565 Acute Reversal of the Lysosomal Transport Defect in the Liver of the Niemann Pick Type C Mouse

Abstract

Nonalcoholic fatty liver disease (NAFLD) affects up to 30% of adults in the United States and is associated with obesity, metabolic syndrome, type II diabetes and hepatocellular carcinoma (HCC). Here we report spontaneous insulin resistance, NAFLD and HCC with parent-specific inheritance in AxB mice. Helicobacter-free F1 offspring (n=59) from wildtype C57BL/6 and A/JCr parents were maintained on a standard chow diet and evaluated at 3, 9 and 15 months. ABF1 (A/J dam x B6 sire) but not BAF1 males (B6 dam x A/J sire) developed progressively severe mixed microvesicular and macrovesicular hepatic steatosis resulting in sporadic HCC. Females were unaffected. NAFLD in males was a component of metabolic syndrome characterized by hyperinsulinemia, hypercholesterolemia and increased body mass (all P<0.05, unpaired t-test). Liver microarray confirmed widely dysregulated metabolic signaling and immune activation. A comprehensive evaluation of uniparentally expressed transcripts including mitochondrial, imprinted and sex-linked genes by qRT-PCR revealed a disease association with X-linked thyroxine-binding globulin. In a follow-up study using full-length chromosome substitution (consomic) C57BL/6J-ChrX/Y_A/NaJ mice on a standard or high-fat diet, we found an additive contribution from both sex chromosomes on disease phenotype. Our results demonstrate that parent-specific inheritance of insulin resistance in AxB mice is polygenic and regulated in part at the chromosomal level. This is a promising new mouse model to study genetic determinants of insulin resistance, metabolic syndrome and NAFLD.