Endocytic adaptors Arh and Dab2 control homeostasis of circulatory cholesterol

J Lipid Res. 2016 May;57(5):809-17. doi: 10.1194/jlr.M063065. Epub 2016 Mar 22.

Abstract

High serum cholesterol (hypercholesterolemia) strongly associates with cardiovascular diseases as the atherogenic LDLs promote atheroma development in arteries (atherosclerosis). LDL clearance from the circulation by LDL receptor (LDLR)-mediated endocytosis by hepatic and peripheral tissues and subsequent feedback regulation of endogenous synthesis of cholesterol is a key determinant of serum LDL level. Human mutation analysis revealed that autosomal recessive hypercholesterolemia (ARH), an LDLR endocytic adaptor, perturbs LDLR function and thus impacts serum cholesterol levels. In our genetic analysis of mutant mice, we found that deletion of another LDLR endocytic adaptor, Disabled-2 (Dab2), only slightly affected serum cholesterol levels. However, elimination of both arh and dab2 genes in mice resulted in profound hypercholesterolemia similar to that resulting from ldlr homozygous deletion. In the liver, Dab2 is expressed in sinusoid endothelial cells but not in hepatocytes. When deleting both Dab2 and Arh, HMG-CoA reductase level increased to the level similar to that of ldlr knockout. Thus, in the absence of Arh, Dab2 in liver endothelial cells regulates cholesterol synthesis in hepatocytes. We conclude that the combination of Arh and Dab2 is responsible for the majority of adaptor function in LDLR endocytosis and LDLR-mediated cholesterol homeostasis.

Keywords: Disabled-2; autosomal recessive hypercholesterolemia; endocytic trafficking; low density liproprotein; low density liproprotein receptor; serum cholesterol.

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology*
  • Adaptor Proteins, Vesicular Transport / physiology*
  • Animals
  • Apoptosis Regulatory Proteins
  • Atherosclerosis / blood
  • Atherosclerosis / etiology
  • Cells, Cultured
  • Cholesterol / blood*
  • Endocytosis*
  • Female
  • Gene Expression
  • Homeostasis
  • Hypercholesterolemia / blood*
  • Hypercholesterolemia / complications
  • Lipoproteins, LDL / metabolism
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Apoptosis Regulatory Proteins
  • Dab2 protein, mouse
  • Ldlrap1 protein, mouse
  • Lipoproteins, LDL
  • Receptors, LDL
  • Cholesterol