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PO3-6-31

Crucial role of STARD10 in regulating lipid storage in mouse model of nonalcoholic steatohepatitis (NASH)

[Speaker] Masanori Ito:1
[Co-author] Taichiro Tomida:1, Yoshinori Mikami:1, Shingo Murakami:1, Satomi Adachi-Akahane:1
1:Department of Physiology, Faculty of Medicine, Toho University, Japan

NASH is characterized by lipid accumulation with inflammation and fibrosis in the liver. We have previously shown that STARD10 is highly expressed in the liver. STARD10, steroidogenic acute regulatory protein-related lipid transfer domain containing 10, is a member of the START domain-containing lipid transfer protein family. We have previously shown that STARD10 is highly expressed in the liver and involved in regulating bile acid metabolism. When fed a high fat diet, Stard10 knockout (Stard10-/-) mice accumulated significantly less cholesterol and triglycerides (TG) in the liver than wild type (WT) mice. The purpose of this study was to elucidate the role of STARD10 in lipid accumulation associated with NASH in the liver. NASH model mice were produced by feeding a choline-deficient L-amino acid-defined diet (CDAA). Stard10-/- mice fed CDAA gained weight and epididymal fat in a manner similar to WT mice. However, the liver of Stard10-/- mice was smaller in size and the area of LD in hepatocytes was significantly smaller compared to those of WT mice. Gene expression levels of pro-inflammatory cytokines and fibrosis marker genes were lower in the liver of Stard10-/- mice compared with WT mice. We hypothesized that size of LD should depend on the surface to volume ratio. If the surface to volume ratio is smaller, LD should become Larger. LD surface membrane consists of a single monolayer of phospholipids such as phosphatidylcholine (PC). Lysophosphatidylcholine acyltransferase1 (LPCAT1) catalyzes the conversion of lysophosphatidylcholine to PC. The expression level of LPCAT1 was elevated by CDAA, and a significant difference in PC compositions of LD in the liver was observed between normal diet and CDAA. We showed that STARD10 interacts with LPCAT1 and that STARD10 and LPCAT1 promote LD formation in Hepa1-6 cells. STARD10 was partly co-localized with LPCAT1 at the surface of LDs in hepatocytes. Importantly, we found that STARD10 promotes the formation of large LDs through the interaction with LPCAT1. These results indicate that STARD10 and LPCAT1 play crucial roles in promoting LD formation in mouse NASH model.
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