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J Lipid Res. 2017 Sep;58(9):1903-1915. doi: 10.1194/jlr.M078980. Epub 2017 Jul 28.

Osteopontin regulates the cross-talk between phosphatidylcholine and cholesterol metabolism in mouse liver.

Author information

1
Departments of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain.
2
Biocruces Health Research Institute, Barakaldo, Spain.
3
Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain.
4
Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
5
Cellular Biology and Histology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain.
6
Liver Research Unit, Santa Cristina University Hospital, Instituto de Investigación Sanitaria Princesa, Madrid, Spain.
7
Hospital Universitario Cruces, Barakaldo, Spain.
8
Pediatrics Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain.
9
CIBERDEM, CIBERER Carlos III National Institute of Health, Madrid, Spain.
10
Regeneration and Repair, Institute of Hepatology, Foundation for Liver Research, London, United Kingdom.
11
Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC.
12
Section of Gastroenterology, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC.
13
Departments of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain patricia.aspichueta@ehu.eus.

Abstract

Osteopontin (OPN) is involved in different liver pathologies in which metabolic dysregulation is a hallmark. Here, we investigated whether OPN could alter liver, and more specifically hepatocyte, lipid metabolism and the mechanism involved. In mice, lack of OPN enhanced cholesterol 7α-hydroxylase (CYP7A1) levels and promoted loss of phosphatidylcholine (PC) content in liver; in vivo treatment with recombinant (r)OPN caused opposite effects. rOPN directly decreased CYP7A1 levels through activation of focal adhesion kinase-AKT signaling in hepatocytes. PC content was also decreased in OPN-deficient (OPN-KO) hepatocytes in which de novo FA and PC synthesis was lower, whereas cholesterol (CHOL) synthesis was higher, than in WT hepatocytes. In vivo inhibition of cholesterogenesis normalized liver PC content in OPN-KO mice, demonstrating that OPN regulates the cross-talk between liver CHOL and PC metabolism. Matched liver and serum samples showed a positive correlation between serum OPN levels and liver PC and CHOL concentration in nonobese patients with nonalcoholic fatty liver. In conclusion, OPN regulates CYP7A1 levels and the metabolic fate of liver acetyl-CoA as a result of CHOL and PC metabolism interplay. The results suggest that CYP7A1 is a main axis and that serum OPN could disrupt liver PC and CHOL metabolism, contributing to nonalcoholic fatty liver disease progression in nonobese patients.

KEYWORDS:

de novo lipogenesis; glycerolipids; nonalcoholic fatty liver disease

PMID:
28754826
PMCID:
PMC5580904
DOI:
10.1194/jlr.M078980
[Indexed for MEDLINE]
Free PMC Article

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