Elevation of urinary methylmolonic acid induces the suppression of megalin-mediated endocytotic cycles during vitamin B12 deficiency

Biochem Biophys Res Commun. 2015 Sep 18;465(2):206-12. doi: 10.1016/j.bbrc.2015.07.151. Epub 2015 Aug 4.

Abstract

Megalin is a scavenger receptor that serves in the endocytosis of a highly diverse group of ligands that includes Vitamin B12. We found an accumulation of megalin closed to apical region in renal proximal tubule cells of Vitamin B12-deficient rats. Interestingly, Vitamin B12 levels also controlled resorption of renal retinol binding protein. Using L2 yolk sac cells, megalin localized to the submembrane compartment by methylmalonic acid (MMA), which accumulates during vitamin B12 deficiency. In addition, MMA inhibited megalin-mediated endocytosis via YWTD repeats motif in an ectodomain of megalin. Therefore, megalin endocytosis may be regulated by MMA.

Keywords: Dab2; Endocytosis; Megalin; Methylmolonic acid; Vitamin B(12).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Suckling
  • Cell Line
  • Endocytosis*
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Kidney Tubules, Proximal / metabolism*
  • Kidney Tubules, Proximal / physiopathology
  • Low Density Lipoprotein Receptor-Related Protein-2 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-2 / metabolism*
  • Methylmalonic Acid / pharmacology
  • Methylmalonic Acid / urine*
  • Rats
  • Rats, Wistar
  • Retinol-Binding Proteins / genetics
  • Retinol-Binding Proteins / metabolism
  • Signal Transduction
  • Vitamin B 12 / metabolism*
  • Vitamin B 12 Deficiency / genetics
  • Vitamin B 12 Deficiency / metabolism*
  • Vitamin B 12 Deficiency / physiopathology
  • Yolk Sac / cytology
  • Yolk Sac / drug effects
  • Yolk Sac / metabolism

Substances

  • Low Density Lipoprotein Receptor-Related Protein-2
  • Retinol-Binding Proteins
  • Methylmalonic Acid
  • Vitamin B 12