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

Emily Igel; Anja Jaeschke; April Haller; Melissa Asman; Ushodaya Mattam; Jeyashree Alagarsamy; Karthickeyan Chella Krishnan; David Y Hui

doi:10.1016/j.jbc.2026.111421

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

J Biol Chem. 2026 May;302(5):111421. doi: 10.1016/j.jbc.2026.111421. Epub 2026 Mar 31.

Authors

Emily Igel¹, Anja Jaeschke², April Haller², Melissa Asman², Ushodaya Mattam¹, Jeyashree Alagarsamy³, Karthickeyan Chella Krishnan¹, David Y Hui⁴

Affiliations

¹ Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
² Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio USA.
³ Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio USA.
⁴ Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio USA. Electronic address: huidy@ucmail.uc.edu.

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 DVGGVLL⁴⁴⁸⁸ to DVGGVAA⁴⁴⁸⁸ 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^LLLdlr^-/- and Lrp1^AALdlr^-/- mice, but less adipocyte hypertrophy and adipose tissue inflammation, as well as reduced hepatosteatosis in the mutant Lrp1^AALdlr^-/- 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^AALdlr^-/- mice after oxidized LDL (oxLDL) or LPS activation, resulting in suppression of acute leukocyte inflammatory response. Despite this apparent anti-inflammatory response, the Lrp1^AALdlr^-/- 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^AALdlr^-/- 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.

Keywords: atherosclerosis; lipoprotein metabolism; lipoprotein receptor-related protein (LRP); macrophage; peroxisomal proliferator-activated receptor (PPAR).

MeSH terms

Amino Acid Motifs
Animals
Atherosclerosis* / metabolism
Atherosclerosis* / pathology
Low Density Lipoprotein Receptor-Related Protein-1* / chemistry
Low Density Lipoprotein Receptor-Related Protein-1* / genetics
Low Density Lipoprotein Receptor-Related Protein-1* / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptors, LDL / metabolism

Substances

Low Density Lipoprotein Receptor-Related Protein-1
Lrp1 protein, mouse
Receptors, LDL