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. IntroductionIncreased hepatic VLDL secretion is a characteristic feature of type 2 diabetes and obesity, leading to dyslipidemia characterized by increased triglycerides (TGs) and apoB levels, increased VLDL and LDL cholesterol, reduced HDL, and increased atherosclerosis (1-4). apoB is the major apolipoprotein of VLDL and LDL, which transport TGs and cholesterol from the liver into the bloodstream (5). The regulation of hepatic apoB secretion occurs primarily on a posttranscriptional level and appears to involve intracellular protein degradation both in the ER and post-Golgi (6, 7). The mechanisms underlying the dysregulation of VLDL apoB secretion in obesity are poorly understood.Recently, human GWAS have identified several novel genetic loci associated with LDL cholesterol levels and coronary artery disease risk. SNPs at a widely replicated chromosome 1p13 locus have been associated with myocardial infarction (MI) and with total and LDL cholesterol levels (8-10). The minor alleles at this locus are present in approximately 20%-35% of individuals of mixed European descent, and homozygosity for the minor alleles, as opposed to homozygosity for the major alleles, is associated with a 20%-40%

Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism

“…Our current study also reveals a previously unrecognized function of SORT1 in regulating LDLR protein levels in hepatocytes. This finding is consistent with recent reports demonstrating that SORT1 deficiency leads to increased plasma LDL cholesterol, 29,40 and provides an additional mechanism that may contribute to this outcome. In addition, our results may also provide an explanation why genetic ablation or silencing of SORT1 resulted in a less pronounced increase in plasma LDLcholesterol on a Ldlr −/− background.…”

Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice

“…Palmitate is a strong inducer of ER stress in hepatocytes ( 34 ). One recent study reports that sort1 gene transcription is repressed in obese mice by mechanisms involving activation of ER stress, mTORC1, and an ER stress-induced transcriptional factor ATF3 ( 35 ). Our results showed decreased hepatic Sort1 mRNA in Western diet-fed mice but not in ob / ob mice or in human steatotic livers.…”

mTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion

“…This effect of insulin on LDLR protein expression is mediated in part by mTORC1 activity (34). In addition, mTORC1 activity represses sortillin 1, which in addition to apoB metabolism, contributes to VLDL-TAG export (35). In this study, we identified another major role of mTORC1 in the regulation of lipid export and neutral lipid content in liver.…”