Xue B

References (20)

Title : IL-13 induced inflammation increases DPP4 abundance but does not enhance MERS-CoV replication in airway epithelia - Li_2023_J.Infect.Dis__
Author(s) : Li K , Bartlett JA , Wohlford-Lenane CL , Xue B , Thurman AL , Gallagher TM , Pezzulo AA , McCray PB
Ref : J Infect Dis , : , 2023
Abstract : BACKGROUND: Chronic pulmonary conditions such as asthma and COPD increase the risk of morbidity and mortality during infection with the Middle East respiratory syndrome coronavirus (MERS-CoV). We hypothesized that individuals with such comorbidities are more susceptible to MERS-CoV infection due to increased expression of its receptor, dipeptidyl peptidase 4 (DPP4). METHODS: We modeled chronic airway disease by treating primary human airway epithelia with the Th2 cytokine IL-13, examining how this impacted DPP4 protein levels along with MERS-CoV entry and replication. RESULTS: IL-13 exposure for 3 days led to increased DPP4 protein abundance, while a 21-day treatment increased DPP4 levels and caused goblet cell metaplasia. Surprisingly, despite this increase in receptor availability, MERS-CoV entry and replication were not significantly impacted by IL-13 treatment. CONCLUSIONS: Our results suggest that increased DPP4 abundance is likely not the primary mechanism leading to increased MERS severity in the setting of Th2 inflammation. Transcriptional profiling analysis highlighted the complexity of IL-13 induced changes in airway epithelia, including altered expression of genes involved in innate immunity, antiviral responses, and maintenance of the extracellular mucus barrier. These data suggest that additional factors likely interact with DPP4 abundance to determine MERS-CoV infection outcomes.
ESTHER : Li_2023_J.Infect.Dis__
PubMedSearch : Li_2023_J.Infect.Dis__
PubMedID: 37698016

Title : Structure-based molecular docking and molecular dynamics simulations study for the identification of dipeptidyl peptidase 4 inhibitors in type 2 diabetes - Chen_2023_J.Biomol.Struct.Dyn__1
Author(s) : Chen X , Xue B , Wahab S , Sultan A , Khalid M , Yang S
Ref : J Biomol Struct Dyn , :1 , 2023
Abstract : Inhibition of dipeptidyl peptidase-4 (DPP4) activity has emerged as a promising therapeutic approach for the treatment of type 2 diabetes mellitus (T2DM). Bioinformatics-driven approaches have emerged as crucial tools in drug discovery. Molecular docking and molecular dynamics (MD) simulations are effective tools in drug discovery, as they reduce the time and cost associated with experimental screening. In this study, we employed structure-assisted in-silico methods, including molecular docking and MD simulations, to identify SRT2183, a small molecule that may potentially inhibit the activity of DPP4 enzyme. The interaction between the small molecule "SRT2183" and DPP4 exhibited a binding affinity of -9.9 Kcal/Mol, leading to the formation of hydrogen bonds with the amino acid residues MET348, SER376, and THR351 of DPP4. The MD simulations over a period of 100 ns indicated stable protein-ligand interactions, with no significant conformational rearrangements observed within the simulated timeframe. In conclusion, our results suggest that the small molecule SRT2183 may have the potential to inhibit the DPP4 enzyme and pave the way for the therapeutics of T2DM.Communicated by Ramaswamy H. Sarma.
ESTHER : Chen_2023_J.Biomol.Struct.Dyn__1
PubMedSearch : Chen_2023_J.Biomol.Struct.Dyn__1
PubMedID: 38100564

Title : A Novel Lipase from Lasiodiplodia theobromae Efficiently Hydrolyses C8-C10 Methyl Esters for the Preparation of Medium-Chain Triglycerides' Precursors - Ng_2021_Int.J.Mol.Sci_22_10339
Author(s) : Ng AMJ , Yang R , Zhang H , Xue B , Yew WS , Nguyen GKT
Ref : Int J Mol Sci , 22 : , 2021
Abstract : Medium-chain triglycerides (MCTs) are an emerging choice to treat neurodegenerative disorders such as Alzheimer's disease. They are triesters of glycerol and three medium-chain fatty acids, such as capric (C8) and caprylic (C10) acids. The availability of C8-C10 methyl esters (C8-C10 ME) from vegetable oil processes has presented an opportunity to use methyl esters as raw materials for the synthesis of MCTs. However, there are few reports on enzymes that can efficiently hydrolyse C8-C10 ME to industrial specifications. Here, we report the discovery and identification of a novel lipase from Lasiodiplodia theobromae fungus (LTL1), which hydrolyses C8-C10 ME efficiently. LTL1 can perform hydrolysis over pH ranges from 3.0 to 9.0 and maintain thermotolerance up to 70 degreesC. It has high selectivity for monoesters over triesters and displays higher activity over commercially available lipases for C8-C10 ME to achieve 96.17% hydrolysis within 31 h. Structural analysis by protein X-ray crystallography revealed LTL1's well-conserved lipase core domain, together with a partially resolved N-terminal subdomain and an inserted loop, which may suggest its hydrolytic preference for monoesters. In conclusion, our results suggest that LTL1 provides a tractable route towards to production of C8-C10 fatty acids from methyl esters for the synthesis of MCTs.
ESTHER : Ng_2021_Int.J.Mol.Sci_22_10339
PubMedSearch : Ng_2021_Int.J.Mol.Sci_22_10339
PubMedID: 34638680
Gene_locus related to this paper: 9pezi-a0a5n5dna6

Title : Antidiabetic Agent DPP-4i Facilitates Murine Breast Cancer Metastasis by Oncogenic ROS-NRF2-HO-1 Axis via a Positive NRF2-HO-1 Feedback Loop - Li_2021_Front.Oncol_11_679816
Author(s) : Li R , Zeng X , Yang M , Xu X , Feng J , Bao L , Xue B , Wang X , Huang Y
Ref : Front Oncol , 11 :679816 , 2021
Abstract : Cancer has been as one of common comorbidities of diabetes. Long-term antidiabetic treatment may potentially exert uncertain impacts on diabetic patients with cancer including breast cancer (BC). Dipeptidyl peptidase-4 inhibitors (DPP-4i) are currently recommended by the AACE as first-line hypoglycemic drugs in type 2 diabetes mellitus (T2DM). Although the safety of DPP-4i has been widely evaluated, the potential side-effects of DPP-4i in cancer metastasis were also reported and remain controversial. Here, we revealed that Saxagliptin (Sax) and Sitagliptin (Sit), two common DPP-4i compounds, potentially promoted murine BC 4T1 metastasis in vitro and in vivo under immune-deficient status. Mechanically, we observed that DPP-4i treatment induced aberrant oxidative stress by triggering ROS overproduction, as well as ROS-dependent NRF2 and HO-1 activations in BC cells, while specific inhibition of ROS, NRF2 or HO-1 activations abrogated DPP-4i-driven BC metastasis and metastasis-associated gene expression in vitro. Furthermore, ALA, a NRF2 activator significantly promoted BC metastasis in vitro and in vivo, which can be abrogated by specific HO-1 inhibition in vitro. Moreover, specific HO-1 inhibition not only reversed DPP-4i-induced NRF2 activation but also abrogated ALA-induced NRF2 activation, resulting in a decrease of metastasis-associated genes, indicating a positive-feedback NRF2-HO-1 loop. Our findings suggest that DPP-4i accelerates murine BC metastasis through an oncogenic ROS-NRF2-HO-1 axis via a positive-feedback NRF2-HO-1 loop. Therefore, this study not only offers novel insights into an oncogenic role of DPP-4i in BC progression but also provides new strategies to alleviate the dark side of DPP-4i by targeting HO-1.
ESTHER : Li_2021_Front.Oncol_11_679816
PubMedSearch : Li_2021_Front.Oncol_11_679816
PubMedID: 34123848

Title : A Novel Lipase from Lasiodiplodia theobromae Efficiently Hydrolyses C8-C10 Methyl Esters for the Preparation of Medium-Chain Triglycerides' Precursors - Ng_2021_Int.J.Mol.Sci_22_
Author(s) : Ng AMJ , Yang RL , Zhang HF , Xue B , Yew WS , Nguyen GKT
Ref : Int J Mol Sci , 22 : , 2021
Abstract : Medium-chain triglycerides (MCTs) are an emerging choice to treat neurodegenerative disorders such as Alzheimer's disease. They are triesters of glycerol and three medium-chain fatty acids, such as capric (C8) and caprylic (C10) acids. The availability of C8-C10 methyl esters (C8-C10 ME) from vegetable oil processes has presented an opportunity to use methyl esters as raw materials for the synthesis of MCTs. However, there are few reports on enzymes that can efficiently hydrolyse C8-C10 ME to industrial specifications. Here, we report the discovery and identification of a novel lipase from Lasiodiplodia theobromae fungus (LTL1), which hydrolyses C8-C10 ME efficiently. LTL1 can perform hydrolysis over pH ranges from 3.0 to 9.0 and maintain thermotolerance up to 70C. It has high selectivity for monoesters over triesters and displays higher activity over commercially available lipases for C8C10 ME to achieve 96.17% hydrolysis within 31 h. Structural analysis by protein X-ray crystallography revealed LTL1's well-conserved lipase core domain, together with a partially resolved N-terminal subdomain and an inserted loop, which may suggest its hydrolytic preference for monoesters. In conclusion, our results suggest that LTL1 provides a tractable route towards to production of C8-C10 fatty acids from methyl esters for the synthesis of MCTs
ESTHER : Ng_2021_Int.J.Mol.Sci_22_
PubMedSearch : Ng_2021_Int.J.Mol.Sci_22_
PubMedID:

Title : Loss of Abhd5 Promotes Colorectal Tumor Development and Progression by Inducing Aerobic Glycolysis and Epithelial-Mesenchymal Transition -
Author(s) : Ou J , Miao H , Ma Y , Guo F , Deng J , Wei X , Zhou J , Xie G , Shi H , Xue B , Liang H , Yu L
Ref : Cell Rep , 24 :2795 , 2018
PubMedID: 30184511
Gene_locus related to this paper: human-ABHD5

Title : Lipolysis in Brown Adipocytes Is Not Essential for Cold-Induced Thermogenesis in Mice - Shin_2017_Cell.Metab_26_764
Author(s) : Shin H , Ma Y , Chanturiya T , Cao Q , Wang Y , Kadegowda AKG , Jackson R , Rumore D , Xue B , Shi H , Gavrilova O , Yu L
Ref : Cell Metab , 26 :764 , 2017
Abstract : Lipid droplet (LD) lipolysis in brown adipose tissue (BAT) is generally considered to be required for cold-induced nonshivering thermogenesis. Here, we show that mice lacking BAT Comparative Gene Identification-58 (CGI-58), a lipolytic activator essential for the stimulated LD lipolysis, have normal thermogenic capacity and are not cold sensitive. Relative to littermate controls, these animals had higher body temperatures when they were provided food during cold exposure. The increase in body temperature in the fed, cold-exposed knockout mice was associated with increased energy expenditure and with increased sympathetic innervation and browning of white adipose tissue (WAT). Mice lacking CGI-58 in both BAT and WAT were cold sensitive, but only in the fasted state. Thus, LD lipolysis in BAT is not essential for cold-induced nonshivering thermogenesis in vivo. Rather, CGI-58-dependent LD lipolysis in BAT regulates WAT thermogenesis, and our data uncover an essential role of WAT lipolysis in fueling thermogenesis during fasting.
ESTHER : Shin_2017_Cell.Metab_26_764
PubMedSearch : Shin_2017_Cell.Metab_26_764
PubMedID: 28988822

Title : Integrated regulation of AMPA glutamate receptor phosphorylation in the striatum by dopamine and acetylcholine - Xue_2017_Neuropharmacol_112_57
Author(s) : Xue B , Chen EC , He N , Jin DZ , Mao LM , Wang JQ
Ref : Neuropharmacology , 112 :57 , 2017
Abstract : Dopamine (DA) and acetylcholine (ACh) signals converge onto protein kinase A (PKA) in medium spiny neurons of the striatum to control cellular and synaptic activities of these neurons, although underlying molecular mechanisms are less clear. Here we measured phosphorylation of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) at a PKA site (S845) as an indicator of AMPAR responses in adult rat brains in vivo to explore how DA and ACh interact to modulate AMPARs. We found that subtype-selective activation of DA D1 receptors (D1Rs), D2 receptors (D2Rs), or muscarinic M4 receptors (M4Rs) induced specific patterns of GluA1 S845 responses in the striatum. These defined patterns support a local multitransmitter interaction model in which D2Rs inhibited an intrinsic inhibitory element mediated by M4Rs to enhance the D1R efficacy in modulating AMPARs. Consistent with this, selective enhancement of M4R activity by a positive allosteric modulator resumed the cholinergic inhibition of D1Rs. In addition, D1R and D2R coactivation recruited GluA1 and PKA preferentially to extrasynaptic sites. In sum, our in vivo data support an existence of a dynamic DA-ACh balance in the striatum which actively modulates GluA1 AMPAR phosphorylation and trafficking. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.
ESTHER : Xue_2017_Neuropharmacol_112_57
PubMedSearch : Xue_2017_Neuropharmacol_112_57
PubMedID: 27060412

Title : Macrophage ABHD5 promotes colorectal cancer growth by suppressing spermidine production by SRM - Miao_2016_Nat.Commun_7_11716
Author(s) : Miao H , Ou J , Peng Y , Zhang X , Chen Y , Hao L , Xie G , Wang Z , Pang X , Ruan Z , Li J , Yu L , Xue B , Shi H , Shi C , Liang H
Ref : Nat Commun , 7 :11716 , 2016
Abstract : Metabolic reprogramming in stromal cells plays an essential role in regulating tumour growth. The metabolic activities of tumour-associated macrophages (TAMs) in colorectal cancer (CRC) are incompletely characterized. Here, we identify TAM-derived factors and their roles in the development of CRC. We demonstrate that ABHD5, a lipolytic co-activator, is ectopically expressed in CRC-associated macrophages. We demonstrate in vitro and in mouse models that macrophage ABHD5 potentiates growth of CRC cells. Mechanistically, ABHD5 suppresses spermidine synthase (SRM)-dependent spermidine production in macrophages by inhibiting the reactive oxygen species-dependent expression of C/EBPvarepsilon, which activates transcription of the srm gene. Notably, macrophage-specific ABHD5 transgene-induced CRC growth in mice can be prevented by an additional SRM transgene in macrophages. Altogether, our results show that the lipolytic factor ABHD5 suppresses SRM-dependent spermidine production in TAMs and potentiates the growth of CRC. The ABHD5/SRM/spermidine axis in TAMs might represent a potential target for therapy.
ESTHER : Miao_2016_Nat.Commun_7_11716
PubMedSearch : Miao_2016_Nat.Commun_7_11716
PubMedID: 27189574

Title : Expression and effects of mutant Bombyx mori acetylcholinesterase 1 in BmN Cells - Wang_2016_Arch.Insect.Biochem.Physiol_93_110
Author(s) : Wang BB , Xie Y , Li FC , Ni M , Xu KZ , Tian JH , Hu JS , Xue B , Shen WD , Li B
Ref : Archives of Insect Biochemistry & Physiology , 93 :110 , 2016
Abstract : The main mechanism of toxicity of organophosphate (OP) and carbamate (CB) insecticides is their irreversible binding and inhibition of acetylcholinestrase (AChE), encoded by ace1 (acetylcholinestrase gene 1), leading to eventual death of insects. Mutations in AChE may significantly reduce insects susceptibility to these pesticides. Bombyx mori is an important beneficial insect, and no OP- or CB-resistant strains have been generated. In this study, wild-type ace1 (wace1) and mutant ace1 (mace1) were introduced into BmN cells, confirmed by screening and identification. The expression of wace1 and mace1 in the cells was confirmed by Western blot and their expression levels were about 21-fold higher than the endogenous ace1 level. The activities of AChE in wace1 and mace1 transgenic cells were 10.6 and 20.2% higher compared to control cells, respectively. mace1 transgenic cells had higher remaining activity than wace1 transgenic cells under the treatment of physostigmine (a reversible cholinesterase inhibitor) and phoxim (an OP acaricide). The results showed that ace1 transgene can significantly improve ace1 expression, and ace1 mutation at a specific site can reduce the sensitivity to AChE inhibitors. Our study provides a new direction for the exploration of the relationship between AChE mutations and drug resistance.
ESTHER : Wang_2016_Arch.Insect.Biochem.Physiol_93_110
PubMedSearch : Wang_2016_Arch.Insect.Biochem.Physiol_93_110
PubMedID: 27402326
Gene_locus related to this paper: bommo-ACHE1

Title : Muscle-specific deletion of comparative gene identification-58 (CGI-58) causes muscle steatosis but improves insulin sensitivity in male mice - Xie_2015_Endocrinology_156_1648
Author(s) : Xie P , Kadegowda AK , Ma Y , Guo F , Han X , Wang M , Groban L , Xue B , Shi H , Li H , Yu L
Ref : Endocrinology , 156 :1648 , 2015
Abstract : Intramyocellular accumulation of lipids is often associated with insulin resistance. Deficiency of comparative gene identification-58 (CGI-58) causes cytosolic deposition of triglyceride (TG)-rich lipid droplets in most cell types, including muscle due to defective TG hydrolysis. It was unclear, however, whether CGI-58 deficiency-induced lipid accumulation in muscle influences insulin sensitivity. Here we show that muscle-specific CGI-58 knockout mice relative to their controls have increased glucose tolerance and insulin sensitivity on a Western-type high-fat diet, despite TG accumulation in both heart and oxidative skeletal muscle and cholesterol deposition in heart. Although the intracardiomyocellular lipid deposition results in cardiac ventricular fibrosis and systolic dysfunction, muscle-specific CGI-58 knockout mice show increased glucose uptake in heart and soleus muscle, improved insulin signaling in insulin-sensitive tissues, and reduced plasma concentrations of glucose, insulin, and cholesterol. Hepatic contents of TG and cholesterol are also decreased in these animals. Cardiac steatosis is attributable, at least in part, to decreases in cardiac TG hydrolase activity and peroxisome proliferator-activated receptor-alpha/peroxisome proliferator-activated receptor-gamma coactivator-1-dependent mitochondrial fatty acid oxidation. In conclusion, muscle CGI-58 deficiency causes cardiac dysfunction and fat deposition in oxidative muscles but induces a series of favorable metabolic changes in mice fed a high-fat diet.
ESTHER : Xie_2015_Endocrinology_156_1648
PubMedSearch : Xie_2015_Endocrinology_156_1648
PubMedID: 25751639

Title : Macrophage CGI-58 deficiency promotes IL-1beta transcription by activating the SOCS3-FOXO1 pathway - Miao_2015_Clin.Sci.(Lond)_128_493
Author(s) : Miao H , Ou J , Zhang X , Chen Y , Xue B , Shi H , Gan L , Yu L , Liang H
Ref : Clinical Science (Lond) , 128 :493 , 2015
Abstract : Over-nutrition induces low-grade inflammation that dampens insulin sensitivity, but the underlying molecular mediators are not fully understood. Comparative gene identification-58 (CGI-58) is an intracellular lipolytic activator. In the present study, we show that in mouse visceral fat-derived macrophages or human peripheral blood monocytes, CGI-58 negatively and interleukin (IL)-1beta positively correlate with obesity. Saturated non-esterified fatty acid (NEFA) suppresses CGI-58 expression in macrophages and this suppression activates FOXO1 (forkhead box-containing protein O subfamily-1) through inhibition of FOXO1 phosphorylation. Activated FOXO1 binds to an insulin-responsive element in IL-1beta promoter region to potentiate IL-1beta transcription. Gain- and loss-of-function studies demonstrate that NEFA-induced CGI-58 suppression activates FOXO1 to augment IL-1beta transcription by dampening insulin signalling through induction of SOCS3 (suppressor of cytokine signalling 3) expression. CGI-58 deficiency-induced SOCS3 expression is NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome-dependent. Our data thus identified a vicious cycle (IL-1beta-SOCS3-FOXO1-IL-1beta) that amplifies IL-1beta secretion and is initiated by CGI-58 deficiency-induced activation of the NLRP3 inflammasome in macrophages. We further show that blocking this cycle with a FOXO1 inhibitor, an antioxidant that inhibits FOXO1 or IL-1 receptor antagonist alleviates chronic inflammation and insulin resistance in high-fat diet (HFD)-fed mice. Collectively, our data suggest that obesity-associated factors such as NEFA and lipopolysaccharide (LPS) probably adopt this vicious cycle to promote inflammation and insulin resistance.
ESTHER : Miao_2015_Clin.Sci.(Lond)_128_493
PubMedSearch : Miao_2015_Clin.Sci.(Lond)_128_493
PubMedID: 25431838

Title : Intestinal Cgi-58 deficiency reduces postprandial lipid absorption - Xie_2014_PLoS.One_9_e91652
Author(s) : Xie P , Guo F , Ma Y , Zhu H , Wang F , Xue B , Shi H , Yang J , Yu L
Ref : PLoS ONE , 9 :e91652 , 2014
Abstract : Comparative Gene Identification-58 (CGI-58), a lipid droplet (LD)-associated protein, promotes intracellular triglyceride (TG) hydrolysis in vitro. Mutations in human CGI-58 cause TG accumulation in numerous tissues including intestine. Enterocytes are thought not to store TG-rich LDs, but a fatty meal does induce temporary cytosolic accumulation of LDs. Accumulated LDs are eventually cleared out, implying existence of TG hydrolytic machinery in enterocytes. However, identities of proteins responsible for LD-TG hydrolysis remain unknown. Here we report that intestine-specific inactivation of CGI-58 in mice significantly reduces postprandial plasma TG concentrations and intestinal TG hydrolase activity, which is associated with a 4-fold increase in intestinal TG content and large cytosolic LD accumulation in absorptive enterocytes during the fasting state. Intestine-specific CGI-58 knockout mice also display mild yet significant decreases in intestinal fatty acid absorption and oxidation. Surprisingly, inactivation of CGI-58 in intestine significantly raises plasma and intestinal cholesterol, and reduces hepatic cholesterol, without altering intestinal cholesterol absorption and fecal neutral sterol excretion. In conclusion, intestinal CGI-58 is required for efficient postprandial lipoprotein-TG secretion and for maintaining hepatic and plasma lipid homeostasis. Our animal model will serve as a valuable tool to further define how intestinal fat metabolism influences the pathogenesis of metabolic disorders, such as obesity and type 2 diabetes.
ESTHER : Xie_2014_PLoS.One_9_e91652
PubMedSearch : Xie_2014_PLoS.One_9_e91652
PubMedID: 24618586

Title : Loss of abhd5 promotes colorectal tumor development and progression by inducing aerobic glycolysis and epithelial-mesenchymal transition - Ou_2014_Cell.Rep_9_1798
Author(s) : Ou J , Miao H , Ma Y , Guo F , Deng J , Wei X , Zhou J , Xie G , Shi H , Xue B , Liang H , Yu L
Ref : Cell Rep , 9 :1798 , 2014
Abstract : How cancer cells shift metabolism to aerobic glycolysis is largely unknown. Here, we show that deficiency of alpha/beta-hydrolase domain-containing 5 (Abhd5), an intracellular lipolytic activator that is also known as comparative gene identification 58 (CGI-58), promotes this metabolic shift and enhances malignancies of colorectal carcinomas (CRCs). Silencing of Abhd5 in normal fibroblasts induces malignant transformation. Intestine-specific knockout of Abhd5 in Apc(Min/+) mice robustly increases tumorigenesis and malignant transformation of adenomatous polyps. In colon cancer cells, Abhd5 deficiency induces epithelial-mesenchymal transition by suppressing the AMPKalpha-p53 pathway, which is attributable to increased aerobic glycolysis. In human CRCs, Abhd5 expression falls substantially and correlates negatively with malignant features. Our findings link Abhd5 to CRC pathogenesis and suggest that cancer cells develop aerobic glycolysis by suppressing Abhd5-mediated intracellular lipolysis.
ESTHER : Ou_2014_Cell.Rep_9_1798
PubMedSearch : Ou_2014_Cell.Rep_9_1798
PubMedID: 25482557
Gene_locus related to this paper: human-ABHD5

Title : Macrophage CGI-58 deficiency activates ROS-inflammasome pathway to promote insulin resistance in mice - Miao_2014_Cell.Rep_7_223
Author(s) : Miao H , Ou J , Ma Y , Guo F , Yang Z , Wiggins M , Liu C , Song W , Han X , Wang M , Cao Q , Chung BH , Yang D , Liang H , Xue B , Shi H , Gan L , Yu L
Ref : Cell Rep , 7 :223 , 2014
Abstract : Overnutrition activates a proinflammatory program in macrophages to induce insulin resistance (IR), but its molecular mechanisms remain incompletely understood. Here, we show that saturated fatty acid and lipopolysaccharide, two factors implicated in high-fat diet (HFD)-induced IR, suppress macrophage CGI-58 expression. Macrophage-specific CGI-58 knockout (MaKO) in mice aggravates HFD-induced glucose intolerance and IR, which is associated with augmented systemic/tissue inflammation and proinflammatory activation of adipose tissue macrophages. CGI-58-deficient macrophages exhibit mitochondrial dysfunction due to defective peroxisome proliferator-activated receptor (PPAR)gamma signaling. Consequently, they overproduce reactive oxygen species (ROS) to potentiate secretion of proinflammatory cytokines by activating NLRP3 inflammasome. Anti-ROS treatment or NLRP3 silencing prevents CGI-58-deficient macrophages from oversecreting proinflammatory cytokines and from inducing proinflammatory signaling and IR in the cocultured fat slices. Anti-ROS treatment also prevents exacerbation of inflammation and IR in HFD-fed MaKO mice. Our data thus establish CGI-58 as a suppressor of overnutrition-induced NLRP3 inflammasome activation in macrophages.
ESTHER : Miao_2014_Cell.Rep_7_223
PubMedSearch : Miao_2014_Cell.Rep_7_223
PubMedID: 24703845

Title : Deficiency of liver Comparative Gene Identification-58 causes steatohepatitis and fibrosis in mice - Guo_2013_J.Lipid.Res_54_2109
Author(s) : Guo F , Ma Y , Kadegowda AK , Betters JL , Xie P , Liu G , Liu X , Miao H , Ou J , Su X , Zheng Z , Xue B , Shi H , Yu L
Ref : J Lipid Res , 54 :2109 , 2013
Abstract : Triglyceride (TG) accumulation in hepatocytes (hepatic steatosis) preludes the development of advanced nonalcoholic fatty liver diseases (NAFLDs) such as steatohepatitis, fibrosis, and cirrhosis. Mutations in human Comparative Gene Identification-58 (CGI-58) cause cytosolic TG-rich lipid droplets to accumulate in almost all cell types including hepatocytes. However, it is unclear if CGI-58 mutation causes hepatic steatosis locally or via altering lipid metabolism in other tissues. To directly address this question, we created liver-specific CGI-58 knockout (LivKO) mice. LivKO mice on standard chow diet displayed microvesicular and macrovesicular panlobular steatosis, and progressed to advanced NAFLD stages over time, including lobular inflammation and centrilobular fibrosis. Compared with CGI-58 floxed control littermates, LivKO mice showed 8-fold and 52-fold increases in hepatic TG content, which was associated with 40% and 58% decreases in hepatic TG hydrolase activity at 16 and 42 weeks, respectively. Hepatic cholesterol also increased significantly in LivKO mice. At 42 weeks, LivKO mice showed increased hepatic oxidative stress, plasma aminotransferases, and hepatic mRNAs for genes involved in fibrosis and inflammation, such as alpha-smooth muscle actin, collagen type 1 alpha1, tumor necrosis factor alpha, and interleukin-1beta. In conclusion, CGI-58 deficiency in the liver directly causes not only hepatic steatosis but also steatohepatitis and fibrosis.
ESTHER : Guo_2013_J.Lipid.Res_54_2109
PubMedSearch : Guo_2013_J.Lipid.Res_54_2109
PubMedID: 23733885

Title : CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance - Brown_2010_J.Lipid.Res_51_3306
Author(s) : Brown JM , Betters JL , Lord C , Ma Y , Han X , Yang K , Alger HM , Melchior J , Sawyer J , Shah R , Wilson MD , Liu X , Graham MJ , Lee R , Crooke R , Shulman GI , Xue B , Shi H , Yu L
Ref : J Lipid Res , 51 :3306 , 2010
Abstract : Mutations of Comparative Gene Identification-58 (CGI-58) in humans cause triglyceride (TG) accumulation in multiple tissues. Mice genetically lacking CGI-58 die shortly after birth due to a skin barrier defect. To study the role of CGI-58 in integrated lipid and energy metabolism, we utilized antisense oligonucleotides (ASOs) to inhibit CGI-58 expression in adult mice. Treatment with two distinct CGI-58-targeting ASOs resulted in approximately 80-95% knockdown of CGI-58 protein expression in both liver and white adipose tissue. In chow-fed mice, ASO-mediated depletion of CGI-58 did not alter weight gain, plasma TG, or plasma glucose, yet raised hepatic TG levels approximately 4-fold. When challenged with a high-fat diet (HFD), CGI-58 ASO-treated mice were protected against diet-induced obesity, but their hepatic contents of TG, diacylglycerols, and ceramides were all elevated, and intriguingly, their hepatic phosphatidylglycerol content was increased by 10-fold. These hepatic lipid alterations were associated with significant decreases in hepatic TG hydrolase activity, hepatic lipoprotein-TG secretion, and plasma concentrations of ketones, nonesterified fatty acids, and insulin. Additionally, HFD-fed CGI-58 ASO-treated mice were more glucose tolerant and insulin sensitive. Collectively, this work demonstrates that CGI-58 plays a critical role in limiting hepatic steatosis and maintaining hepatic glycerophospholipid homeostasis and has unmasked an unexpected role for CGI-58 in promoting HFD-induced obesity and insulin resistance.
ESTHER : Brown_2010_J.Lipid.Res_51_3306
PubMedSearch : Brown_2010_J.Lipid.Res_51_3306
PubMedID: 20802159
Gene_locus related to this paper: human-ABHD5 , mouse-abhd5

Title : Regulation of gene expression by FSP27 in white and brown adipose tissue - Li_2010_BMC.Genomics_11_446
Author(s) : Li D , Zhang Y , Xu L , Zhou L , Wang Y , Xue B , Wen Z , Li P , Sang J
Ref : BMC Genomics , 11 :446 , 2010
Abstract : BACKGROUND: Brown and white adipose tissues (BAT and WAT) play critical roles in controlling energy homeostasis and in the development of obesity and diabetes. The mouse Fat-Specific protein 27 (FSP27), a member of the cell death-inducing DFF45-like effector (CIDE) family, is expressed in both BAT and WAT and is associated with lipid droplets. Over-expression of FSP27 promotes lipid storage, whereas FSP27 deficient mice have improved insulin sensitivity and are resistant to diet-induced obesity. In addition, FSP27-deficient white adipocytes have reduced lipid storage, smaller lipid droplets, increased mitochondrial activity and a higher expression of several BAT-selective genes. To elucidate the molecular mechanism by which FSP27 controls lipid storage and gene expression in WAT and BAT, we systematically analyzed the gene expression profile of FSP27-deficient WAT by microarray analysis and compared the expression levels of a specific set of genes in WAT and BAT by semi-quantitative real-time PCR analysis.
RESULTS: BAT-selective genes were significantly up-regulated, whereas WAT-selective genes were down-regulated in the WAT of FSP27-deficient mice. The expression of the BAT-selective genes was also dramatically up-regulated in the WAT of leptin/FSP27 double deficient mice. In addition, the expression levels of genes involved in multiple metabolic pathways, including oxidative phosphorylation, the TCA cycle, fatty acid synthesis and fatty acid oxidation, were increased in the FSP27-deficient WAT. In contrast, the expression levels for genes involved in extracellular matrix remodeling, the classic complement pathway and TGF-beta signaling were down-regulated in the FSP27-deficient WAT. Most importantly, the expression levels of regulatory factors that determine BAT identity, such as CEBP alpha/beta, PRDM16 and major components of the cAMP pathway, were markedly up-regulated in the WAT of FSP27-deficient mice. The expression levels of these regulatory factors were also up-regulated in leptin/FSP27 double deficient mice. Interestingly, distinct gene expression profiles were observed in the BAT of FSP27-deficient mice. Taken together, these data suggest that the WAT of FSP27-deficient mice have a gene expression profile similar to that of BAT.
CONCLUSIONS: FSP27 acts as a molecular determinant that controls gene expression for a diversity of metabolic and signaling pathways and, in particular, the expression of regulatory factors, including CEBP alpha/beta, PRDM16 and components of the cAMP signaling pathway, that control the identity of WAT and BAT.
ESTHER : Li_2010_BMC.Genomics_11_446
PubMedSearch : Li_2010_BMC.Genomics_11_446
PubMedID: 20649970

Title : Hydrolysis and soil sorption of insecticide pyraclofos - Yang_2008_J.Environ.Sci.Health.B_43_219
Author(s) : Yang H , Xue B , Li L , Zhou S , Tu Y , Lin C
Ref : J Environ Sci Health B , 43 :219 , 2008
Abstract : The hydrolysis of the insecticide pyraclofos in buffered solutions at pH 5.0, 7.0 and 9.0, and its sorption on four soils of different physicochemical properties were investigated. The results showed that the degradation of pyraclofos in buffered solutions followed pseudo-first-order kinetics. At 40 degrees C, the rate constants for the hydrolysis of pyraclofos at pH 5.0, 7.0 and 9.0 were 0.0214, 0.1293, and 2.1656 d(-1), respectively. Pyraclofos was relatively stable under both acidic and neutral conditions, while it was readily hydrolyzed under basic conditions. The sorption of pyraclofos on four soils was well described by the Freundlich equation. The sorption constant, K(f), increased with an increase in soil organic carbon content, suggesting that organic carbon content was an important factor affecting sorption. The K(oc) values for Xiaoshan clay loam soil, Hangzhou I clay loam soil, Hangzhou II soil, and Fuyang silt loam soil were 30.4, 6.7, 5.3, and 7.1, respectively. These results suggest that the sorption of pyraclofos on the tested soils was relatively weak.
ESTHER : Yang_2008_J.Environ.Sci.Health.B_43_219
PubMedSearch : Yang_2008_J.Environ.Sci.Health.B_43_219
PubMedID: 18368541

Title : Human and rodent carboxylesterases: immunorelatedness, overlapping substrate specificity, differential sensitivity to serine enzyme inhibitors, and tumor-related expression - Xie_2002_Drug.Metab.Dispos_30_541
Author(s) : Xie M , Yang D , Liu L , Xue B , Yan B
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 30 :541 , 2002
Abstract : Carboxylesterases hydrolyze numerous endogenous and foreign compounds with diverse structures. Humans and rodents express multiple forms of carboxylesterases, which share a high degree of sequence identity (approximately 70%). Alignment analyses locate in carboxylesterases several functional subsites such the catalytic triad as seen in acetylcholinesterase. The aim of this study was to determine among human and rodent carboxylesterases the immunorelatedness, overlapping substrate specificity, differential sensitivity to serine enzyme inhibitors, tissue distribution, and tumor-related expression. Six antibodies against whole carboxylesterases or synthetic peptides were tested for their reactivity toward 11 human or rodent recombinant carboxylesterases. The antibodies against whole proteins generally exhibited a broader cross-reactivity than the anti-peptide antibodies. All carboxylesterases hydrolyzed para-nitrophenylacetate and para-nitrophenylbutyrate. However, the relative activity varied markedly from enzyme to enzyme (>20-fold), and some carboxylesterases showed a clear substrate preference. Carboxylesterases with the same functional subsites had a similar profile on substrate specificity and sensitivity toward phenylmethylsulfonyl fluoride (PMSF) and paraoxon, suggesting that these subsites play determinant roles in the recognition of substrates and inhibitors. Among three human carboxylesterases, HCE-1 hydrolyzed both substrates to a similar extent, whereas HCE-2 and HCE-3 showed an opposite substrate preference. All three enzymes were inhibited by PMSF and paraoxon, but they showed a marked difference in relative sensitivities. Based on immunoblotting analyses, HCE-1 was present in all tissues examined, whereas HCE-2 and HCE-3 were expressed in a tissue-restricted pattern. Colon carcinomas expressed slightly higher levels of HCE-1 and HCE-2 than the adjacent normal tissues, whereas the opposite was true with HCE-3.
ESTHER : Xie_2002_Drug.Metab.Dispos_30_541
PubMedSearch : Xie_2002_Drug.Metab.Dispos_30_541
PubMedID: 11950785