Sidt2 regulates hepatocellular lipid metabolism through autophagy

Chen, Xueru; Gu, Xuefan; Zhang, Huiwen

doi:10.1194/jlr.m073817

Cited by 33 publications

(45 citation statements)

References 42 publications

(20 reference statements)

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“…Other studies have identified a role of Sidt2 also in lipid metabolism. Sidt2 -deficient mice developed an increase in serum of TG, FFAs and liver transaminases, indicating an impaired of liver function [ 16 , 19 , 22 ]. Recently, Mendez-Acevedo et al suggested that SIDT2 is involved in cholesterol transport, but not in RNA transport [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, SIDT2 has been related to lipid and glucose metabolism. Several investigations carried out in Sidt2-/- mice showed that the absence of this gene generates an increase in the TG and free fatty acids (FFA) levels in serum [ 18 , 19 ]. However, it could be involved in several functions, such as maintenance of the integrity of membrane and digestion and transport of lysosomal-products [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

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The Variant rs1784042 of the SIDT2 Gene is Associated with Metabolic Syndrome through Low HDL-c Levels in a Mexican Population

León-Reyes

Rivera‐Paredez

Fernández-López

et al. 2020

Genes

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The Mexican population has one of the highest prevalences of metabolic syndrome (MetS) worldwide. The aim of this study was to investigate the association of single-nucleotide polymorphisms (SNPs) with MetS and its components. First, we performed a pilot Genome-wide association study (GWAS) scan on a sub-sample derived from the Health Workers Cohort Study (HWCS) (n = 411). Based on GWAS results, we selected the rs1784042 and rs17120425 SNPs in the SIDT1 transmembrane family member 2 (SIDT2) gene for replication in the entire cohort (n = 1963), using predesigned TaqMan assays. We observed a prevalence of MetS in the HWCS of 52.6%. The minor allele frequency for the variant rs17120425 was 10% and 29% for the rs1784042. The SNP rs1784042 showed an overall association with MetS (OR = 0.82, p = 0.01) and with low levels of high-density lipoprotein (HDL-c) (odds ratio (OR) = 0.77, p = 0.001). The SNP rs17120425 had a significant association with type 2 diabetes (T2D) risk in the overall population (OR = 1.39, p = 0.033). Our results suggest an association of the rs1784042 and rs17120425 variants with MetS, through different mechanisms in the Mexican population. Further studies in larger samples and other populations are required to validate these findings and the relevance of these SNPs in MetS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Variant rs1784042 of the SIDT2 Gene is Associated with Metabolic Syndrome through Low HDL-c Levels in a Mexican Population

León-Reyes

Rivera‐Paredez

Fernández-López

et al. 2020

Genes

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“…For example, mice lacking SIDT2 demonstrate impaired glucose tolerance, decreased serum insulin levels, and defective insulin secretion (Chang et al., 2016, Gao et al., 2013, Yu et al., 2015). Two recent studies also demonstrated that Sidt2 −/− mice develop non-alcoholic fatty liver disease (Chen et al., 2018, Gao et al., 2016), with one suggesting that this is due to induction of endoplasmic reticulum stress (Gao et al., 2016) and the other proposing that it is the result of defective autophagy (Chen et al., 2018). Finally, work from our group has also demonstrated a potential role for SIDT2 in tumorigenesis (Brady et al., 2011).…”

Section: Introductionmentioning

confidence: 99%

SIDT2 RNA Transporter Promotes Lung and Gastrointestinal Tumor Development

et al. 2019

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SummaryRNautophagy is a newly described type of selective autophagy whereby cellular RNAs are transported into lysosomes for degradation. This process involves the transmembrane protein SIDT2, which transports double-stranded RNA (dsRNA) across the endolysosomal membrane. We previously demonstrated that SIDT2 is a transcriptional target of p53, but its role in tumorigenesis, if any, is unclear. Unexpectedly, we show here that Sidt2−/− mice with concurrent oncogenic KrasG12D activation develop significantly fewer tumors than littermate controls in a mouse model of lung adenocarcinoma. Consistent with this observation, loss of SIDT2 also leads to enhanced survival and delayed tumor development in an Apcmin/+ mouse model of intestinal cancer. Within the intestine, Apcmin/+;Sidt2−/− mice display accumulation of dsRNA in association with increased phosphorylation of eIF2α and JNK as well as elevated rates of apoptosis. Taken together, our data demonstrate a role for SIDT2, and by extension RNautophagy, in promoting tumor development.

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“…Cytosolic dsRNAs are bound by RNA-dependent protein kinase (PKR), leading to its autophosphorylation and activation 18 . Activated PKR subsequently phosphorylates the α subunit of protein synthesis initiation factor eIF2 (eIF2α), resulting in inhibition of protein translation as well as anti-viral and anti-tumor effects (10,11). We therefore wished to determine whether the accumulation of dsRNA in cells deficient for SIDT2 was likely to activate PKR.…”

Section: Sidt2 Is Required To Prevent Dsrna Accumulation and Pkr/eif2mentioning

confidence: 99%

“…For example, mice lacking SIDT2 demonstrate impaired glucose tolerance, decreased serum insulin levels, and defective insulin secretion [7][8][9] . Two recent studies also demonstrated that Sidt2 -/mice develop non-alcoholic fatty liver disease (NAFLD) 10,11 , with one suggesting that this is due to induction of endoplasmic reticulum stress 10 and the other proposing that it is the result of defective autophagy 11 . Finally, work from our group has also demonstrated a potential role for SIDT2 in tumorigenesis 12 .…”

Section: Introductionmentioning

confidence: 99%

SIDT2 RNA transporter promotes lung and gastrointestinal tumor development

Nguyen

Bieging-Rolett

Putoczki

et al. 2019

Preprint

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RNautophagy is a newly-described type of selective autophagy whereby cellular RNAs are transported into lysosomes for degradation. This process involves the transmembrane protein SIDT2, which transports double-stranded RNA (dsRNA) across the endolysosomal membrane. We previously demonstrated that SIDT2 is a transcriptional target of p53, but its role in tumorigenesis -if any -is unclear. Unexpectedly, we show here that Sidt2 -/mice with concurrent oncogenic Kras G12D activation develop significantly fewer tumors than littermate controls in a mouse model of lung adenocarcinoma (LUAD). Consistent with this observation, loss of SIDT2 also leads to enhanced survival and delayed tumor development in an Apc min/+ mouse model of intestinal cancer. Within the intestine, Apc min/+ ;Sidt2 -/mice display accumulation of dsRNA in association with increased phosphorylation of eIF2α and JNK as well as elevated rates of apoptosis. Taken together, our data demonstrate a role for SIDT2 -and by extension RNautophagy -in promoting tumor development.

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Sidt2 regulates hepatocellular lipid metabolism through autophagy

Cited by 33 publications

References 42 publications

The Variant rs1784042 of the SIDT2 Gene is Associated with Metabolic Syndrome through Low HDL-c Levels in a Mexican Population

The Variant rs1784042 of the SIDT2 Gene is Associated with Metabolic Syndrome through Low HDL-c Levels in a Mexican Population

SIDT2 RNA Transporter Promotes Lung and Gastrointestinal Tumor Development

SIDT2 RNA transporter promotes lung and gastrointestinal tumor development

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