ILDR2 Alters Hepatic Phospholipid Composition via MBOAT7—Effects on Liver Fat

Abstract

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes, and increases the risk for liver cirrhosis and cancer. A diabetes susceptibility gene, ILDR2, encodes a transmembrane protein localized to the ER membrane whose primary physiological functions are unclear. We previously purified ILDR2-containing protein complexes using the tandem affinity purification tags and identified MBOAT7, which mediates acyl-chain remodeling of phosphatidylinositols (PIs). The MBOAT7 variant rs641738 T allele is associated with decreased hepatic PI (36:4) and PI (38:3) and an increase in severity of NAFLD. We hypothesized that ILDR2 may influence hepatic Pl composition in NAFLD. We used two mouse models fed a methionine- and choline-deficient (MCD) diet: 1. liver-specific ILDR2 knockout (LKO-ILDR2) using an AAV-Cre/loxP system; and 2. AAV-overexpressing ILDR2 (OX-ILDR2) mice. In LKO-ILDR2 mice compared to AAV-GFP injected ILDR2 floxed (GFP-flox) mice, liver triglyceride (TG) content was significantly increased by 1.6-fold with a significant 1.2-fold increase in plasma TG. In LKO-ILDR2 mice compared to GFP-flox mice, hepatic PI (38:4) was significantly decreased. The livers of LKO-ILDR2 mice showed significantly increased JNK activation, collagen gene expression, and increased in hydroxyproline, suggesting that ILDR2 depletion leads to inflammation and the development of fibrosis. In OX-ILDR2 mice compared to AAV-GFP injected WT (GFP-WT) mice, hepatic PI and PC species were significantly increased. The liver in OX-ILDR2 mice showed decreased expression of JNK and ER stress-related genes, and hydroxyproline, with a slight (9%) decrease in hepatic TG compared to GFP-WT mice. Thus, ILDR2 overexpression attenuated hepatic inflammation, ER stress, and fibrogenesis. Manipulation of hepatic ILDR2 expression is associated with changes in PI and PC molecular species in the liver. Patterns of hepatic phosphatidyl fatty acid composition are associated with NAFLD development. Disclosure K. Watanabe: None. K. Nakayama: None. K. Yoshida: None. E.J. Millings: None. C.A. LeDuc: None. R. Leibel: None. S. Iwamoto: None.