Hepatocyte-derived ApoE is more effective than non-hepatocyte-derived ApoE in remnant lipoprotein clearance

Robert L. Raffaï, Alyssa H. Hasty, Yuwei Wang, Shelley E. Mettler, David A. Sanan, MacRae F. Linton, Sergio Fazio, Karl H. Weisgraber

Research output: Contribution to journalArticle

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Abstract

The importance of hepatocyte-derived apolipoprotein (apo) E in the clearance of remnant lipoproteins in the liver is controversial. To address this controversy, we compared remnant clearance in two mouse models in which apoE is primarily derived either from hepatocytes or from an extrahepatic source. Hypomorphic apoE mice universally express reduced levels of apoE in all tissues, with the liver remaining the primary source of apoE. This mouse model of hepatocyte-derived apoE was compared with Apoe-/- mice transplanted with mouse bone marrow as a model of primarily non-hepatocyte-derived apoE. Immunohistochemical analysis of liver sections revealed that only the hepatocyte-derived apoE model had detectable levels of apoE on hepatic sinusoidal surfaces. The non-hepatocyte-derived apoE model with plasma apoE levels similar to those in the hepatocyte-derived model had 2-fold more total plasma cholesterol, 4-fold more total plasma triglycerides, and 8-fold higher levels of apoB48, similar to Apoe-/- mice. Both the hepatocyte-derived and the non-hepatocyte-derived apoE models had delayed clearance of an infused bolus of 125I-labeled remnants compared with wild-type mice. However, after 3 h, plasma remnants reached wild-type levels only in the hepatocyte-derived apoE model, which had accumulated 70 ± 5% of wild-type levels of remnants in the liver while the non-hepatocyte-derived apoE model had accumulated only 38 ± 4%. These results demonstrate the existence of a role for both hepatically derived and localized apoE in remnant clearance. This role likely represents the enrichment of remnants sequestered on hepatocyte, with hepatocyte-derived apoE, facilitating their receptor-mediated internalization.

Original languageEnglish (US)
Pages (from-to)11670-11675
Number of pages6
JournalJournal of Biological Chemistry
Volume278
Issue number13
DOIs
StatePublished - Mar 28 2003
Externally publishedYes

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Apolipoproteins E
Lipoproteins
Hepatocytes
Liver
Plasmas
Apolipoprotein B-48

ASJC Scopus subject areas

  • Biochemistry

Cite this

Raffaï, R. L., Hasty, A. H., Wang, Y., Mettler, S. E., Sanan, D. A., Linton, M. F., ... Weisgraber, K. H. (2003). Hepatocyte-derived ApoE is more effective than non-hepatocyte-derived ApoE in remnant lipoprotein clearance. Journal of Biological Chemistry, 278(13), 11670-11675. https://doi.org/10.1074/jbc.M212873200

Hepatocyte-derived ApoE is more effective than non-hepatocyte-derived ApoE in remnant lipoprotein clearance. / Raffaï, Robert L.; Hasty, Alyssa H.; Wang, Yuwei; Mettler, Shelley E.; Sanan, David A.; Linton, MacRae F.; Fazio, Sergio; Weisgraber, Karl H.

In: Journal of Biological Chemistry, Vol. 278, No. 13, 28.03.2003, p. 11670-11675.

Research output: Contribution to journalArticle

Raffaï, RL, Hasty, AH, Wang, Y, Mettler, SE, Sanan, DA, Linton, MF, Fazio, S & Weisgraber, KH 2003, 'Hepatocyte-derived ApoE is more effective than non-hepatocyte-derived ApoE in remnant lipoprotein clearance', Journal of Biological Chemistry, vol. 278, no. 13, pp. 11670-11675. https://doi.org/10.1074/jbc.M212873200
Raffaï, Robert L. ; Hasty, Alyssa H. ; Wang, Yuwei ; Mettler, Shelley E. ; Sanan, David A. ; Linton, MacRae F. ; Fazio, Sergio ; Weisgraber, Karl H. / Hepatocyte-derived ApoE is more effective than non-hepatocyte-derived ApoE in remnant lipoprotein clearance. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 13. pp. 11670-11675.
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AU - Raffaï, Robert L.

AU - Hasty, Alyssa H.

AU - Wang, Yuwei

AU - Mettler, Shelley E.

AU - Sanan, David A.

AU - Linton, MacRae F.

AU - Fazio, Sergio

AU - Weisgraber, Karl H.

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AB - The importance of hepatocyte-derived apolipoprotein (apo) E in the clearance of remnant lipoproteins in the liver is controversial. To address this controversy, we compared remnant clearance in two mouse models in which apoE is primarily derived either from hepatocytes or from an extrahepatic source. Hypomorphic apoE mice universally express reduced levels of apoE in all tissues, with the liver remaining the primary source of apoE. This mouse model of hepatocyte-derived apoE was compared with Apoe-/- mice transplanted with mouse bone marrow as a model of primarily non-hepatocyte-derived apoE. Immunohistochemical analysis of liver sections revealed that only the hepatocyte-derived apoE model had detectable levels of apoE on hepatic sinusoidal surfaces. The non-hepatocyte-derived apoE model with plasma apoE levels similar to those in the hepatocyte-derived model had 2-fold more total plasma cholesterol, 4-fold more total plasma triglycerides, and 8-fold higher levels of apoB48, similar to Apoe-/- mice. Both the hepatocyte-derived and the non-hepatocyte-derived apoE models had delayed clearance of an infused bolus of 125I-labeled remnants compared with wild-type mice. However, after 3 h, plasma remnants reached wild-type levels only in the hepatocyte-derived apoE model, which had accumulated 70 ± 5% of wild-type levels of remnants in the liver while the non-hepatocyte-derived apoE model had accumulated only 38 ± 4%. These results demonstrate the existence of a role for both hepatically derived and localized apoE in remnant clearance. This role likely represents the enrichment of remnants sequestered on hepatocyte, with hepatocyte-derived apoE, facilitating their receptor-mediated internalization.

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