molecular Mechanisms for Biliary Phospholipid and Drug Efflux Mediated by ABCB4 and Bile Salts

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Shin-ya Morita ◽  
Tomohiro Terada
Keyword(s):  
Intrahepatic Cholestasis ◽  
Bile Salts ◽  
Molecular Mechanisms ◽  
Mixed Micelles ◽  
Biliary Cirrhosis ◽  
Culture Studies ◽  
Physiological Relevance ◽  
Type 3 ◽  
Cholestasis Of Pregnancy

On the canalicular membranes of hepatocytes, several ABC transporters are responsible for the secretion of bile lipids. Among them, ABCB4, also called MDR3, is essential for the secretion of phospholipids from hepatocytes into bile. The biliary phospholipids are associated with bile salts and cholesterol in mixed micelles, thereby reducing the detergent activity and cytotoxicity of bile salts and preventing cholesterol crystallization. Mutations in theABCB4gene result in progressive familial intrahepatic cholestasis type 3, intrahepatic cholestasis of pregnancy, low-phospholipid-associated cholelithiasis, primary biliary cirrhosis, and cholangiocarcinoma.In vivoand cell culture studies have demonstrated that the secretion of biliary phospholipids depends on both ABCB4 expression and bile salts. In the presence of bile salts, ABCB4 located in nonraft membranes mediates the efflux of phospholipids, preferentially phosphatidylcholine. Despite high homology with ABCB1, ABCB4 expression cannot confer multidrug resistance. This review summarizes our current understanding of ABCB4 functions and physiological relevance, and discusses the molecular mechanism for the ABCB4-mediated efflux of phospholipids.

ABCB4/MDR3 in health and disease – at the crossroads of biochemistry and medicine

2019 ◽  
Vol 400 (10) ◽  
pp. 1245-1259 ◽  
Author(s):  
Martin Prescher ◽  
Tim Kroll ◽  
Lutz Schmitt
Keyword(s):  
Intrahepatic Cholestasis ◽  
Bile Salts ◽  
Biliary Tree ◽  
Drug Induced ◽  
Bile Formation ◽  
Canalicular Membrane ◽  
Outer Leaflet ◽  
Separate Step ◽  
Type 3

Abstract Several ABC transporters of the human liver are responsible for the secretion of bile salts, lipids and cholesterol. Their interplay protects the biliary tree from the harsh detergent activity of bile salts. Among these transporters, ABCB4 is essential for the translocation of phosphatidylcholine (PC) lipids from the inner to the outer leaflet of the canalicular membrane of hepatocytes. ABCB4 deficiency can result in altered PC to bile salt ratios, which led to intrahepatic cholestasis of pregnancy, low phospholipid associated cholelithiasis, drug induced liver injury or even progressive familial intrahepatic cholestasis type 3. Although PC lipids only account for 30–40% of the lipids in the canalicular membrane, 95% of all phospholipids in bile are PC lipids. We discuss this discrepancy in the light of PC synthesis and bile salts favoring certain lipids. Nevertheless, the in vivo extraction of PC lipids from the outer leaflet of the canalicular membrane by bile salts should be considered as a separate step in bile formation. Therefore, methods to characterize disease causing ABCB4 mutations should be considered carefully, but such an analysis represents a crucial point in understanding the currently unknown transport mechanism of this ABC transporter.

A novel etiologic factor of highly elevated cholestanol levels: progressive familial intrahepatic cholestasis

2020 ◽  
Vol 33 (5) ◽  
pp. 665-669
Author(s):  
Aynur Küçükçongar Yavaş ◽  
Büşra Çavdarlı ◽  
Özlem Ünal Uzun ◽  
Ayşen Uncuoğlu ◽  
Mehmet Gündüz
Keyword(s):  
Primary Biliary Cirrhosis ◽  
Intrahepatic Cholestasis ◽  
Density Lipoprotein ◽  
Etiologic Factor ◽  
Compound Heterozygous ◽  
Cholestatic Liver Disease ◽  
Biliary Cirrhosis ◽  
Progressive Familial Intrahepatic Cholestasis ◽  
Turkish Patient ◽  
Type 3

AbstractBackgroundProgressive familial intrahepatic cholestasis type 3 (PFIC3) is an uncommon cholestatic liver disease caused by mutations in the ATP binding cassette subfamily B member 4 (ABCB4) gene. Although PFIC3 is frequently identified in childhood, ABCB4 disease-causing alleles have been described in adults affected by intrahepatic cholestasis of pregnancy, hormone-induced cholestasis, low-phospholipid-associated cholelithiasis syndrome or juvenile cholelithiasis, cholangiocarcinoma and in sporadic forms of primary biliary cirrhosis. Cholestanol is a biomarker which is elevated especially in cerebrotendinous xanthomatosis and rarely in primary biliary cirrhosis (PBC) and Niemann Pick type C.Case presentationHere we report a Turkish patient with compound heterozygous mutations in the ABCB4 gene, who has hepatosplenomegaly, low level of high-density lipoprotein, cholestasis and high level of cholestanol.ConclusionThis is the first PFIC3 case with a high cholestanol level described in the literature. There are very few diseases linked to increased cholestanol levels, two of which are CTX and PBC. From this case, we can conclude that a high cholestanol level might be another indicator of PFIC type 3.

Influence of taurocholate, taurochenodeoxycholate, and taurodehydrocholate on sulfobromophthalein transport into bile.

1979 ◽  
Vol 236 (1) ◽  
pp. E10
Author(s):  
S Binet ◽  
Y Delage ◽  
S Erlinger
Keyword(s):  
Bile Salts ◽  
Mixed Micelle ◽  
Mixed Micelles ◽  
Important Determinant ◽  
Micelle Formation ◽  
Similar Increase ◽  
Mixed Micelle Formation ◽  
Series Of Experiments

To test the hypothesis that incorporation of sulfobromophthalein (BSP) into mixed micelles could account for the increase in its biliary transport maximum (Tmax) by bile salts, we have compared in hamsters the influence on BSP Tmax of taurocholate and taurochenodeoxycholate (two micelle-forming physiological bile salts) to that of taurodehydrocholate, a bile salt which, in vitro, does not form micelles. In a first series of experiments, it was observed that taurocholate and taurochenodeoxycholate increased the secretion of phospholipid (40 and 53%, respectively), and cholesterol (50 and 110%, respectively), whereas taurodehydrocholate decreased the secretion of phospholipid (-31%) and cholesterol (-43%). This result suggests that, in vivo, taurodehydrocholate or its metabolites do not form mixed micelles. In a second series of experiments, it was seen that the three bile salts induced a similar increase in BSP Tmax (63% with taurocholate, 52% with taurochenodeoxycholate, and 51% with taurodehydrocholate). These results provide circumstantial evidence for the hypothesis that mixed micelle formation is not an important determinant of maximal BSP secretion into bile.

scholarly journals Case report: progressive familial intrahepatic cholestasis type 3 with compound heterozygous ABCB4 variants diagnosed 15 years after liver transplantation

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Mariam Goubran ◽  
Ayodeji Aderibigbe ◽  
Emmanuel Jacquemin ◽  
Catherine Guettier ◽  
Safwat Girgis ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Liver Disease ◽  
Intrahepatic Cholestasis ◽  
Autoimmune Response ◽  
Compound Heterozygous ◽  
Biliary Cirrhosis ◽  
Progressive Familial Intrahepatic Cholestasis ◽  
End Stage Liver Disease ◽  
End Stage ◽  
Type 3

Abstract Background Progressive familial intrahepatic cholestasis (PFIC) type 3 is an autosomal recessive disorder arising from mutations in the ATP-binding cassette subfamily B member 4 (ABCB4) gene. This gene encodes multidrug resistance protein-3 (MDR3) that acts as a hepatocanalicular floppase that transports phosphatidylcholine from the inner to the outer canalicular membrane. In the absence of phosphatidylcholine, the detergent activity of bile salts is amplified and this leads to cholangiopathy, bile duct loss and biliary cirrhosis. Patients usually present in infancy or childhood and often progress to end-stage liver disease before adulthood. Case presentation We report a 32-year-old female who required cadaveric liver transplantation at the age of 17 for cryptogenic cirrhosis. When the patient developed chronic ductopenia in the allograft 15 years later, we hypothesized that the patient’s original disease was due to a deficiency of a biliary transport protein and the ductopenia could be explained by an autoimmune response to neoantigen that was not previously encountered by the immune system. We therefore performed genetic analyses and immunohistochemistry of the native liver, which led to a diagnosis of PFIC3. However, there was no evidence of humoral immune response to the MDR3 and therefore, we assumed that the ductopenia observed in the allograft was likely due to chronic rejection rather than autoimmune disease in the allograft. Conclusions Teenage patients referred for liver transplantation with cryptogenic liver disease should undergo work up for PFIC3. An accurate diagnosis of PFIC 3 is key for optimal management, therapeutic intervention, and avoidance of complications before the onset of end-stage liver disease.

scholarly journals Extracellular vesicles: Exosomes, microvesicles, and friends

2013 ◽  
Vol 200 (4) ◽  
pp. 373-383 ◽  
Author(s):  
Graça Raposo ◽  
Willem Stoorvogel
Keyword(s):  
Plasma Membrane ◽  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Membrane Vesicles ◽  
Vesicle Release ◽  
Physiological Relevance ◽  
And Function ◽  
Extracellular Environment

Cells release into the extracellular environment diverse types of membrane vesicles of endosomal and plasma membrane origin called exosomes and microvesicles, respectively. These extracellular vesicles (EVs) represent an important mode of intercellular communication by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and RNA. Deficiencies in our knowledge of the molecular mechanisms for EV formation and lack of methods to interfere with the packaging of cargo or with vesicle release, however, still hamper identification of their physiological relevance in vivo. In this review, we focus on the characterization of EVs and on currently proposed mechanisms for their formation, targeting, and function.

scholarly journals p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shun Kageyama ◽  
Sigurdur Runar Gudmundsson ◽  
Yu-Shin Sou ◽  
Yoshinobu Ichimura ◽  
Naoki Tamura ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Oxidative Stress Response ◽  
Liquid Droplets ◽  
Autophagosome Formation ◽  
Selective Autophagy ◽  
Selective Degradation ◽  
Physiological Relevance ◽  
Related Proteins

AbstractAutophagy contributes to the selective degradation of liquid droplets, including the P-Granule, Ape1-complex and p62/SQSTM1-body, although the molecular mechanisms and physiological relevance of selective degradation remain unclear. In this report, we describe the properties of endogenous p62-bodies, the effect of autophagosome biogenesis on these bodies, and the in vivo significance of their turnover. p62-bodies are low-liquidity gels containing ubiquitin and core autophagy-related proteins. Multiple autophagosomes form on the p62-gels, and the interaction of autophagosome-localizing Atg8-proteins with p62 directs autophagosome formation toward the p62-gel. Keap1 also reversibly translocates to the p62-gels in a p62-binding dependent fashion to activate the transcription factor Nrf2. Mice deficient for Atg8-interaction-dependent selective autophagy show that impaired turnover of p62-gels leads to Nrf2 hyperactivation in vivo. These results indicate that p62-gels are not simple substrates for autophagy but serve as platforms for both autophagosome formation and anti-oxidative stress.

scholarly journals Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo

2017 ◽  
Vol 114 (52) ◽  
pp. E11323-E11332 ◽  
Author(s):  
G. Sebastian Hönes ◽  
Helena Rakov ◽  
John Logan ◽  
Xiao-Hui Liao ◽  
Eugenie Werbenko ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Dna Binding ◽  
Target Genes ◽  
Skeletal Development ◽  
Nuclear Signaling ◽  
Physiological Relevance ◽  
Pituitary Thyroid Axis ◽  
Second Messenger Signaling ◽  
Type 3

Thyroid hormone (TH) and TH receptors (TRs) α and β act by binding to TH response elements (TREs) in regulatory regions of target genes. This nuclear signaling is established as the canonical or type 1 pathway for TH action. Nevertheless, TRs also rapidly activate intracellular second-messenger signaling pathways independently of gene expression (noncanonical or type 3 TR signaling). To test the physiological relevance of noncanonical TR signaling, we generated knockin mice with a mutation in the TR DNA-binding domain that abrogates binding to DNA and leads to complete loss of canonical TH action. We show that several important physiological TH effects are preserved despite the disruption of DNA binding of TRα and TRβ, most notably heart rate, body temperature, blood glucose, and triglyceride concentration, all of which were regulated by noncanonical TR signaling. Additionally, we confirm that TRE-binding–defective TRβ leads to disruption of the hypothalamic–pituitary–thyroid axis with resistance to TH, while mutation of TRα causes a severe delay in skeletal development, thus demonstrating tissue- and TR isoform-specific canonical signaling. These findings provide in vivo evidence that noncanonical TR signaling exerts physiologically important cardiometabolic effects that are distinct from canonical actions. These data challenge the current paradigm that in vivo physiological TH action is mediated exclusively via regulation of gene transcription at the nuclear level.

scholarly journals Gene therapy for progressive familial intrahepatic cholestasis type 3 in a clinically relevant mouse model

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Nicholas D. Weber ◽  
Leticia Odriozola ◽  
Javier Martínez-García ◽  
Veronica Ferrer ◽  
Anne Douar ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Therapeutic Effect ◽  
Intrahepatic Cholestasis ◽  
Bile Salts ◽  
Monogenic Disease ◽  
Progressive Familial Intrahepatic Cholestasis ◽  
Disease Biomarkers ◽  
Type 3 ◽  
Old Females

AbstractProgressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare monogenic disease caused by mutations in the ABCB4 gene, resulting in a reduction in biliary phosphatidylcholine. Reduced biliary phosphatidylcholine cannot counteract the detergent effects of bile salts, leading to cholestasis, cholangitis, cirrhosis and ultimately liver failure. Here, we report results from treating two- or five-week-old Abcb4−/− mice with an AAV vector expressing human ABCB4, resulting in significant decreases of PFIC3 disease biomarkers. All male mice achieved a sustained therapeutic effect up through 12 weeks, but the effect was achieved in only 50% of females. However, two-week-old females receiving a second inoculation three weeks later maintained the therapeutic effect. Upon sacrifice, markers of PFIC3 disease such as, hepatosplenomegaly, biliary phosphatidylcholine and liver histology were significantly improved. Thus, AAV-mediated gene therapy successfully prevented PFIC3 symptoms in a clinically relevant mouse model, representing a step forward in improving potential therapy options for PFIC3 patients.

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