Ostα-/- mice exhibit altered expression of intestinal lipid absorption genes, resistance to age- related weight gain, and modestly improved insulin sensitivity

The organic solute transporter OST alpha-OST beta is a key transporter for the efflux of bile acids across the basolateral membrane of ileocytes and the subsequent return of bile acids to the liver. Ost alpha(-/-) mice exhibit reduced bile acid pools and impaired lipid absorption. In this study, wild-type and Ost alpha(-/-) mice were characterized at 5 and 12 mo of age. Ost alpha(-/-) mice were resistant to age-related weight gain, body fat accumulation, and liver and muscle lipid accumulation, and male Ost alpha(-/-) mice lived slightly longer than wild-type mice. Caloric intake and activity levels were similar for Ost alpha(-/-) and wild-type male mice. Fecal lipid excretion was increased in Ost alpha(-/-) mice, indicating that a defect in lipid absorption contributes to decreased fat accumulation. Analysis of genes involved in intestinal lipid absorption revealed changes consistent with decreased dietary lipid absorption in Ost alpha(-/-) animals. Hepatic expression of cholesterol synthetic genes was upregulated in Ost alpha(-/-) mice, showing that increased cholesterol synthesis partially compensated for reduced dietary cholesterol absorption. Glucose tolerance was improved in male Ost alpha(-/-) mice, and insulin sensitivity was improved in male and female Ost alpha(-/-) mice. Akt phosphorylation was measured in liver and muscle tissue from mice after acute administration of insulin. Insulin responses were significantly larger in male and female Ost alpha(-/-) than wild-type mice. These findings indicate that loss of OST alpha-OST beta protects against age-related weight gain and insulin resistance.