Cell type-specific control of cardiometabolic disease by the dileucine motif of the LDL receptor-related protein LRP1.

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 (Lrp1LL) or harboring DVGGVLL4488 to DVGGVAA4488 mutation (Lrp1AA) after feeding a Western-type high-fat high-cholesterol diet. Results showed comparable body weight gain and overall fat mass between Lrp1LLLdlr-/- and Lrp1AALdlr-/- mice, but less adipocyte hypertrophy and adipose tissue inflammation, as well as reduced hepatosteatosis in the mutant Lrp1AALdlr-/- 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 Lrp1AALdlr-/- mice after oxidized LDL (oxLDL) or LPS activation, resulting in suppression of acute leukocyte inflammatory response. Despite this apparent anti-inflammatory response, the Lrp1AALdlr-/- mice displayed exaggerated atherosclerosis. Reciprocal bone marrow transplant experiments revealed that the Lrp1LL to Lrp1AA mutation in bone marrow-derived cells was responsible for the atherosclerosis increase. Mechanistically, the data showed that Lrp1AA 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 Lrp1AALdlr-/- 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.