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Identification and Characterization of Unique Neutralizing Antibodies to Mouse EGF Receptor.
Jae Huh W, Niitsu H, Carney B, McKinley ET, Houghton JL, Coffey RJ
(2020) Gastroenterology 158: 1500-1502
MeSH Terms: Animals, Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, Azoxymethane, Carcinogens, Cells, Cultured, Colonic Neoplasms, Dextran Sulfate, Disease Models, Animal, ErbB Receptors, Gastritis, Hypertrophic, Genes, Reporter, Hepatocytes, Humans, Mice, Mice, Transgenic, Primary Cell Culture
Added January 31, 2020
1 Communities
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17 MeSH Terms
Surveying heterocycles as amide bioisosteres within a series of mGlu NAMs: Discovery of VU6019278.
Reed CW, Washecheck JP, Quitlag MC, Jenkins MT, Rodriguez AL, Engers DW, Blobaum AL, Jeffrey Conn P, Niswender CM, Lindsley CW
(2019) Bioorg Med Chem Lett 29: 1211-1214
MeSH Terms: Allosteric Regulation, Amides, Animals, Central Nervous System, Hepatocytes, Heterocyclic Compounds, Inhibitory Concentration 50, Pyrazoles, Rats, Receptors, Metabotropic Glutamate, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This letter describes a diversity-oriented library approach to rapidly assess diverse heterocycles as bioisosteric replacements for a metabolically labile amide moiety within a series of mGlu negative allosteric modulators (NAMs). SAR rapidly honed in on either a 1,2,4- or 1,3,4-oxadizaole ring system as an effective bioisostere for the amide. Further optimization of the southern region of the mGlu NAM chemotype led to the discovery of VU6019278, a potent mGlu NAM (IC = 501 nM, 6.3% L-AP Min) with favorable plasma protein binding (rat f = 0.10), low predicted hepatic clearance (rat CL = 27.7 mL/min/kg) and high CNS penetration (rat K = 4.9, K = 0.65).
Copyright © 2019 Elsevier Ltd. All rights reserved.
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MeSH Terms
Isotopic tagging of oxidized and reduced cysteines (iTORC) for detecting and quantifying sulfenic acids, disulfides, and free thiols in cells.
Albertolle ME, Glass SM, Trefts E, Guengerich FP
(2019) J Biol Chem 294: 6522-6530
MeSH Terms: Animals, Benzothiadiazines, Cysteine, Hepatocytes, Isotope Labeling, Male, Mice, Oxidation-Reduction, Sulfenic Acids
Show Abstract · Added March 26, 2019
Oxidative modifications of cysteine residues are an important component in signaling pathways, enzymatic regulation, and redox homeostasis. Current direct and indirect methods detect specific modifications and a general binary population of "free" or "oxidized" cysteines, respectively. In an effort to combine both direct and indirect detection strategies, here we developed a method that we designate isotopic tagging of oxidized and reduced cysteines (iTORC). This method uses synthetic molecules for rapid isotopic coding of sulfenic acids, reduced cysteines, and disulfides in cells. Our approach utilizes isotopically distinct benzothiazine and halogenated benzothiazine probes to sequentially alkylate sulfenic acids and then free thiols and, finally, after a reduction step, cysteines oxidized to disulfides or other phosphine-reducible states. We ascertained that the iodinated benzothiazine probe has reduced cross-reactivity toward primary amines and is highly reactive with the cysteine of GSH, with a calculated rate constant of 2 × 10 m s (pH 8.0, 23 °C) ( 10-20 times faster than ethylmaleimide). We applied iTORC to a mouse hepatocyte lysate to identify known sulfenylated and disulfide-bonded proteins, including elongation factor 1-α1 and mouse serum albumin, and found that iTORC reliably detected their expected oxidation status. This method can be easily employed to study the effects of oxidants on recombinant proteins and cell and tissue extracts, and the efficiencies of the alkylating agents enable completion of all three labeling steps within 2 h. In summary, we demonstrate here that halogenated benzothiazine-based alkylating agents can be utilized to rapidly measure the cellular thiol status in cells.
© 2019 Albertolle et al.
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9 MeSH Terms
Energy metabolism couples hepatocyte integrin-linked kinase to liver glucoregulation and postabsorptive responses of mice in an age-dependent manner.
Trefts E, Hughey CC, Lantier L, Lark DS, Boyd KL, Pozzi A, Zent R, Wasserman DH
(2019) Am J Physiol Endocrinol Metab 316: E1118-E1135
MeSH Terms: Age Factors, Animals, Blood Glucose, Cell Differentiation, Cell Respiration, Energy Metabolism, Gene Knockout Techniques, Glucose, Glucose Tolerance Test, Hepatocytes, Homeostasis, Inflammation, Insulin, Insulin Resistance, Liver, Liver Cirrhosis, Mice, Obesity, Protein-Serine-Threonine Kinases
Show Abstract · Added March 26, 2019
Integrin-linked kinase (ILK) is a critical intracellular signaling node for integrin receptors. Its role in liver development is complex, as ILK deletion at E10.5 (before hepatocyte differentiation) results in biochemical and morphological differences that resolve as mice age. Nevertheless, mice with ILK depleted specifically in hepatocytes are protected from the hepatic insulin resistance during obesity. Despite the potential importance of hepatocyte ILK to metabolic health, it is unknown how ILK controls hepatic metabolism or glucoregulation. The present study tested the role of ILK in hepatic metabolism and glucoregulation by deleting it specifically in hepatocytes, using a cre-lox system that begins expression at E15.5 (after initiation of hepatocyte differentiation). These mice develop the most severe morphological and glucoregulatory abnormalities at 6 wk, but these gradually resolve with age. After identifying when the deletion of ILK caused a severe metabolic phenotype, in depth studies were performed at this time point to define the metabolic programs that coordinate control of glucoregulation that are regulated by ILK. We show that 6-wk-old ILK-deficient mice have higher glucose tolerance and decreased net glycogen synthesis. Additionally, ILK was shown to be necessary for transcription of mitochondrial-related genes, oxidative metabolism, and maintenance of cellular energy status. Thus, ILK is required for maintaining hepatic transcriptional and metabolic programs that sustain oxidative metabolism, which are required for hepatic maintenance of glucose homeostasis.
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19 MeSH Terms
Systemic bile acids induce insulin resistance in a TGR5-independent manner.
Syring KE, Cyphert TJ, Beck TC, Flynn CR, Mignemi NA, McGuinness OP
(2019) Am J Physiol Endocrinol Metab 316: E782-E793
MeSH Terms: Animals, Bile Acids and Salts, Cholagogues and Choleretics, Cholic Acids, Deoxycholic Acid, Gene Expression Profiling, Gluconeogenesis, Glucose Clamp Technique, Hep G2 Cells, Hepatocytes, Humans, Insulin Resistance, Liver, Mice, Mice, Knockout, Obesity, Primary Cell Culture, Receptors, G-Protein-Coupled, Taurocholic Acid
Show Abstract · Added April 15, 2019
Bile acids are involved in the emulsification and absorption of dietary fats, as well as acting as signaling molecules. Recently, bile acid signaling through farnesoid X receptor and G protein-coupled bile acid receptor (TGR5) has been reported to elicit changes in not only bile acid synthesis but also metabolic processes, including the alteration of gluconeogenic gene expression and energy expenditure. A role for bile acids in glucose metabolism is also supported by a correlation between changes in the metabolic state of patients (i.e., obesity or postbariatric surgery) and altered serum bile acid levels. However, despite evidence for a role for bile acids during metabolically challenging settings, the direct effect of elevated bile acids on insulin action in the absence of metabolic disease has yet to be investigated. The present study examines the impact of acutely elevated plasma bile acid levels on insulin sensitivity using hyperinsulinemic-euglycemic clamps. In wild-type mice, elevated bile acids impair hepatic insulin sensitivity by blunting the insulin suppression of hepatic glucose production. The impaired hepatic insulin sensitivity could not be attributed to TGR5 signaling, as TGR5 knockout mice exhibited a similar inhibition of insulin suppression of hepatic glucose production. Canonical insulin signaling pathways, such as hepatic PKB (or Akt) activation, were not perturbed in these animals. Interestingly, bile acid infusion directly into the portal vein did not result in an impairment in hepatic insulin sensitivity. Overall, the data indicate that acute increases in circulating bile acids in lean mice impair hepatic insulin sensitivity via an indirect mechanism.
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19 MeSH Terms
Treating Nonalcoholic Fatty Liver Disease From the Outside In?
Flynn CR
(2019) Cell Mol Gastroenterol Hepatol 7: 682-683
MeSH Terms: Animals, Hepatocytes, Intracellular Signaling Peptides and Proteins, Mice, Non-alcoholic Fatty Liver Disease, Oligonucleotides, Antisense, Protein-Serine-Threonine Kinases
Added April 15, 2019
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7 MeSH Terms
Glutamate-oxaloacetate transaminase activity promotes palmitate lipotoxicity in rat hepatocytes by enhancing anaplerosis and citric acid cycle flux.
Egnatchik RA, Leamy AK, Sacco SA, Cheah YE, Shiota M, Young JD
(2019) J Biol Chem 294: 3081-3090
MeSH Terms: Animals, Aspartate Aminotransferases, Cell Death, Cell Line, Citric Acid Cycle, Extracellular Space, Glutamine, Hepatocytes, Ketoglutaric Acids, Male, Oxidative Stress, Oxygen, Palmitates, Rats, Rats, Sprague-Dawley
Show Abstract · Added March 28, 2019
Hepatocyte lipotoxicity is characterized by aberrant mitochondrial metabolism, which predisposes cells to oxidative stress and apoptosis. Previously, we reported that translocation of calcium from the endoplasmic reticulum to mitochondria of palmitate-treated hepatocytes activates anaplerotic flux from glutamine to α-ketoglutarate (αKG), which subsequently enters the citric acid cycle (CAC) for oxidation. We hypothesized that increased glutamine anaplerosis fuels elevations in CAC flux and oxidative stress following palmitate treatment. To test this hypothesis, primary rat hepatocytes or immortalized H4IIEC3 rat hepatoma cells were treated with lipotoxic levels of palmitate while modulating anaplerotic pathways leading to αKG. We found that culture media supplemented with glutamine, glutamate, or dimethyl-αKG increased palmitate lipotoxicity compared with media that lacked these anaplerotic substrates. Knockdown of glutamate-oxaloacetate transaminase activity significantly reduced the lipotoxic effects of palmitate, whereas knockdown of glutamate dehydrogenase (Glud1) had no effect on palmitate lipotoxicity. C flux analysis of H4IIEC3 cells co-treated with palmitate and the pan-transaminase inhibitor aminooxyacetic acid confirmed that reductions in lipotoxic markers were associated with decreases in anaplerosis, CAC flux, and oxygen consumption. Taken together, these results demonstrate that lipotoxic palmitate treatments enhance anaplerosis in cultured rat hepatocytes, causing a shift to aberrant transaminase metabolism that fuels CAC dysregulation and oxidative stress.
© 2019 Egnatchik et al.
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15 MeSH Terms
In vitro safety pharmacology evaluation of 2-hydroxybenzylamine acetate.
Fuller JC, Pitchford LM, Morrison RD, Daniels JS, Flynn CR, Abumrad NN, Oates JA, Boutaud O, Rathmacher JA
(2018) Food Chem Toxicol 121: 541-548
MeSH Terms: Adult, Benzylamines, Blood Proteins, Cytochrome P-450 Enzyme System, ERG1 Potassium Channel, Erythrocytes, Female, Gene Expression Regulation, Enzymologic, Hepatocytes, Humans, Male, Middle Aged, Mutagenicity Tests, Salmonella typhimurium
Show Abstract · Added April 15, 2019
2-hydroxybenzylamine (2-HOBA), a compound found in buckwheat, is a potent scavenger of reactive γ-ketoaldehydes, which are increased in diseases associated with inflammation and oxidative stress. While the potential of 2-HOBA is promising, studies were needed to characterize the safety of the compound before clinical trials. In a series of experiments, the risks of 2-HOBA-mediated mutagenicity and cardio-toxicity were assessed in vitro. The effects of 2-HOBA on the mRNA expression of select cytochrome P450 (CYP) enzymes were also assessed in cryopreserved human hepatocytes. Further, the distribution and metabolism of 2-HOBA in blood were determined. Our results indicate that 2-HOBA is not cytotoxic or mutagenic in vitro and does not induce the expression of CYP1A2, CYP2B6, or CYP3A4 in human hepatocytes. The results of the hERG testing showed a low risk of cardiac QT wave prolongation. Plasma protein binding and red blood cell distribution characteristics indicate low protein binding and no preferential distribution into erythrocytes. The major metabolites identified were salicylic acid and the glycoside conjugate of 2-HOBA. Together, these findings support development of 2-HOBA as a nutritional supplement and provide important information for the design of further preclinical safety studies in animals as well as for human clinical trials with 2-HOBA.
Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.
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Hepatic Gi signaling regulates whole-body glucose homeostasis.
Rossi M, Zhu L, McMillin SM, Pydi SP, Jain S, Wang L, Cui Y, Lee RJ, Cohen AH, Kaneto H, Birnbaum MJ, Ma Y, Rotman Y, Liu J, Cyphert TJ, Finkel T, McGuinness OP, Wess J
(2018) J Clin Invest 128: 746-759
MeSH Terms: Animals, Blood Glucose, Extracellular Signal-Regulated MAP Kinases, Female, GTP-Binding Protein alpha Subunits, Gi-Go, Gene Expression Profiling, Glucagon, Gluconeogenesis, Glucose, Hepatocytes, Homeostasis, Humans, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Oxygen, Phosphatidylinositol 3-Kinases, Phosphorylation, Reactive Oxygen Species, Receptors, Glucagon, Signal Transduction
Show Abstract · Added March 14, 2018
An increase in hepatic glucose production (HGP) is a key feature of type 2 diabetes. Excessive signaling through hepatic Gs-linked glucagon receptors critically contributes to pathologically elevated HGP. Here, we tested the hypothesis that this metabolic impairment can be counteracted by enhancing hepatic Gi signaling. Specifically, we used a chemogenetic approach to selectively activate Gi-type G proteins in mouse hepatocytes in vivo. Unexpectedly, activation of hepatic Gi signaling triggered a pronounced increase in HGP and severely impaired glucose homeostasis. Moreover, increased Gi signaling stimulated glucose release in human hepatocytes. A lack of functional Gi-type G proteins in hepatocytes reduced blood glucose levels and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Additionally, we delineated a signaling cascade that links hepatic Gi signaling to ROS production, JNK activation, and a subsequent increase in HGP. Taken together, our data support the concept that drugs able to block hepatic Gi-coupled GPCRs may prove beneficial as antidiabetic drugs.
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23 MeSH Terms
Hepatocyte estrogen receptor alpha mediates estrogen action to promote reverse cholesterol transport during Western-type diet feeding.
Zhu L, Shi J, Luu TN, Neuman JC, Trefts E, Yu S, Palmisano BT, Wasserman DH, Linton MF, Stafford JM
(2018) Mol Metab 8: 106-116
MeSH Terms: Animals, Atherosclerosis, Biological Transport, Cells, Cultured, Cholesterol, Diet, Western, Estrogen Receptor alpha, Female, Hepatocytes, Insulin Resistance, Macrophages, Male, Mice, Mice, Inbred C57BL, Obesity, Sex Factors
Show Abstract · Added April 10, 2018
OBJECTIVE - Hepatocyte deletion of estrogen receptor alpha (LKO-ERα) worsens fatty liver, dyslipidemia, and insulin resistance in high-fat diet fed female mice. However, whether or not hepatocyte ERα regulates reverse cholesterol transport (RCT) in mice has not yet been reported.
METHODS AND RESULTS - Using LKO-ERα mice and wild-type (WT) littermates fed a Western-type diet, we found that deletion of hepatocyte ERα impaired in vivo RCT measured by the removal of H-cholesterol from macrophages to the liver, and subsequently to feces, in female mice but not in male mice. Deletion of hepatocyte ERα decreased the capacity of isolated HDL to efflux cholesterol from macrophages and reduced the ability of isolated hepatocytes to accept cholesterol from HDL ex vivo in both sexes. However, only in female mice, LKO-ERα increased serum cholesterol levels and increased HDL particle sizes. Deletion of hepatocyte ERα increased adiposity and worsened insulin resistance to a greater degree in female than male mice. All of the changes lead to a 5.6-fold increase in the size of early atherosclerotic lesions in female LKO-ERα mice compared to WT controls.
CONCLUSIONS - Estrogen signaling through hepatocyte ERα plays an important role in RCT and is protective against lipid retention in the artery wall during early stages of atherosclerosis in female mice fed a Western-type diet.
Published by Elsevier GmbH.
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16 MeSH Terms