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

Maitane Nuñez-Garcia,Beatriz Gomez-Santos,Xabier Buqué,Juan L García-Rodriguez,Marta R Romero,Jose J.G Marin,Beatriz Arteta,Carmelo García-Monzón,Luis Castaño,Wing-Kin Syn,Olatz Fresnedo,Patricia Aspichueta

doi:10.1194/jlr.m078980

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.

Highlights

Osteopontin (OPN) is involved in different liver pathologies in which metabolic dysregulation is a hallmark
The results suggest that modulation of cholesterol 7 -hydroxylase (CYP7A1) protein levels by OPN represents a main axis in the dysregulated metabolic profile and that, in nonobese nonalcoholic fatty liver (NAFL) patients, circulating OPN could disrupt liver PC and CHOL metabolism that is involved in nonalcoholic fatty liver disease (NAFLD) progression
We found that in nonobese NAFL patients, in whom serum OPN farnesoid X receptor (FXR) and liver X receptor (LXR) increased (Fig. 1A), serum OPN correlated positively with liver PC, liver PE, and liver CHOL concentration (Fig. 1B), while there was no correlation between serum OPN and liver TG concentration

Summary

Introduction

Osteopontin (OPN) is involved in different liver pathologies in which metabolic dysregulation is a hallmark. Protects against obesity-induced hepatic steatosis and attenuates glucose production in mice [4] and neutralization of circulating OPN abrogates liver fibrogenesis in mice [8] Even though it plays a major role in liver diseases, OPN is involved in the pathophysiology of other malignancies [11], such as breast [12] and lung cancer [13]. PC metabolism is altered in a variety of tumors and cancer cells because of the role of PC in provision of membranes and lipid second messengers [16,17,18]

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Results

Conclusion