Activation of ER stress and mTORC1 suppresses hepatic sortilin-1 levels in obese mice
Ding Ai, … , Daniel J. Rader, Alan R. Tall
Ding Ai, … , Daniel J. Rader, Alan R. Tall
Published April 2, 2012
Citation Information: J Clin Invest. 2012;122(5):1677-1687. https://doi.org/10.1172/JCI61248.
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Research Article Metabolism

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

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.

Authors

Ding Ai, Juan M. Baez, Hongfeng Jiang, Donna M. Conlon, Antonio Hernandez-Ono, Maria Frank-Kamenetsky, Stuart Milstein, Kevin Fitzgerald, Andrew J. Murphy, Connie W. Woo, Alanna Strong, Henry N. Ginsberg, Ira Tabas, Daniel J. Rader, Alan R. Tall

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Figure 8

Atf3 deficiency rescued sortilin-1 expression and reduced apoB production in ob/ob mice.

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Atf3 deficiency rescued sortilin-1 expression and reduced apoB productio...
(A) WT and ob/ob mice were injected with control or Atf3 siRNA, and expression of Atf3 and sortilin-1 was measured by Western blot. (B) Mice were fasted for 5 hours before TritonWR1339 and 35S-methionine injection. TG secretion was measured at the indicated times after injection. ANOVA revealed significant differences for both treatment (F6,34 = 3.103, P = 0.0156) and time point (#P < 0.05, control vs. Atf3 siRNA in ob/ob animals at 1.5 hours, Bonferroni post-test). (C) Representative autoradiogram showing plasma apoB at the 2-hour time point. (D) Quantification of relative apoB levels of WT and ob/ob mice was performed by cutting out apoB100 and apoB48 bands for each sample and counting. *P < 0.05, unpaired t test.