HMGCS2 promotes autophagic degradation of the amyloid-β precursor protein through ketone body-mediated mechanisms

Hu, Li-Tian; Zhu, Binglin; Lai, Yu‐Jie; Long, Yan; Zha, Jing-Si; Zhang, Junyi; Chen, Guojun

doi:10.1016/j.bbrc.2017.03.069

Cited by 26 publications

(21 citation statements)

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“…3 Functions of significantly differentially expressed genes in placenta. Venn diagrams of function categories for DEGs with known gene ontologies [ 39 , 84 , 85 , 93 , 97 , 98 , 100 – 106 , 114 – 126 ]. Autosome genes are underlined.…”

Section: Resultsmentioning

confidence: 99%

“…Humanin promotes insulin sensitivity which may contribute to increased fetal growth seen in males [ 97 ]. HMGCS2 (1.60-fold upregulated in males) encodes an enzyme that promotes autophagy by catalyzing the first step in ketogenesis, a pathway that derives energy from lipids when carbohydrates are depleted [ 98 ]. This is consistent with previous pregnancy studies that find greater risk for nutrient deficit in males [ 99 ].…”

Section: Discussionmentioning

confidence: 99%

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Sex differences in the late first trimester human placenta transcriptome

et al. 2018

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BackgroundDevelopment of the placenta during the late first trimester is critical to ensure normal growth and development of the fetus. Developmental differences in this window such as sex-specific variation are implicated in later placental disease states, yet gene expression at this time is poorly understood.MethodsRNA-sequencing was performed to characterize the transcriptome of 39 first trimester human placentas using chorionic villi following genetic testing (17 females, 22 males). Gene enrichment analysis was performed to find enriched canonical pathways and gene ontologies in the first trimester. DESeq2 was used to find sexually dimorphic gene expression. Patient demographics were analyzed for sex differences in fetal weight at time of chorionic villus sampling and birth.ResultsRNA-sequencing analyses detected 14,250 expressed genes, with chromosome 19 contributing the greatest proportion (973/2852, 34.1% of chromosome 19 genes) and Y chromosome contributing the least (16/568, 2.8%). Several placenta-enriched genes as well as histone-coding genes were identified to be unique to the first trimester and common to both sexes. Further, we identified 58 genes with significantly different expression between males and females: 25 X-linked, 15 Y-linked, and 18 autosomal genes. Genes that escape X inactivation were highly represented (59.1%) among X-linked genes upregulated in females. Many genes differentially expressed by sex consisted of X/Y gene pairs, suggesting that dosage compensation plays a role in sex differences. These X/Y pairs had roles in parallel, ancient canonical pathways important for eukaryotic cell growth and survival: chromatin modification, transcription, splicing, and translation.ConclusionsThis study is the first characterization of the late first trimester placenta transcriptome, highlighting similarities and differences among the sexes in ongoing human pregnancies resulting in live births. Sexual dimorphism may contribute to pregnancy outcomes, including fetal growth and birth weight, which was seen in our cohort, with males significantly heavier than females at birth. This transcriptome provides a basis for development of early diagnostic tests of placental function that can indicate overall pregnancy heath, fetal-maternal health, and long-term adult health.Electronic supplementary materialThe online version of this article (10.1186/s13293-018-0165-y) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sex differences in the late first trimester human placenta transcriptome

et al. 2018

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“…Control of gene expression mediated by nutritional molecules affects metabolism similarly, although independently, to hormonal regulations and may require the activation of specific transcription factors (Wolfrum, Asilmaz, Luca, Friedman, & Stoffel, 2004). HMGCS2 is a key enzyme that constantly controls ketogenesis, depending on metabolic conditions (Hu et al, 2017;Vilà-Brau, De Sousa-Coelho, Mayordomo, Haro, & Marrero, 2011). It is one of the highest induced genes in liver during fasting (Cheon et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Human mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) catalyzes the first step of ketogenesis, the condensation of acetoacetyl-CoA and acetyl-CoA to form HMG-CoA (Hu et al, 2017). Ketone bodies (β-hydroxybutyrate, acetoacetate, and acetone), which are later produced, are essential products allowing the transfer of energy from liver to extra hepatic tissues like brain, heart, and kidneys (Grabacka, Pierzchalska, Dean, & Reiss, 2016;Robinson & Williamson, 1980;Williamson, Bates, & Krebs, 1968), especially during fat feeding, fasting, and other conditions in which carbohydrate availability is limited (Hegardt, 1999).…”

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confidence: 99%

Involvement of nutrients and nutritional mediators in mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase gene expression

Rescigno

Capasso

Tecce

2017

Journal Cellular Physiology

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Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS2) catalyses the first step of ketogenesis and is critical in various metabolic conditions. Several nutrient molecules were able to differentially modulate HMGCS2 expression levels. Docosahexaenoic acid (DHA, C22:6, n-3), eicosapentaenoic acid (EPA, C20:5, n-3), arachidonic acid (AA, C20:4, n-6), and glucose increased HMGCS2 mRNA and protein levels in HepG2 hepatoma cells, while fructose decreased them. The effect of n-6 AA resulted significantly higher than that of n-3 PUFA, but when combined all these molecules were far less efficient. Insulin reduced HMGCS2 mRNA and protein levels in HepG2 cells, even when treated with PUFA and monosaccharides. Several nuclear receptors and transcription factors are involved in HMGCS2 expression regulation. While peroxysome proliferator activated receptor α (PPAR-α) agonist WY14643 increased HMGCS2 expression, this treatment was unable to affect PUFA-mediated regulation of HMGCS2 expression. Forkhead box O1 (FoxO1) inhibitor AS1842856 reduced HMGCS2 expression and suppressed induction promoted by fatty acids. Cells treatment with liver X receptor alpha (LXRα) agonist T0901317 reduced HMGCS2 mRNA, indicating a role for this transcription factor as suppressor of HMGCS2 gene. Previous observations already indicated HMGCS2 expression as possible nutrition status reference: our results show that several nutrients as well as specific nutritional related hormonal conditions are able to affect significantly HMGCS2 gene expression, indicating a relevant role for PUFA, which are mostly derived from nutritional intake. These insights into mechanisms of its regulation, specifically through nutrients commonly associated with disease risk, indicate HMGCS2 expression as possible reference marker of metabolic and nutritional status.

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“…To further identify how cosmosiin controls the expression of ADAM10 protein, we first assessed the levels of the ADAM10 protein after treatment with transcription inhibitor ActD (0.1 μM for 12 h), translation inhibitor CHX (5 μM for 6 h), proteasome inhibitor MG132 (1 μM for 6 h), and lysosome inhibitor CQ (100 μM for 6 h; Chen et al, 2014 ; Zhan et al, 2016 ; Hu L. T. et al, 2017 ). Under basal conditions, both ActD and CHX significantly decreased the levels of the ADAM10 protein.…”

Section: Resultsmentioning

confidence: 99%

Cosmosiin Increases ADAM10 Expression via Mechanisms Involving 5’UTR and PI3K Signaling

Zhuo

Tang

Zhu

et al. 2018

Front. Mol. Neurosci.

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The α-secretase “a disintegrin and metalloproteinase domain-containing protein” (ADAM10) is involved in the processing of amyloid precursor protein (APP). Upregulation of ADAM10 precludes the generation of neurotoxic β-amyloid protein (Aβ) and represents a plausible therapeutic strategy for Alzheimer’s disease (AD). In this study, we explored compounds that can potentially promote the expression of ADAM10. Therefore, we performed high-throughput small-molecule screening in SH-SY5Y (human neuroblastoma) cells that stably express a luciferase reporter gene driven by the ADAM10 promoter, including a portion of its 5’-untranslated region (5’UTR). This has led to the discovery of cosmosiin (apigenin 7-O-β-glucoside). Here, we report that in human cell lines (SH-SY5Y and HEK293), cosmosiin proportionally increased the levels of the immature and mature forms of the ADAM10 protein without altering its mRNA level. This effect was attenuated by translation inhibitors or by deleting the 5’UTR of ADAM10, suggesting that a translational mechanism was responsible for the increased levels of ADAM10. Luciferase deletion assays revealed that the first 144 nucleotides of the 5’UTR were necessary for mediating the cosmosiin-induced enhancement of ADAM10 expression in SH-SY5Y cells. Cosmosiin failed to increase the levels of the ADAM10 protein in murine cells, which lack native expression of the ADAM10 transcript containing the identified 5’UTR element. The potential signaling pathway may involve phosphatidylinositide 3-kinase (PI3K) because pharmacological inhibition of PI3K attenuated the effect of cosmosiin on the expression of the ADAM10 protein. Finally, cosmosiin attenuated Aβ generation because the levels of Aβ40/42 in HEK-APP cells were significantly reduced after cosmosiin treatment. Collectively, we found that the first 144 nucleotides of the ADAM10 5’UTR, and PI3K signaling, are involved in cosmosiin-induced enhancement of the expression of ADAM10 protein. These results suggest that cosmosiin may be a potential therapeutic agent in the treatment of AD.

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HMGCS2 promotes autophagic degradation of the amyloid-β precursor protein through ketone body-mediated mechanisms

Cited by 26 publications

References 28 publications

Sex differences in the late first trimester human placenta transcriptome

Sex differences in the late first trimester human placenta transcriptome

Involvement of nutrients and nutritional mediators in mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase gene expression

Cosmosiin Increases ADAM10 Expression via Mechanisms Involving 5’UTR and PI3K Signaling

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