Autophagy is required for sortilin-mediated degradation of apolipoprotein B100

Jaume Amengual, Liang Guo, Alanna Strong, Julio Madrigal-Matute, Haizhen Wang, Susmita Kaushik, Jeffrey L. Brodsky, Daniel J. Rader, Ana Maria Cuervo, Edward A. Fisher

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Rationale: Genome-wide association studies identifed single-nucleotide polymorphisms near the SORT1 locus strongly associated with decreased plasma LDL-C (low-density lipoprotein cholesterol) levels and protection from atherosclerotic cardiovascular disease and myocardial infarction. The minor allele of the causal SORT1 singlenucleotide polymorphism locus creates a putative C/EBPa (CCAAT/enhancer-binding protein a)-binding site in the SORT1 promoter, thereby increasing in homozygotes sortilin expression by 12-fold in liver, which is rich in this transcription factor. Our previous studies in mice have showed reductions in plasma LDL-C and its principal protein component, apoB (apolipoprotein B) with increased SORT1 expression, and in vitro studies suggested that sortilin promoted the presecretory lysosomal degradation of apoB associated with the LDL precursor, VLDL (very-low-density lipoprotein). Objective: To determine directly that SORT1 overexpression results in apoB degradation and to identify the mechanisms by which this reduces apoB and VLDL secretion by the liver, thereby contributing to understanding the clinical phenotype of lower LDL-C levels. Methods and Results: Pulse-chase studies directly established that SORT1 overexpression results in apoB degradation. As noted above, previous work implicated a role for lysosomes in this degradation. Through in vitro and in vivo studies, we now demonstrate that the sortilin-mediated route of apoB to lysosomes is unconventional and intersects with autophagy. Increased expression of sortilin diverts more apoB away from secretion, with both proteins traffcking to the endosomal compartment in vesicles that fuse with autophagosomes to form amphisomes. The amphisomes then merge with lysosomes. Furthermore, we show that sortilin itself is a regulator of autophagy and that its activity is scaled to the level of apoB synthesis. Conclusions: These results strongly suggest that an unconventional lysosomal targeting process dependent on autophagy degrades apoB that was diverted from the secretory pathway by sortilin and provides a mechanism contributing to the reduced LDL-C found in individuals with SORT1 overexpression.

Original languageEnglish (US)
Pages (from-to)568-582
Number of pages15
JournalCirculation Research
Volume122
Issue number4
DOIs
StatePublished - Feb 1 2018

Fingerprint

Apolipoproteins
Autophagy
Apolipoproteins B
LDL Cholesterol
Lysosomes
VLDL Lipoproteins
CCAAT-Enhancer-Binding Proteins
sortilin
Secretory Pathway
Genome-Wide Association Study
Liver
Homozygote
Protein Binding
Single Nucleotide Polymorphism
Proteins
Transcription Factors
Cardiovascular Diseases
Alleles
Myocardial Infarction
Binding Sites

Keywords

  • Amphisomes
  • apoB100
  • Autophagy
  • Liver
  • Sortilin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Amengual, J., Guo, L., Strong, A., Madrigal-Matute, J., Wang, H., Kaushik, S., ... Fisher, E. A. (2018). Autophagy is required for sortilin-mediated degradation of apolipoprotein B100. Circulation Research, 122(4), 568-582. https://doi.org/10.1161/CIRCRESAHA.117.311240

Autophagy is required for sortilin-mediated degradation of apolipoprotein B100. / Amengual, Jaume; Guo, Liang; Strong, Alanna; Madrigal-Matute, Julio; Wang, Haizhen; Kaushik, Susmita; Brodsky, Jeffrey L.; Rader, Daniel J.; Cuervo, Ana Maria; Fisher, Edward A.

In: Circulation Research, Vol. 122, No. 4, 01.02.2018, p. 568-582.

Research output: Contribution to journalArticle

Amengual, J, Guo, L, Strong, A, Madrigal-Matute, J, Wang, H, Kaushik, S, Brodsky, JL, Rader, DJ, Cuervo, AM & Fisher, EA 2018, 'Autophagy is required for sortilin-mediated degradation of apolipoprotein B100', Circulation Research, vol. 122, no. 4, pp. 568-582. https://doi.org/10.1161/CIRCRESAHA.117.311240
Amengual, Jaume ; Guo, Liang ; Strong, Alanna ; Madrigal-Matute, Julio ; Wang, Haizhen ; Kaushik, Susmita ; Brodsky, Jeffrey L. ; Rader, Daniel J. ; Cuervo, Ana Maria ; Fisher, Edward A. / Autophagy is required for sortilin-mediated degradation of apolipoprotein B100. In: Circulation Research. 2018 ; Vol. 122, No. 4. pp. 568-582.
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AU - Wang, Haizhen

AU - Kaushik, Susmita

AU - Brodsky, Jeffrey L.

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