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J Biol Chem. 2019 Aug 2;294(31):11853-11862. doi: 10.1074/jbc.RA118.007179. Epub 2019 Jun 14.

Increased sulfation of bile acids in mice and human subjects with sodium taurocholate cotransporting polypeptide deficiency.

Mao F1,2, Liu T3,4,5, Hou X2,6, Zhao H2, He W2, Li C2,6, Jing Z2, Sui J1,2,7, Wang F2,7, Liu X8, Han J9,10, Borchers CH9,10,11,12,13, Wang JS14,4, Li W15,7.

Author information

1
School of Life Sciences, Beijing Normal University, Beijing 100875, China.
2
National Institute of Biological Sciences, Beijing 102206, China.
3
Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai 201102, China.
4
Department of Pediatrics, Shanghai Medical College of Fudan University, Shanghai 200333, China.
5
Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai 201512, China.
6
School of Life Sciences, Peking University, Beijing 100091, China.
7
Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 100091, China.
8
School of Life Sciences, Tsinghua University, Beijing 100091, China.
9
UVic-Genome BC Proteomics Centre, University of Victoria, Victoria, British Columbia V8Z 5N3, Canada.
10
Division of Medical Sciences, University of Victoria, Victoria, British Columbia V8P 5C2, Canada.
11
Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia V8P 5C2, Canada.
12
Gerald Bronfman Department of Oncology, Jewish General Hospital, McGill University, Montreal, Quebec H4A 3T2, Canada.
13
Proteomics Centre, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec H4A 3T2, Canada.
14
Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai 201102, China jshwang@shmu.edu.cn.
15
National Institute of Biological Sciences, Beijing 102206, China liwenhui@nibs.ac.cn.

Abstract

Sodium taurocholate cotransporting polypeptide (NTCP, encoded by Slc10a1/SLC10A1) deficiency can result in hypercholanemia but no obvious symptoms in both mice and humans. However, the consequence of and response to long-term hypercholanemia caused by NTCP deficiency remain largely unexplored. Here, we analyzed lifelong dynamics of serum total bile acid (TBA) levels in Slc10a1 -/- mice, and we also assessed changes of TBA levels in 33 young individuals with SLC10A1 loss-of-function variant p.Ser267Phe. We found that overall serum TBA levels tended to decrease gradually with age in both Slc10a1 -/- mice and p.Ser267Phe individuals. Liver mRNA profiling revealed notable transcription alterations in hypercholanemic Slc10a1 -/- mice, including inhibition of bile acid (BA) synthesis, enhancement of BA detoxification, and altered BA transport. Members of the sulfotransferase (SULT) family showed the most dramatic increases in livers of hypercholanemic Slc10a1 -/- mice, and one of their BA sulfates, taurolithocholic acid 3-sulfate, significantly increased. Importantly, consistent with the mouse studies, comprehensive profiling of 58 BA species in sera of p.Ser267Phe individuals revealed a markedly increased level of BA sulfates. Together, our findings indicate that the enhanced BA sulfation is a major mechanism for BA detoxification and elimination in both mice and humans with Slc10a1/SLC10A1 deficiency.

KEYWORDS:

SLC10A1; Sult2a1; TLCA-3-sulfate; bile acid; hypercholanemia; lipid metabolism; liver metabolism; mass spectrometry (MS); sulfation; sulfotransferase

PMID:
31201272
PMCID:
PMC6682732
[Available on 2020-08-02]
DOI:
10.1074/jbc.RA118.007179

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