Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2 through competitive oxidation

Wang, Yongjian; Bian, Yan; Luo, Jie; Lü, Ming; Xiong, Ying; Guo, Shuyuan; Yin, Huiyong; Lin, Xu; Li, Qin; Chang, Catherine C.Y.; Chang, Ta−Yuan; Li, Bo-Liang; Song, Bao-Liang

doi:10.1038/ncb3551

Cited by 95 publications

(74 citation statements)

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“…including ABCA1, ABCG1, ABCG5 and ABCG8, or converted to less toxic cholesteryl esters (CEs) by acyl-coenzyme A:cholesterol acyltransferases (ACATs; also known as SOATs) and then stored in lipid droplets or secreted within lipoproteins 14,15 .…”

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Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

2020

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C holesterol is vital for the survival and growth of mammalian cells. More than a membrane constituent, cholesterol is a precursor to bile acids and steroid hormones, which can initiate or promote colon, breast and prostate cancers 1-3 . Cholesterol can also modulate signalling pathways involved in tumourigenesis and cancer progression by covalently modifying proteins including hedgehog and smoothened 4,5 , and by facilitating the formation of specialized membrane microdomains 6,7 . Brief overview of cholesterol metabolismEvery mammalian cell can synthesize cholesterol through the mevalonate pathway (Fig. 1a). Two acetyl-CoA molecules in the cytosol condense, thus forming acetoacetyl-CoA, which reacts with the third acetyl-CoA and yields 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). HMG-CoA is reduced to mevalonate by HMG-CoA reductase (HMGCR), the primary rate-limiting enzyme in cholesterol biosynthesis. A series of enzymatic reactions convert mevalonate to farnesyl pyrophosphate (FPP), a precursor of sterols and all non-sterol isoprenoids. The condensation of two FPP molecules to squalene commits the process to sterol production. FPP also gives rise to geranylgeranyl pyrophosphate (GGPP), and both FPP and GGPP can prenylate and activate several oncogenic proteins such as Ras 8 . Squalene is then oxidized by squalene epoxidase (SQLE) to 2,3-epoxysqualene, which is cyclized to lanosterol. In the next steps, lanosterol follows the Bloch pathway, the Kandutsch-Russell pathway or a hybrid pathway before it is finally converted to cholesterol.Beyond de novo cholesterol biosynthesis, most cells acquire cholesterol from low-density lipoprotein (LDL) taken up from the circulation via LDL receptor (LDLR)-mediated endocytosis 9 . Enterocytes absorb dietary cholesterol from the intestinal lumen in a process involving the cholesterol transporter NPC1L1, the clathrin adaptor NUMB and the adaptor protein LIMA1 (refs. 10-12 ). Cholesterol within the cell is dynamically transported, reaching the destined membranes for structural and functional needs 13 . Cholesterol in excess of the current cellular demand is either exported from the cell by ATP-binding cassette (ABC) transporters, Reprogrammed cholesterol metabolism in cancer cellsHallmark features of cancer cholesterol metabolism. As fastproliferating cells, cancer cells require high levels of cholesterol for membrane biogenesis and other functional needs. For example, the cholesterol-derived oncometabolite 6-oxo-cholestan-3β,5α-diol, which is enriched in patients with breast cancer, binds glucocorticoid receptors and subsequently promotes tumour growth 19 . In general, cholesterol metabolism substantially contributes to cancer progression, including cell proliferation, migration and invasion 20-23 .Cholesterol metabolism produces essential membrane components as well as metabolites with a variety of biological functions. In the tumour microenvironment, cell-intrinsic and cell-extrinsic cues reprogram cholesterol metabolism and consequently promote tumourigenesis. Cholesterol-de...

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Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

2020

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“…2c, d). Because ubiquitin can also be covalently attached to the SH moiety of cysteine residues 17,18 , we next replaced the cysteine residues on the cytoplasmic side with alanines ( Fig. 2c).…”

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confidence: 99%

“…Next, we compared the ubiquitylation level of Insig-2 in the absence or presence of DL-Dithiothreitol (DTT) and beta-mercaptoethanol (BME). These reducing agents can disrupt the thioester bond between ubiquitin and cysteine residues, producing unubiquitylated proteins with smaller molecular mass 18 . Indeed, addition of DTT and BME apparently downshifted the transfected Insig-2 protein to its original molecular weight of~33 kDa (Fig.…”

Section: Resultsmentioning

confidence: 99%

Competitive oxidation and ubiquitylation on the evolutionarily conserved cysteine confer tissue-specific stabilization of Insig-2

Zhou

Liu

et al. 2020

Nat Commun

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Insig-2 is an ER membrane protein negatively controlling lipid biosynthesis. Here, we find that Insig-2 is increased in the tissues, including liver, but unaltered in the muscle of gp78deficient mice. In hepatocytes and undifferentiated C2C12 myoblasts, Insig-2 is ubiquitylated on Cys215 by gp78 and degraded. However, the C215 residue is oxidized by elevated reactive oxygen species (ROS) during C2C12 myoblasts differentiating into myotubes, preventing Insig-2 from ubiquitylation and degradation. The stabilized Insig-2 downregulates lipogenesis through inhibiting the SREBP pathway, helping to channel the carbon flux to ATP generation and protecting myotubes from lipid over-accumulation. Evolutionary analysis shows that the YECK (in which C represents Cys215 in human Insig-2) tetrapeptide sequence in Insig-2 is highly conserved in amniotes but not in aquatic amphibians and fishes, suggesting it may have been shaped by differential selection. Together, this study suggests that competitive oxidation-ubiquitylation on Cys215 of Insig-2 senses ROS and prevents muscle cells from lipid accumulation.

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“…Fatty acids and cholesterol are essential lipids involved in lots of crucial biological processes, however, excessive free fatty acids and free cholesterol are major risk factors for type 2 diabetes and atherosclerosis [35]. Previous studies on intermediate metabolites in cholesterol biosynthesis have showed that squalene epoxidase (SQLE) acts as a crucial regulator downstream HMG-CoA reductase in cholesterol synthesis and the rst oxygenation step in cholesterol biosynthesis catalyzed by SQLE [36].…”

Section: Discussionmentioning

confidence: 99%

Weighted gene co-expression network analysis to identify key modules and hub genes related to hyperlipidaemia

Liao

Zheng

Guan

et al. 2020

Preprint

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Background: The purpose of this study was to explore the potential molecular targets of hyperlipidaemia and the related molecular mechanisms.Methods: The microarray data set of GSE66676 obtained from patients with hyperlipidaemia was downloaded. The weighted gene co‑expression network (WGCNA) analysis was used to analyze the gene expression profile and royalblue module was considered as the highest correlation. Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and genomes (KEGG) pathway enrichment analyses were implemented for the identification of genes in the royalblue module using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool (version 6.8; http://david.abcc.ncifcrf.gov). A protein-protein interaction (PPI) network was established by using the online STRING tool. Then, several hub genes were identified by the MCODE and cytoHubba plug-ins in Cytoscape software.Results: The significant module (royalblue) identified was associated with TC, TG and Non-HDL-C. GO and KEGG enrichment analyses revealed that the genes in the royalblue module were associated with carbon metabolism, steroid biosynthesis, fatty acid metabolism and biosynthesis of unsaturated fatty acids pathways. SQLE (degree = 17) was revealed as key molecules that associated with hypercholesterolemia (HCH) and SCD was revealed as key molecules that associated with hypertriglyceridemia (HTG). Meanwhile, RT-qPCR analysis also confirmed the above results based on our HCH/HTG samples.Conclusions: SQLE and SCD are related to hyperlipidaemia, SQLE/SCD may be new targets for cholesterol-lowering or triglyceride-lowering therapy, respectively.

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Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2 through competitive oxidation

Cited by 95 publications

References 50 publications

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

Competitive oxidation and ubiquitylation on the evolutionarily conserved cysteine confer tissue-specific stabilization of Insig-2

Weighted gene co-expression network analysis to identify key modules and hub genes related to hyperlipidaemia

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