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

Abstract

Osteopontin (OPN), a multifunctional cytokine that controls liver glycerolipid metabolism, is involved in activation and proliferation of several liver cell types during regeneration, a condition of high metabolic demands. Here we investigated the role of OPN in modulating the liver lipidome during regeneration after partial-hepatectomy (PH) and the impact that atorvastatin treatment has over regeneration in OPN knockout (KO) mice. The results showed that OPN deficiency leads to remodeling of phosphatidylcholine and triacylglycerol (TG) species primarily during the first 24 h after PH, with minimal effects on regeneration. Changes in the quiescent liver lipidome in OPN-KO mice included TG enrichment with linoleic acid and were associated with higher lysosome TG-hydrolase activity that maintained 24 h after PH but increased in WT mice. OPN-KO mice showed increased beta-oxidation 24 h after PH with less body weight loss. In OPN-KO mice, atorvastatin treatment induced changes in the lipidome 24 h after PH and improved liver regeneration while no effect was observed 48 h post-PH. These results suggest that increased dietary-lipid uptake in OPN-KO mice provides the metabolic precursors required for regeneration 24 h and 48 h after PH. However, atorvastatin treatment offers a new metabolic program that improves early regeneration when OPN is deficient.

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

“…We previously observed that in young mice, OPN is a regulator of liver lipid metabolism during regeneration after partial hepatectomy (Nuñez‐Garcia et al., 2018). As intermediate‐age (10m) OPN‐KO mice was noted to store more lipids, we investigated the mechanisms by which OPN regulate liver lipid metabolism.…”

“…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).…”