ATP8B1 and ATP11C: Two Lipid Flippases Important for Hepatocyte Function

2015 ◽  
Vol 33 (3) ◽  
pp. 314-318 ◽  
Author(s):  
Jyoti Naik ◽  
Dirk R. de Waart ◽  
Karina Utsunomiya ◽  
Suzanne Duijst ◽  
Kam Ho Mok ◽  
...  
Keyword(s):  
Intrahepatic Cholestasis ◽  
Bile Salts ◽  
Membrane Transporters ◽  
Cholestatic Liver Disease ◽  
Canalicular Membrane ◽  
Transport Vesicles ◽  
Benign Recurrent Intrahepatic Cholestasis ◽  
Conjugated Hyperbilirubinemia ◽  
Deficient Mice

P4 ATPases are lipid flippases and transport phospholipids from the exoplasmic to the cytosolic leaflet of biological membranes. Lipid flipping is important for the biogenesis of transport vesicles. Recently it was shown that loss of the P4 ATPases ATP8B1 and ATP11C are associated with severe Cholestatic liver disease. Mutation of ATP8B1 cause progressive familial Intrahepatic Cholestasis type 1 (PFIC1)and benign recurrent intrahepatic cholestasis type 1 (BRIC 1). From our observations we hypothesized that ATP8B1 deficiency causes a phospholipids randomization at the canalicular membrane, which results in extraction of cholesterol due to increase sensitivity of the canalicular membrane. Deficiency of ATP11C causes conjugated hyperbilirubinemia. In our preliminary result we observed accumulation of unconjugated bile salts in Atp11c deficient mice probably because of regulation in the expression or function of OATP1B2. Similar to ATP8B1, ATP11C have regulation on membrane transporters.

PROGRESSIVE FAMILY INTRAHEPATIC CHOLESTASIS: DIAGNOSTICS, TREATMENT (CLINICAL OBSERVATION)

2021 ◽  
Vol 19 (4) ◽  
pp. 462-467
Author(s):  
A. R. Obuhovich ◽  
◽  
N. N. Iaskevich ◽  
Keyword(s):  
Case Report ◽  
Intrahepatic Cholestasis ◽  
Clinical Observation ◽  
Gene Mutations ◽  
Literature Analysis ◽  
Genetic Progress ◽  
Benign Recurrent Intrahepatic Cholestasis

Jaundice is a manifestation of many diseases both benign and malignant. Genetic progress allowed to distinguish the group of unknown earlier rare cholestatic jaundices, which are resulted from gene mutations. There are no described algorithms of their diagnosis or treatment. In this article case report of the patient with benign recurrent intrahepatic cholestasis type 1 is presented. There is also literature analysis of this theme.

PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS

PEDIATRICS ◽  
1973 ◽  
Vol 51 (6) ◽  
pp. 998-1007
Author(s):  
Mark Ballow ◽  
Carmi Margolis ◽  
Bernard Schachtel ◽  
Y. Edward Hsia
Keyword(s):  
Intrahepatic Cholestasis ◽  
Autosomal Recessive ◽  
Elevated Serum ◽  
Intermediate Form ◽  
Elevated Alkaline Phosphatase ◽  
Benign Recurrent Intrahepatic Cholestasis ◽  
Conjugated Hyperbilirubinemia ◽  
Genetically Determined ◽  
Fat Soluble Vitamins ◽  
Autosomal Recessive Pattern

Two brothers with an early onset of fluctuating jaundice, pruritus, malabsorption, and rickets are reported. Biochemical features included conjugated hyperbilirubinemia, elevated alkaline phosphatase, normal cholesterol, slightly elevated transaminase, elevated serum bile salts, and hypoglycemia. There was also evidence of rickets and deficiency of the fat soluble vitamins. Histological appearance of the liver showed bile stasis and paucity of the interlobular bile ducts. The familial incidence, clinical course, biochemical findings, and liver histology in our cases and in similar reported cases, are distinctive of an intermediate form of familial progressive intrahepatic cholestasis, milder than congenital intrahepatic biliary atresia, but more severe than benign recurrent intrahepatic cholestasis. A defect in the hepatic excretory mechanism is postulated for this group of intrahepatic cholestatic disorders which appear to be genetically determined with an autosomal recessive pattern of inheritance. Both brothers had symptomatic and chemical improvement with phenobarbital therapy.

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.

scholarly journals Case Report: A Novel Homozygous Variant Identified in a Chinese Patient With Benign Recurrent Intrahepatic Cholestasis-Type 1

2021 ◽  
Vol 8 ◽  
Author(s):  
Huayu Chen ◽  
Dongbo Wu ◽  
Wei Jiang ◽  
Ting Lei ◽  
Changli Lu ◽  
...  
Keyword(s):  
Intrahepatic Cholestasis ◽  
Liver Function Tests ◽  
Liver Disorder ◽  
Chinese Patient ◽  
The Novel ◽  
Homozygous Variant ◽  
Benign Recurrent Intrahepatic Cholestasis ◽  
Common Causes ◽  
Work Up

Benign recurrent intrahepatic cholestasis (BRIC) is a rare hereditary cholestatic liver disorder. Accurate diagnosis and timely interventions are important in determining outcomes. Besides clinical and pathologic diagnosis, genetic study of BRIC remains limited. Here, we report a young man enduring recurrent jaundice and severe pruritus for 15 years. The increased level of direct bilirubin was the main biochemical abnormality, and the work-up for common causes of jaundice were unremarkable. Liver biopsy showed extensive cholestasis of hepatocytes in zone 3. The novel homozygous variant including c.1817T > C and p.I606T was detected on his ATP8B1gene. The patient was finally diagnosed with BRIC-1. His symptoms were relieved, and liver function tests returned to normal after taking ursodeoxycholic acid. This case provides a different perspective to the methodology employed when dealing with cases of jaundice and helping diagnose rare diseases.

scholarly journals New Insights in Genetic Cholestasis: From Molecular Mechanisms to Clinical Implications

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Eva Sticova ◽  
Milan Jirsa ◽  
Joanna Pawłowska
Keyword(s):  
Intrahepatic Cholestasis ◽  
Bile Salts ◽  
Autosomal Recessive ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Clinical Manifestations ◽  
Bile Secretion ◽  
Drug Induced ◽  
Benign Recurrent Intrahepatic Cholestasis ◽  
End Stage

Cholestasis is characterised by impaired bile secretion and accumulation of bile salts in the organism. Hereditary cholestasis is a heterogeneous group of rare autosomal recessive liver disorders, which are characterised by intrahepatic cholestasis, pruritus, and jaundice and caused by defects in genes related to the secretion and transport of bile salts and lipids. Phenotypic manifestation is highly variable, ranging from progressive familial intrahepatic cholestasis (PFIC)—with onset in early infancy and progression to end-stage liver disease—to a milder intermittent mostly nonprogressive form known as benign recurrent intrahepatic cholestasis (BRIC). Cases have been reported of initially benign episodic cholestasis that subsequently transitions to a persistent progressive form of the disease. Therefore, BRIC and PFIC seem to represent two extremes of a continuous spectrum of phenotypes that comprise one disease. Thus far, five representatives of PFIC (named PFIC1-5) caused by pathogenic mutations present in both alleles ofATP8B1,ABCB11,ABCB4,TJP2,andNR1H4have been described. In addition to familial intrahepatic cholestasis, partial defects inATP8B1,ABCB11,andABCB4predispose patients to drug-induced cholestasis and intrahepatic cholestasis in pregnancy. This review summarises the current knowledge of the clinical manifestations, genetics, and molecular mechanisms of these diseases and briefly outlines the therapeutic options, both conservative and invasive, with an outlook for future personalised therapeutic strategies.

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