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

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.

Liver osteopontin is required to prevent the progression of age‐related nonalcoholic fatty liver disease

“…The results showed a positive correlation between serum OPN concentration and age (Figure 1a). Given that OPN is increased in liver (Lima‐Cabello et al, 2010) and serum of NAFLD patients (Nunez‐Garcia et al., 2017), OPN levels were also measured in a cohort of NAFLD patients ( n = 89) (Figure 1b) (Table 1). The correlation between serum OPN concentration and age was lost in NAFLD patients, in which OPN levels were already high in younger patients (Figure 1b).…”

“…Osteopontin (OPN) is a multifunctional protein that is expressed in a variety of tissues and has many functions, both physiological and pathological (Ashkar et al, 2000; Ramaiah & Rittling, 2007). It is involved in liver pathologies and acts as a modulator of liver lipid metabolism (Nunez‐Garcia et al., 2017; Nuñez‐Garcia et al, 2018). OPN is involved in NAFLD pathogenesis (Kiefer et al., 2011), and its liver expression is increased in obesity and correlates with steatosis and insulin resistance (Gómez‐Ambrosi et al., 2007).…”

“…OPN expression is also upregulated in liver cancers such as in HCC and cholangiocarcinoma (Wen, Jeong, Xia, & Kong, 2016; Zheng et al., 2018). Regarding its role as a metabolic modulator, it controls the fate of acetyl‐CoA in liver (Nunez‐Garcia et al., 2017; Nuñez‐Garcia et al., 2018) and rewires liver lipid metabolism after partial hepatectomy (Nuñez‐Garcia et al., 2018). OPN is considered a senescence‐associated secretory phenotype (SASP) factor (Flanagan et al., 2017; Pazolli et al., 2009).…”

Atorvastatin provides a new lipidome improving early regeneration after partial hepatectomy in osteopontin deficient mice

“…It also modulates the activation and proliferation of several cell types during regeneration 16 . Recently, we reported that OPN controls de novo FA synthesis in hepatocytes and that liver PC concentration is regulated by circulating OPN 17 . In fact, high levels of OPN increase liver PC concentration, while PC concentration is low in OPN deficient mice 17 .…”

“…Recently, we reported that OPN controls de novo FA synthesis in hepatocytes and that liver PC concentration is regulated by circulating OPN 17 . In fact, high levels of OPN increase liver PC concentration, while PC concentration is low in OPN deficient mice 17 . We also found that inhibiting de novo cholesterogenesis, which is increased in OPN-KO mice liver, results in the restoration of PC concentration in OPN-KO mice, exemplifying the cross-talk between these metabolic pathways 17 .…”