Abstract 58: Adipose-Specific Deletion of ARV1 Results in Decreased HDL Cholesterol, Reduced White Adipose Tissue Mass and Improved Glucose Tolerance in Mice

Abstract

ACAT related enzyme 2 required for viability 1 (ARV1) was identified as a gene required for viability in yeast in the absence of cholesterol esterification. ARV1 encodes a putative lipid transporter believed to be important in trafficking of lipids from the ER to the Golgi. ARV1 deficient yeast exhibit profound alterations in cholesterol, phospholipid, and sphingolipid metabolism, accompanied by a constitutively activated unfolded protein response and impaired GPI anchor synthesis. To study the role of ARV1 in mammalian lipid metabolism, we have generated mice with an adipose specific deletion of ARV1 using Cre/loxP technology with Cre expression driven by the Ap2 promoter. ARV1 adipose specific knockout (ASKO) mice exhibited significant reductions in plasma total cholesterol (↓21%, p < 0.05), HDL cholesterol (↓25%, p < 0.01), and phospholipid (↓17.6%, p < 0.05) levels, while fasting triglyceride levels were unaffected. ARV1 ASKO mice also had substantial reductions in epididymal adipose (WT: 0.41 +/- 0.07 g vs. KO: 0.10 +/- 0.07 g, p = 0.0002) and subcutaneous adipose tissue mass (WT: 0.32 +/- 0.03 g vs. KO: 0.11 +/- 0.08 g; p= 0.0002) on a chow diet. In contrast to nearly every other lipodystrophic mouse model, the reduced fat mass in these animals was paradoxically accompanied by improved glucose tolerance (WT AUC: 32,055 vs. KO AUC: 21,470 mg/dl*minutes, p<0.05). These data identify mammalian ARV1 as an important player in adipose tissue biology, and support an important role for adipose tissue in circulating lipoprotein metabolism.