1. Osteopontin regulates the cross-talk between phosphatidylcholine and cholesterol metabolism in mouse liver.
- Author
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Nuñez-Garcia M, Gomez-Santos B, Buqué X, García-Rodriguez JL, Romero MR, Marin JJG, Arteta B, García-Monzón C, Castaño L, Syn WK, Fresnedo O, and Aspichueta P
- Subjects
- Adult, Aged, Animals, Cholesterol 7-alpha-Hydroxylase metabolism, Disease Progression, Extracellular Space metabolism, Female, Gene Knockout Techniques, Hepatocytes metabolism, Humans, Male, Mice, Middle Aged, Non-alcoholic Fatty Liver Disease genetics, Non-alcoholic Fatty Liver Disease metabolism, Osteopontin blood, Osteopontin deficiency, Osteopontin genetics, Young Adult, Cholesterol metabolism, Liver metabolism, Osteopontin metabolism, Phosphatidylcholines metabolism
- 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.
- Published
- 2017
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