Loss of the nutrient receptor Tas1R3 reduces atherosclerotic plaque accumulation and hepatic steatosis in ApoE-/- mice

Abstract

The taste receptor type I (Tas1R) family consists of three G protein-coupled receptors (T1R1, T1R2, and T1R3) that form heterodimers recognizing sweet compounds (T1R2/T1R3) or amino acids (T1R1/T1R3). These receptors are nutrient sensors that facilitate appropriate physiological responses with nutrient availability. However, their contribution to the development of pathologies associated with overnutrition (e.g., atherosclerosis) is unclear. The aim of the present study was to determine if T1R3 deletion would reduce atherosclerotic plaque development in mice. We generated atherosclerotic mice with whole-body deletion of T1R3 by crossing T1R3^-/- mice with ApoE^-/- mice. T1R3^+/+ ApoE^-/- and T1R3^-/- ApoE^-/- mice were maintained on an atherogenic high-fat diet for 8 weeks. Weight gain and food consumption were measured during the 8-week diet. Atherosclerotic lesion development and size were assessed by en face analysis of intact aortas and microscopic analysis of aortic roots. Our results indicate that T1R3 deletion in male and female ApoE^-/- mice reduces aortic atherosclerotic plaque accumulation. Hepatic triglyceride accumulation, which was measured by quantification of oil red O staining, was also reduced in T1R3^-/- mice. While the ablation of T1R3 reduced the final body weight of both males and females by approximately 12%, serum lipids, insulin, and glucose were either unchanged or slightly reduced. Immunoblot analysis of the phosphorylation of p70S6K, an effector of mTORC1, suggests T1R3 ablation reduces mTORC1 activity by approximately 50% in the male livers. Collectively, these findings suggest that the whole-body deletion of T1R3 reduces atherosclerosis and hepatic steatosis in a manner largely independent of the measured effects on whole-body glucose and lipid homeostasis.

Keywords: ApoE; Atherosclerosis; Hepatic steatosis; Hyperinsulinemia; T1R1; T1R2; T1R3; Tas1R1; Tas1R2; Tas1R3; Taste receptor; mTORC1.