NTCP Deficiency Causes Gallbladder Abnormalities in Mice and Human Beings

Mao, Fengfeng; Wang, Mengxuan; Hou, Xinfeng; Zhou, Zhongmin; Yan, Yanyan; Fang, Ling-Juan; Tan, Zexi; Fang, Weiyuan; Liu, Teng; Wang, He; Li, Cong; Xie, Xin‐Bao; Lu, Shi-Qi; Sui, Jianhua; Wang, Fengchao; Han, Jun; Wang, Jianshe; Li, Wenhui

doi:10.1016/j.jcmgh.2020.09.001

Cited by 8 publications

(5 citation statements)

References 18 publications

(19 reference statements)

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“…Subsequently, multiple other NTCP‐deficient individuals have been reported with isolated hypercholanemia as the common denominator, showing mild and transient neonatal hyperbilirubinemia and gallbladder anomalities but with no apparent long‐term clinical consequences. ( 38‐40 ) Pruritus was notably absent in these individuals, suggesting that isolated hypercholanemia may not be so detrimental as once thought. Interestingly, the p.Ser267Phe mutation in SLC10A1 (rs2296651), leading to transporter inactivation, is highly prevalent in East Asia, with an allele frequency of 8%‐12% in individuals in Southern China.…”

Section: Figmentioning

confidence: 66%

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Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology

et al. 2021

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Bile salts play a pivotal role in lipid homeostasis, are sensed by specialized receptors, and have been implicated in various disorders affecting the gut or liver. They may play a role either as culprit or as potential panacea. Four very efficient transporters mediate most of the hepatic and intestinal bile salt uptake and efflux, and are each essential for the efficient enterohepatic circulation of bile salts. Starting from the intestinal lumen, conjugated bile salts cross the otherwise impermeable lipid bilayer of (primarily terminal ileal) enterocytes through the apical sodium–dependent bile acid transporter (gene SLC10A2 ) and leave the enterocyte through the basolateral heteromeric organic solute transporter, which consists of an alpha and beta subunit (encoded by SLC51A and SLC51B ). The Na + ‐taurocholate cotransporting polypeptide (gene SLC10A1 ) efficiently clears the portal circulation of bile salts, and the apical bile salt export pump (gene ABCB11 ) pumps the bile salts out of the hepatocyte into primary bile, against a very steep concentration gradient. Recently, individuals lacking either functional Na + ‐taurocholate cotransporting polypeptide or organic solute transporter have been described, completing the quartet of bile acid transport deficiencies, as apical sodium–dependent bile acid transporter and bile salt export pump deficiencies were already known for years. Novel pathophysiological insights have been obtained from knockout mice lacking functional expression of these genes and from pharmacological transporter inhibition in mice or humans. Conclusion : We provide a concise overview of the four main bile salt transport pathways and of their status as possible targets of interventions in cholestatic or metabolic disorders.

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Section: Figmentioning

confidence: 66%

“…( 53 ) Elevated levels of FGF15 may also explain the gallbladder abnormalities found in hyperchloremic 4‐week‐old NTCP KO mice. ( 39 ) In addition, NTCP deficiency induces bile salt sulfation, leading to increased elimination through urine, thus dampening the hypercholanemia. ( 55 )…”

Section: Figmentioning

confidence: 99%

Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology

et al. 2021

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“…Over time the massive deposition of bile pigments can lead to damage of hepatocytes and bile ducts and even increase the risk of gallstones[ 20 , 21 ]. Similarly, Mao et al [ 22 ] observed in an animal test model of knockout mice with SLC10A1 gene that SlC10A1 deficiency resulted in various abnormal manifestations of the gallbladder, including gallbladder wall thickening, gallbladder enlargement (wall thickening), gallbladder enlargement with black-green bile and diaphragm cap malformation. Furthermore, in an animal model by Zhang et al [ 23 ], it was observed that the metabolism of tyrosine, glycine, taurine, fatty acids and glycerophospholipids as well as the biosynthesis of tryptophan, pantothenic acid and coenzyme A were significantly dysregulated in NTCP knockout mice by metabolic pathway analysis, suggesting that NTCP is closely associated with these metabolic pathways.…”

Section: Discussionmentioning

confidence: 99%

De novo mutation loci and clinical analysis in a child with sodium taurocholate cotransport polypeptide deficiency: A case report

Liu¹,

Li²,

Li³

2021

WJCC

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BACKGROUND Sodium taurocholate cotransport polypeptide (NTCP) deficiency disease is a genetic metabolic disorder due to mutations in the SLC10A1 gene and impaired bile acid salt uptake by the basolateral membrane transport protein NTCP in hepatocytes. A variety of clinical manifestations and genetic mutation loci have been reported for this disease. However, specific therapeutic measures are lacking, and the long-term effects are unknown. CASE SUMMARY An infant with elevated bile acids and behavioral neurodevelopmental delay failed to respond to bile acid-lowering therapy. Genetic testing for metabolic liver disease revealed that the child had NTCP deficiency due to the SLC10A1 mutation: c.422dupA ( p.Y141X ), which is a novel mutation site. The current follow-up revealed a gradual decrease in bile acid levels after 1 year of age, but the child still had behavioral neurodevelopmental delays. CONCLUSION The clinical manifestations, genetic characteristics, treatment and long-term prognosis due to NTCP deficiency remain poorly defined and need to be further confirmed by more studies and reports.

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“…Similarly, Mao et al described in two infants with NTCP p.Ser267Phe variant the presence of cholelithiasis. Interestingly, NTCP knockout ( SLC10A1 −/− ) mice develop multiple abnormal phenotypes of the gallbladder and hypercholanemia, but not cholelithiasis [ 29 ]. This data may suggest that abnormalities in bile acid metabolism caused by NTCP deficiency predispose to gallstone formation.…”

Section: Reviewmentioning

confidence: 99%

The Etiology of Cholelithiasis in Children and Adolescents—A Literature Review

Zdanowicz

Daniluk

Lebensztejn

et al. 2022

IJMS

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The incidence of gallstone disease has increased in recent years. The pathogenesis of cholelithiasis is not fully understood. The occurrence of the disease is influenced by both genetic and environmental factors. This article reviews the literature on cholelithiasis in children, with the exception of articles on hematological causes of cholelithiasis and cholelithiasis surgery. The aim of this review is to present the latest research on the pathogenesis of gallstone disease in children. The paper discusses the influence of all factors known so far, such as genetic predisposition, age, infections, medications used, parenteral nutrition, and comorbidities, on the development of gallstone disease. The course of cholelithiasis in the pediatric population is complex, ranging from asymptomatic to life-threatening. Understanding the course of the disease and predisposing factors can result in a faster diagnosis of the disease and administration of appropriate treatment.

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NTCP Deficiency Causes Gallbladder Abnormalities in Mice and Human Beings

Cited by 8 publications

References 18 publications

Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology

Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology

De novo mutation loci and clinical analysis in a child with sodium taurocholate cotransport polypeptide deficiency: A case report

The Etiology of Cholelithiasis in Children and Adolescents—A Literature Review

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