"Metabolite-protein covariation architecture identified a cysteine shunt regulating liver cholesterol
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive HF-X, Orbitrap Exploris 120
ORGANISM(S): Homo Sapiens (ncbitaxon:9606) Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
Edward T. Chouchani
PROVIDER: MSV000098306 | MassIVE | Tue Jun 24 11:36:00 BST 2025
REPOSITORIES: MassIVE
Similar Datasets
Project description:Metabolomics raw data for manuscript Xiao, H. et al. "Metabolite-protein covariation architecture identified a cysteine shunt regulating liver cholesterol".
2025-06-24 | MSV000098306 | GNPS
Project description:Protein regulation of metabolic processes is foundational to biology. Here we develop a mass spectrometry-based approach that leverages genetic diversity to nominate functional relationships between 285 metabolites and 11,868 proteins in living tissues. This Metabolite Protein Covariation Architecture (MPCA) recapitulates protein-metabolite functional relationships mediated by direct physical interactions and local metabolic pathway regulation, while nominating 3,542 relationships not previously described. Using MPCA, we discover a mechanism of regulation over liver cysteine utilization and cholesterol handling, regulated by the poorly characterized protein leucine rich repeats-containing protein 58 (LRRC58). We show that LRRC58 is the substrate adaptor of an E3 ubiquitin ligase that mediates proteasomal degradation of CDO1, the rate-limiting enzyme of the hypotaurine-taurine pathway1. Cysteine abundance regulates LRRC58-mediated CDO1 degradation, and depletion of LRRC58 is sufficient to stabilize CDO1 to drive consumption of cysteine to produce taurine. Taurine is central to cholesterol handling by promoting its excretion from the liver2, and we show that depletion of LRRC58 in hepatocytes elevates cysteine flux to taurine, and is sufficient to lower hepatic cholesterol in mice. Uncovering a mechanism of LRRC58 regulation over the cysteine shunt to taurine exemplifies the utility of MPCA as a platform to identify modes of protein regulation of metabolic processes.
2025-07-28 | PXD065355 | Pride
Project description:Deoxycholic acid (DCA) is a secondary bile acid produced by a small number of commensal species of bacteria present in the mammalian gut. Elevated DCA concentration correlates with disease states including colon cancer and cholesterol gallstones, but the associated mechanisms are not fully understood. Both primary and secondary bile acids are also capable of affecting gene expression through nuclear receptors such as FXR. To better understand the impact of a commensal-derived secondary bile acid on host metabolism we fed DCA to germ-free (GF) mice, which normally lack DCA, and compared the hepatic transcriptomes of bile acid fed GF mice to GF mice receiving a control diet, as well as to those of conventionally housed control animals. Interestingly, the feeding of DCA to GF mice, but not the feeding of cholic acid (CA) from which DCA is derived, results in an up-regulation of genes of cholesterol biosynthetic pathways. GF mice normally have elevated hepatic cholesterol compared to conventionally housed mice. Despite increase in the expression of cholesterol biosynthetic genes, the DCA fed GF mice showed a markedly decreased level of hepatic cholesterol equivalent to the hepatic cholesterol concentration of conventionally colonized animals. Total cholesterol in the serum was unaffected by DCA, but there was a decrease in the HDL lipoprotein fraction as well as an increase in the non-HDL lipoprotein fraction of the serum cholesterol. DCA, but not CA, is sufficient to modulate host lipoprotein metabolism. Taken together, these results suggests that a minor component of the gut microbiome has a significant impact on cholesterol homeostasis through secondary metabolism of bile acids and suggests a possible therapeutic intervention route through the microbial metabolic pathways. two mouse strains, three diets, one time point
2015-01-08 | E-GEOD-34730 | biostudies-arrayexpress
Project description:Deoxycholic acid (DCA) is a secondary bile acid produced by a small number of commensal species of bacteria present in the mammalian gut. Elevated DCA concentration correlates with disease states including colon cancer and cholesterol gallstones, but the associated mechanisms are not fully understood. Both primary and secondary bile acids are also capable of affecting gene expression through nuclear receptors such as FXR. To better understand the impact of a commensal-derived secondary bile acid on host metabolism we fed DCA to germ-free (GF) mice, which normally lack DCA, and compared the hepatic transcriptomes of bile acid fed GF mice to GF mice receiving a control diet, as well as to those of conventionally housed control animals. Interestingly, the feeding of DCA to GF mice, but not the feeding of cholic acid (CA) from which DCA is derived, results in an up-regulation of genes of cholesterol biosynthetic pathways. GF mice normally have elevated hepatic cholesterol compared to conventionally housed mice. Despite increase in the expression of cholesterol biosynthetic genes, the DCA fed GF mice showed a markedly decreased level of hepatic cholesterol equivalent to the hepatic cholesterol concentration of conventionally colonized animals. Total cholesterol in the serum was unaffected by DCA, but there was a decrease in the HDL lipoprotein fraction as well as an increase in the non-HDL lipoprotein fraction of the serum cholesterol. DCA, but not CA, is sufficient to modulate host lipoprotein metabolism. Taken together, these results suggests that a minor component of the gut microbiome has a significant impact on cholesterol homeostasis through secondary metabolism of bile acids and suggests a possible therapeutic intervention route through the microbial metabolic pathways.
2015-01-08 | GSE34730 | GEO
Project description:Despite considerable progress understanding genes that affect the HDL particle, its function, and cholesterol content, genes identified to date explain only a small percentage of the genetic variation. We used N-ethyl-N-nitrosourea mutagenesis in mice to discover novel genes that affect HDL cholesterol levels. Two mutant lines (Hlb218 and Hlb320) with low HDL cholesterol levels were established. Causal mutations in these lines were mapped using linkage analysis: For line Hlb218 within a 12 Mbp region on Chr 10; and for line Hlb320 within a 17 Mbp region on Chr 7. High-throughput sequencing of Hlb218 liver RNA identified a mutation in Pla2g12b. The transition of G to A leads to a cysteine to tyrosine change and most likely causes a loss of a disulfide bridge. Microarray analysis of Hlb320 liver RNA showed a 7-fold downregulation of Hpn; sequencing identified a mutation in the 3M-bM-^@M-2 splice site of exon 8. Northern blot confirmed lower mRNA expression level in Hlb320 and did not show a difference in splicing, suggesting that the mutation only affects the splicing rate. In addition to affecting HDL cholesterol, the mutated genes also lead to reduction in serum non-HDL cholesterol and triglyceride levels. Despite low HDL cholesterol levels, the mice from both mutant lines show similar atherosclerotic lesion sizes compared to control mice. These new mutant mouse models are valuable tools to further study the role of these genes, their affect on HDL cholesterol levels, and metabolism. Mutant mice were generated as part of The Jackson LaboratoryM-bM-^@M-^Ys Heart, Lung, Blood, and Sleep Disorder Mutagenesis Program by treating male C57BL/6J (B6) mice with N-ethyl-N-nitrosourea (ENU). Third generation (G3) mice were phenotyped to ensure capture of both dominant and recessive mutations. Two unique G3 animals with low HDL cholesterol levels were then used to establish new inbred lines (Hlb218 and Hlb320) by mating them with B6 mice and intercrossing the offspring with low HDL cholesterol for 7 generations. Livers from 3 Hlb218, 3 Hlb320 males, and 6 B6 male controls were obtained for gene expression analysis. The samples were randomized over Illumina Mouse-6 Expression 1.1 BeadChips .
2012-06-30 | E-GEOD-37902 | biostudies-arrayexpress
Project description:Despite considerable progress understanding genes that affect the HDL particle, its function, and cholesterol content, genes identified to date explain only a small percentage of the genetic variation. We used N-ethyl-N-nitrosourea mutagenesis in mice to discover novel genes that affect HDL cholesterol levels. Two mutant lines (Hlb218 and Hlb320) with low HDL cholesterol levels were established. Causal mutations in these lines were mapped using linkage analysis: For line Hlb218 within a 12 Mbp region on Chr 10; and for line Hlb320 within a 17 Mbp region on Chr 7. High-throughput sequencing of Hlb218 liver RNA identified a mutation in Pla2g12b. The transition of G to A leads to a cysteine to tyrosine change and most likely causes a loss of a disulfide bridge. Microarray analysis of Hlb320 liver RNA showed a 7-fold downregulation of Hpn; sequencing identified a mutation in the 3′ splice site of exon 8. Northern blot confirmed lower mRNA expression level in Hlb320 and did not show a difference in splicing, suggesting that the mutation only affects the splicing rate. In addition to affecting HDL cholesterol, the mutated genes also lead to reduction in serum non-HDL cholesterol and triglyceride levels. Despite low HDL cholesterol levels, the mice from both mutant lines show similar atherosclerotic lesion sizes compared to control mice. These new mutant mouse models are valuable tools to further study the role of these genes, their affect on HDL cholesterol levels, and metabolism.
2012-07-01 | GSE37902 | GEO
Project description:Astrocytes engage in metabolic interactions with nearby neurons by supplying various substances. However, how they regulate learning and memory through changes in the metabolic state of neurons is still unclear. In this study, we show that knocking down astrocytic hepaCAM silences genes related to cholesterol biosynthesis in astrocytes, leading to a decrease in cholesterol levels. Additionally, astrocytes play a crucial role in synapse development and function by releasing signals that guide neurons. Consequently, without enough cholesterol, the level of neuronal synaptic proteins and the density of dendritic spines decrease. Then we demonstrate that knocking down hepaCAM leads to impaired learning and memory in mice. Collectively, hepaCAM, a cell adhesion molecules specifically expressed in astrocytes, regulates learning and memory by regulating the cholesterol synthesis pathway.
2025-07-01 | GSE280264 | GEO
Project description:An improved mechanistic understanding of the thyroid hormone (TH) action on bile acid (BA) synthetic pathway, the major route for cholesterol elimination, will facilitate the identification of novel therapeutic targets for hypercholesterolemia. Here, we show that hepatic miR-378 is positively regulated by TH. Transient overexpression of miR-378 in the liver of mice reduces the serum cholesterol levels, which is accompanied with an upregulation of key enzymes involved in the intrahepatic conversion of cholesterol to BAs. Importantly, transgenic mice with liver-specific and moderate overexpression of miR-378 also display a decrease in serum cholesterol levels accompanied with an enhanced BA synthesis and are resistant to diet-induced hypercholesterolemia. In contrast, mice lacking miR-378 exhibit an elevation of serum cholesterol levels accompanied with an impaired BA synthesis. Mechanistic studies reveal that hepatic miR-378 regulates BA synthesis and cholesterol homeostasis through its direct target gene MAFG, which is a transcriptional repressor of BA synthetic genes. We also show that miR-378 serves as an essential component in either incoherent or coherent feed-forward loop to confer robust and precise controls on BA synthesis in response to TH signalling. Together, we identify a previously undescribed miR-378-mediated mechanism underlying the cholesterol-lowering effect of TH. Our findings not only add a new dimension to our understanding the regulation of BA synthesis by TH, but also provide new therapeutic regimens to manage serum cholesterol levels
2019-10-29 | GSE139491 | GEO
Project description:We designed CRISPR-Cas9 whole genome screens to identify and rank critical genes for cholesterol metabolism in modified LDL treated BMDMs
2024-11-01 | GSE190474 | GEO
Project description:β-Glucocerebrosidase (GBA) hydrolyzes glucosylceramide (GlcCer) to generate ceramide. Previously, we demonstrated that lysosomal GBA1 and nonlysosomal GBA2 possess not only GlcCer hydrolase activity, but also transglucosylation activity to transfer the glucose residue from GlcCer to cholesterol to form β-cholesterylglucoside (β-GlcChol) in vitro β-GlcChol is a member of sterylglycosides present in diverse species. How GBA1 and GBA2 mediate β-GlcChol metabolism in the brain is unknown. Here, we purified and characterized sterylglycosides from rodent and fish brains. Although glucose is thought to be the sole carbohydrate component of sterylglycosides in vertebrates, structural analysis of rat brain sterylglycosides revealed the presence of galactosylated cholesterol (β-GalChol), in addition to β-GlcChol. Analyses of brain tissues from GBA2-deficient mice and GBA1- and/or GBA2-deficient Japanese rice fish (Oryzias latipes) revealed that GBA1 and GBA2 are responsible for β-GlcChol degradation and formation, respectively, and that both GBA1 and GBA2 are responsible for β-GalChol formation. Liquid chromatography-tandem MS revealed that β-GlcChol and β-GalChol are present throughout development from embryo to adult in the mouse brain. We found that β-GalChol expression depends on galactosylceramide (GalCer), and developmental onset of β-GalChol biosynthesis appeared to be during myelination. We also found that β-GlcChol and β-GalChol are secreted from neurons and glial cells in association with exosomes. In vitro enzyme assays confirmed that GBA1 and GBA2 have transgalactosylation activity to transfer the galactose residue from GalCer to cholesterol to form β-GalChol. This is the first report of the existence of β-GalChol in vertebrates and how β-GlcChol and β-GalChol are formed in the brain.
| S-EPMC7170530 | biostudies-literature