Activation of ER stress and mTORC1 suppresses hepatic sortilin-1 levels in obese mice

J Clin Invest. 2012 May;122(5):1677-87. doi: 10.1172/JCI61248. Epub 2012 Apr 2.

Abstract

Recent GWAS have identified SNPs at a human chromosom1 locus associated with coronary artery disease risk and LDL cholesterol levels. The SNPs are also associated with altered expression of hepatic sortilin-1 (SORT1), which encodes a protein thought to be involved in apoB trafficking and degradation. Here, we investigated the regulation of Sort1 expression in mouse models of obesity. Sort1 expression was markedly repressed in both genetic (ob/ob) and high-fat diet models of obesity; restoration of hepatic sortilin-1 levels resulted in reduced triglyceride and apoB secretion. Mouse models of obesity also exhibit increased hepatic activity of mammalian target of rapamycin complex 1 (mTORC1) and ER stress, and we found that administration of the mTOR inhibitor rapamycin to ob/ob mice reduced ER stress and increased hepatic sortilin-1 levels. Conversely, genetically increased hepatic mTORC1 activity was associated with repressed Sort1 and increased apoB secretion. Treating WT mice with the ER stressor tunicamycin led to marked repression of hepatic sortilin-1 expression, while administration of the chemical chaperone PBA to ob/ob mice led to amelioration of ER stress, increased sortilin-1 expression, and reduced apoB and triglyceride secretion. Moreover, the ER stress target Atf3 acted at the SORT1 promoter region as a transcriptional repressor, whereas knockdown of Atf3 mRNA in ob/ob mice led to increased hepatic sortilin-1 levels and decreased apoB and triglyceride secretion. Thus, in mouse models of obesity, induction of mTORC1 and ER stress led to repression of hepatic Sort1 and increased VLDL secretion via Atf3. This pathway may contribute to dyslipidemia in metabolic disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Activating Transcription Factor 3 / genetics
  • Activating Transcription Factor 3 / metabolism
  • Activating Transcription Factor 3 / physiology
  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Animals
  • Apolipoproteins B / blood
  • Apolipoproteins B / metabolism
  • Base Sequence
  • Binding Sites
  • Diet, High-Fat
  • Down-Regulation
  • Endoplasmic Reticulum Stress*
  • Gene Expression Regulation
  • Humans
  • Lipid Metabolism
  • Lipoproteins, VLDL / blood
  • Lipoproteins, VLDL / metabolism
  • Liver / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Multiprotein Complexes
  • Obesity / metabolism
  • Promoter Regions, Genetic
  • Proteins / antagonists & inhibitors
  • Proteins / genetics
  • Proteins / metabolism*
  • Sirolimus / pharmacology
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • TOR Serine-Threonine Kinases
  • Transcription, Genetic
  • Triglycerides / blood
  • Triglycerides / metabolism
  • fas Receptor / genetics
  • fas Receptor / metabolism

Substances

  • Activating Transcription Factor 3
  • Adaptor Proteins, Vesicular Transport
  • Apolipoproteins B
  • Atf3 protein, mouse
  • Fas protein, mouse
  • Lipoproteins, VLDL
  • Multiprotein Complexes
  • Proteins
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Triglycerides
  • fas Receptor
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus
  • sortilin