Abstract
The LDL receptor-related protein-1 (LRP1) modulates cardiometabolic diseases in a cell type-specific manner and is regulated via several motifs in its cytoplasmic domain. This study compared the cardiometabolic disease phenotype of Ldlr(-/-) mice expressing the normal Lrp1 gene (Lrp1(LL)) or harboring DVGGVLL(4488) to DVGGVAA(4488) mutation (Lrp1(AA)) after feeding a Western-type high-fat high-cholesterol diet. Results showed comparable body weight gain and overall fat mass between Lrp1(LL)Ldlr(-/-) and Lrp1(AA)Ldlr(-/-) mice, but less adipocyte hypertrophy and adipose tissue inflammation, as well as reduced hepatosteatosis in the mutant Lrp1(AA)Ldlr(-/-) mice. The reduced hepatosteatosis coincided with reduced expression of cholesterol synthesis genes and increased expression of PPAR-responsive fatty acid oxidation genes in the liver. Elevated expression of PPAR-responsive genes was also observed in blood cells of Lrp1(AA)Ldlr(-/-) mice after oxidized LDL (oxLDL) or LPS activation, resulting in suppression of acute leukocyte inflammatory response. Despite this apparent anti-inflammatory response, the Lrp1(AA)Ldlr(-/-) mice displayed exaggerated atherosclerosis. Reciprocal bone marrow transplant experiments revealed that the Lrp1(LL) to Lrp1(AA) mutation in bone marrow-derived cells was responsible for the atherosclerosis increase. Mechanistically, the data showed that Lrp1(AA) mutation in cholesterol-loaded macrophages caused mitochondrial dysfunction, with lower levels of mitochondrial fission proteins and reduced fatty acid oxidation capabilities. Taken together, these results documented a cell-specific role of the LRP1 proximal dileucine motif in LRP1 modulation of cardiometabolic diseases. The cardiometabolic phenotype of Lrp1(AA)Ldlr(-/-) mice differs from phenotypes observed in mice with LRP1 inactivation or NPxY motif mutation, thus highlighting a unique role of this LRP1 motif in mediating LRP1 functions.