Publications by authors named "Frank J Gonzalez"

761 Publications

6β-Hydroxytestosterone Promotes Angiotensin II-Induced Hypertension via Enhanced Cytosolic Phospholipase Aα Activity.

Hypertension 2021 Sep 23;78(4):1053-1066. Epub 2021 Aug 23.

Department of Pharmacology, Addiction Research, and Toxicology, College of Medicine, University of Tennessee Health Science Center, Memphis (P.S., C.Y.S., S.R.D., A.P., J.S.S., K.U.M.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.17927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415516PMC
September 2021

YAP-TEAD mediates peroxisome proliferator-activated receptor α-induced hepatomegaly and liver regeneration in mice.

Hepatology 2021 Aug 13. Epub 2021 Aug 13.

Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.

Background & Aims: Peroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy homeostasis. PPARα activation induces hepatomegaly and plays an important role in liver regeneration, but the underlying mechanisms remain unclear.

Approach & Results: In this study, the effect of PPARα activation on liver enlargement and regeneration was investigated in several strains of genetically-modified mice. PPARα activation by the specific agonist WY-14643 significantly induced hepatomegaly and accelerated liver regeneration after 70% partial hepatectomy (PHx) in wild-type mice and Ppara mice, while these effects were abolished in hepatocyte-specific Pparα-deficient (Ppara ) mice. Moreover, PPARα activation promoted hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Mechanistically, PPARα activation regulated expression of yes-associated protein (YAP) and its downstream targets (CTGF, CYR61 and ANKRD1) as well as proliferation-related proteins (CCNA1, CCND1 and CCNE1). Binding of YAP with the PPARα E domain was critical for the interaction between YAP and PPARα. PPARα activation further induced nuclear translocation of YAP. Disruption of the YAP-transcriptional enhancer factor domain family member (TEAD) association significantly suppressed PPARα-induced hepatomegaly, and hepatocyte enlargement and proliferation. In addition, PPARα failed to induce hepatomegaly in AAV-Yap shRNA-treated mice and liver-specific Yap-deficient (Yap ) mice. Blockade of YAP signaling abolished PPARα-induced hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area.

Conclusions: This study revealed a novel function of PPARα in regulating liver size and liver regeneration via activation of the YAP-TEAD signaling pathway. These findings have implications for understanding the physiological functions of PPARα and suggest its potential for manipulation of liver size and liver regeneration.
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http://dx.doi.org/10.1002/hep.32105DOI Listing
August 2021

Deficiency of peroxisome proliferator-activated receptor α attenuates apoptosis and promotes migration of vascular smooth muscle cells.

Biochem Biophys Rep 2021 Sep 28;27:101091. Epub 2021 Jul 28.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education; Beijing, China.

Peroxisome proliferator-activated receptor (PPAR) α is widely expressed in the vasculature and has pleiotropic and lipid-lowering independent effects, but its role in the growth and function of vascular smooth muscle cells (VSMCs) during vascular pathophysiology is still unclear. Herein, VSMC-specific PPARα-deficient mice ( ) were generated by Cre-LoxP site-specific recombinase technology and VSMCs were isolated from mice aorta. PPARα deficiency attenuated VSMC apoptosis induced by angiotensin (Ang) II and hydrogen peroxide, and increased the migration of Ang II-challenged cells.
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http://dx.doi.org/10.1016/j.bbrep.2021.101091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339143PMC
September 2021

Feedback repression of PPARα signaling by Let-7 microRNA.

Cell Rep 2021 Aug;36(6):109506

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Peroxisome proliferator-activated receptor α (PPARα) controls hepatic lipid homeostasis and is the target of lipid-lowering fibrate drugs. PPARα activation represses expression of let-7 microRNA (miRNA), but the function of let-7 in PPARα signaling and lipid metabolism is unknown. In the current study, a hepatocyte-specific let-7b/c2 knockout (let7b/c2) mouse line is generated, and these mice are found to exhibit pronounced resistance to diet-induced obesity and fatty liver. Let-7 inhibition by hepatocyte-specific let-7 sponge expression shows similar phenotypes as let7b/c2 mice. RNA sequencing (RNA-seq) analysis reveals that hepatic PPARα signaling is repressed in let7b/c2 mice. Protein expression of the obligate PPARα heterodimer partner retinoid X receptor α (RXRα) is reduced in the livers of let7b/c2 mice. Ring finger protein 8 (Rnf8), which is a direct target of let-7, is elevated in let7b/c2 mouse liver and identified as a E3 ubiquitin ligase for RXRα. This study highlights a let-7-RNF8-RXRα regulatory axis that modulates hepatic lipid catabolism.
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http://dx.doi.org/10.1016/j.celrep.2021.109506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424520PMC
August 2021

Cardiomyocyte peroxisome proliferator-activated receptor α is essential for energy metabolism and extracellular matrix homeostasis during pressure overload-induced cardiac remodeling.

Acta Pharmacol Sin 2021 Aug 10. Epub 2021 Aug 10.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.

Peroxisome proliferator-activated receptor α (PPARα), a ligand-activated nuclear receptor critical for systemic lipid homeostasis, has been shown closely related to cardiac remodeling. However, the roles of cardiomyocyte PPARα in pressure overload-induced cardiac remodeling remains unclear because of lacking a cardiomyocyte-specific Ppara-deficient (Ppara) mouse model. This study aimed to determine the specific role of cardiomyocyte PPARα in transverse aortic constriction (TAC)-induced cardiac remodeling using an inducible Ppara mouse model. Ppara and Ppara mice were randomly subjected to sham or TAC for 2 weeks. Cardiomyocyte PPARα deficiency accelerated TAC-induced cardiac hypertrophy and fibrosis. Transcriptome analysis showed that genes related to fatty acid metabolism were dramatically downregulated, but genes critical for glycolysis were markedly upregulated in Ppara hearts. Moreover, the hypertrophy-related genes, including genes involved in extracellular matrix (ECM) remodeling, cell adhesion, and cell migration, were upregulated in hypertrophic Ppara hearts. Western blot analyses demonstrated an increased HIF1α protein level in hypertrophic Ppara hearts. PET/CT analyses showed an enhanced glucose uptake in hypertrophic Ppara hearts. Bioenergetic analyses further revealed that both basal and maximal oxygen consumption rates and ATP production were significantly increased in hypertrophic Ppara hearts; however, these increases were markedly blunted in Ppara hearts. In contrast, hypertrophic Ppara hearts exhibited enhanced extracellular acidification rate (ECAR) capacity, as reflected by increased basal ECAR and glycolysis but decreased glycolytic reserve. These results suggest that cardiomyocyte PPARα is crucial for the homeostasis of both energy metabolism and ECM during TAC-induced cardiac remodeling, thus providing new insights into potential therapeutics of cardiac remodeling-related diseases.
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http://dx.doi.org/10.1038/s41401-021-00743-zDOI Listing
August 2021

Mutant Idh2 cooperates with a NUP98-HOXD13 fusion to induce early immature thymocyte precursor ALL.

Cancer Res 2021 Jul 28. Epub 2021 Jul 28.

Genetics Branch, NIH/NCI

Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are frequently observed in a wide variety of hematologic malignancies, including myeloid and T-cell leukemias. In this study, we generated Idh2R140Q transgenic mice to examine the role of the Idh2R140Q mutation in leukemia. No leukemia developed in Idh2R140Q transgenic mice, suggesting a need for additional genetic events for leukemia development. Since myeloid cells from NUP98-HOXD13 fusion (NHD13) transgenic mice frequently acquire somatic Idh mutations when they transform to AML, we generated Idh2R140Q/NHD13 double transgenic mice. Idh2R140Q/NHD13 transgenic mice developed an immature T cell leukemia with an immunophenotype similar to double-negative 1 (DN1) or DN2 thymocytes. Idh2R140Q/NHD13 leukemic cells were enriched for an early thymic precursor transcriptional signature, and the gene expression profile for Idh2R140Q/NHD13 DN1/DN2 T-ALL closely matched that of human early/immature T cell precursor (EITP) ALL. Moreover, recurrent mutations found in EITP ALL patients, including KRAS, PTPN11, JAK3, SH2B3, and EZH2 were also found in Idh2R140Q/NHD13 DN1/DN2 T-ALL. In vitro treatment of Idh2R140Q/NHD13 thymocytes with enasidenib, a selective inhibitor of mutant IDH2, led to a marked decrease in leukemic cell proliferation. These findings demonstrate that Idh2R140Q/NHD13 mice can serve as a useful in vivo model for the study of EITP ALL development and therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-1027DOI Listing
July 2021

Metabolic map of the antiviral drug podophyllotoxin provides insights into hepatotoxicity.

Xenobiotica 2021 Sep 9;51(9):1047-1059. Epub 2021 Aug 9.

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Podophyllotoxin (POD) is a natural compound with antiviral and anticancer activities. The purpose of the present study was to determine the metabolic map of POD and .Mouse and human liver microsomes were employed to identify POD metabolites and recombinant drug-metabolizing enzymes were used to identify the mono-oxygenase enzymes involved in POD metabolism. All incubation mixtures and bile samples from mice treated with POD were analysed with ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry.A total of 38metabolites, including six phase-I metabolites and 32 phase-II metabolites, of POD were identified from bile and faeces samples after oral administration, and their structures were elucidated through interpreting MS/MS fragmentation patterns.Nine metabolites, including two phase-I metabolites, five glucuronide conjugates, and two GSH conjugates were detected in both human and mouse liver microsome incubation systems and the generation of all metabolites were NADPH-dependent. The main phase-I enzymes involved in metabolism of POD include CYP2C9, CYP2C19, CYP3A4, and CYP3A5.POD administration to mice caused hepatic and intestinal toxicity, and the cellular damage was exacerbated when 1-aminobenzotriazole, a broad-spectrum inhibitor of CYPs, was administered with POD, indicating that POD, but not its metabolites, induced hepatic and intestinal toxicities.This study elucidated the metabolic map and provides important reference basis for the safety evaluation and rational for the clinical application of POD.
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http://dx.doi.org/10.1080/00498254.2021.1961920DOI Listing
September 2021

Pregnane X receptor exacerbates nonalcoholic fatty liver disease accompanied by obesity- and inflammation-prone gut microbiome signature.

Biochem Pharmacol 2021 Jul 22:114698. Epub 2021 Jul 22.

Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina, United States. Electronic address:

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease due to the current epidemics of obesity and diabetes. The pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor known for trans-activating liver genes involved in drug metabolism and transport, and more recently implicated in energy metabolism. The gut microbiota can modulate the host xenobiotic biotransformation and contribute to the development of obesity. While the male sex confers a higher risk for NAFLD than women before menopause, the mechanism remains unknown. We hypothesized that the presence of PXR promotes obesity by modifying the gut-liver axis in a sex-specific manner. Male and female C57BL/6 (wild-type/WT) and PXR-knockout (PXR-KO) mice were fed control or high fat diet (HFD) for 16-weeks. Serum parameters, liver histopathology, transcriptomic profiling, 16S-rDNA sequencing, and bile acid (BA) metabolomics were performed. PXR enhanced HFD-induced weight gain, hepatic steatosis and inflammation especially in males, accompanied by PXR-dependent up-regulation in hepatic genes involved in microbial response, inflammation, oxidative stress, and cancer; PXR-dependent increase in intestinal Firmicutes/Bacteroides ratio (hallmark of obesity) and the pro-inflammatory Lactobacillus, as well as a decrease in the anti-obese Allobaculum and the anti-inflammatory Bifidobacterum, with a PXR-dependent reduction of beneficial BAs in liver. The resistance to NAFLD in females may be explained by PXR-dependent decrease in pro-inflammatory bacteria (Ruminococcus gnavus and Peptococcaceae). In conclusion, PXR exacerbates hepatic steatosis and inflammation accompanied by obesity- and inflammation-prone gut microbiome signature, suggesting that gut microbiome may contribute to PXR-mediated exacerbation of NAFLD.
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http://dx.doi.org/10.1016/j.bcp.2021.114698DOI Listing
July 2021

Lipidomics reveals carnitine palmitoyltransferase 1C protects cancer cells from lipotoxicity and senescence.

J Pharm Anal 2021 Jun 21;11(3):340-350. Epub 2020 Apr 21.

Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.

Lipotoxicity, caused by intracellular lipid accumulation, accelerates the degenerative process of cellular senescence, which has implications in cancer development and therapy. Previously, carnitine palmitoyltransferase 1C (CPT1C), a mitochondrial enzyme that catalyzes carnitinylation of fatty acids, was found to be a critical regulator of cancer cell senescence. However, whether loss of CPT1C could induce senescence as a result of lipotoxicity remains unknown. An LC/MS-based lipidomic analysis of PANC-1, MDA-MB-231, HCT-116 and A549 cancer cells was conducted after siRNA depletion of CPT1C. Cellular lipotoxicity was further confirmed by lipotoxicity assays. Significant changes were found in the lipidome of CPT1C-depleted cells, including major alterations in fatty acid, diacylglycerol, triacylglycerol, oxidative lipids, cardiolipin, phosphatidylglycerol, phosphatidylcholine/phosphatidylethanolamine ratio and sphingomyelin. This was coincident with changes in expressions of mRNAs involved in lipogenesis. Histological and biochemical analyses revealed higher lipid accumulation and increased malondialdehyde and reactive oxygen species, signatures of lipid peroxidation and oxidative stress. Reduction of ATP synthesis, loss of mitochondrial transmembrane potential and down-regulation of expression of mitochondriogenesis gene mRNAs indicated mitochondrial dysfunction induced by lipotoxicity, which could further result in cellular senescence. Taken together, this study demonstrated CPT1C plays a critical role in the regulation of cancer cell lipotoxicity and cell senescence, suggesting that inhibition of CPT1C may serve as a new therapeutic strategy through induction of tumor lipotoxicity and senescence.
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http://dx.doi.org/10.1016/j.jpha.2020.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264383PMC
June 2021

Intestinal MYC modulates obesity-related metabolic dysfunction.

Nat Metab 2021 07 1;3(7):923-939. Epub 2021 Jul 1.

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

MYC is a transcription factor with broad biological functions, notably in the control of cell proliferation. Here, we show that intestinal MYC regulates systemic metabolism. We find that MYC expression is increased in ileum biopsies from individuals with obesity and positively correlates with body mass index. Intestine-specific reduction of MYC in mice improves high-fat-diet-induced obesity, insulin resistance, hepatic steatosis and steatohepatitis. Mechanistically, reduced expression of MYC in the intestine promotes glucagon-like peptide-1 (GLP-1) production and secretion. Moreover, we identify Cers4, encoding ceramide synthase 4, catalysing de novo ceramide synthesis, as a MYC target gene. Finally, we show that administration of the MYC inhibitor 10058-F4 has beneficial effects on high-fat-diet-induced metabolic disorders, and is accompanied by increased GLP-1 and reduced ceramide levels in serum. This study positions intestinal MYC as a putative drug target against metabolic diseases, including non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
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http://dx.doi.org/10.1038/s42255-021-00421-8DOI Listing
July 2021

Endothelial Aryl Hydrocarbon Receptor Nuclear Translocator Mediates the Angiogenic Response to Peripheral Ischemia in Mice With Type 2 Diabetes Mellitus.

Front Cell Dev Biol 2021 10;9:691801. Epub 2021 Jun 10.

Biological Sciences Division - Cardiology, Department of Medicine, University of Chicago, Chicago, IL, United States.

Hypoxia-inducible factors (HIFs) are the master regulators of angiogenesis, a process that is impaired in patients with diabetes mellitus (DM). The transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF1β) has been implicated in the development and progression of diabetes. Angiogenesis is driven primarily by endothelial cells (ECs), but both global and EC-specific loss of ARNT-cause are associated with embryonic lethality. Thus, we conducted experiments in a line of mice carrying an inducible, EC-specific ARNT-knockout mutation ( ) to determine whether aberrations in ARNT expression might contribute to the vascular deficiencies associated with diabetes. Mice were first fed with a high-fat diet to induce diabetes. mice were then adminstrated with oral tamoxifen to disrupt and peripheral angiogenesis was evaluated by using laser-Doppler perfusion imaging to monitor blood flow after hindlimb ischemia. The mice had impaired blood flow recovery under both non-diabetic and diabetic conditions, but the degree of impairment was greater in diabetic animals. In addition, siRNA-mediated knockdown of ARNT activity reduced measurements of tube formation, and cell viability in human umbilical vein endothelial cells (HUVECs) cultured under high-glucose conditions. The mutation also reduced measures of cell viability, while increasing the production of reactive oxygen species (ROS) in microvascular endothelial cells (MVECs) isolated from mouse skeletal muscle, and the viability of MVECs under high-glucose concentrations increased when the cells were treated with an ROS inhibitor. Collectively, these observations suggest that declines in endothelial ARNT expression contribute to the suppressed angiogenic phenotype in diabetic mice, and that the cytoprotective effect of ARNT expression in ECs is at least partially mediated by declines in ROS production.
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http://dx.doi.org/10.3389/fcell.2021.691801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222825PMC
June 2021

Oleuropein-Induced Acceleration of Cytochrome P450-Catalyzed Drug Metabolism: Central Role for Nuclear Receptor Peroxisome Proliferator-Activated Receptor α.

Drug Metab Dispos 2021 Sep 23;49(9):833-843. Epub 2021 Jun 23.

Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece (F.M., C.E.A., A.K., M.K.); Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.); and Faculty of Pharmacy, School of Health Sciences, University of Athens, Athens, Greece (A.-L.S.)

Oleuropein (OLE), the main constituent of , displays pleiotropic beneficial effects in health and disease, which are mainly attributed to its anti-inflammatory and cardioprotective properties. Several food supplements and herbal medicines contain OLE and are available without a prescription. This study investigated the effects of OLE on the main cytochrome P450s (P450s) catalyzing the metabolism of many prescribed drugs. Emphasis was given to the role of peroxisome proliferator-activated receptor α (PPARα), a nuclear transcription factor regulating numerous genes including s. 129/Sv wild-type and -null mice were treated with OLE for 6 weeks. OLE induced , , , , , , , , and mRNAs in liver of wild-type mice, whereas no similar effects were observed in -null mice, indicating that the OLE-induced effect on these s is mediated by PPARα. Activation of the pathways related to phosphoinositide 3-kinase/protein kinase B (AKT)/forkhead box protein O1, c-Jun N-terminal kinase, AKT/p70, and extracellular signal-regulated kinase participates in P450 induction by OLE. These data indicate that consumption of herbal medicines and food supplements containing OLE could accelerate the metabolism of drug substrates of the above-mentioned P450s, thus reducing their efficacy and the outcome of pharmacotherapy. Therefore, OLE-induced activation of PPARα could modify the effects of drugs due to their increased metabolism and clearance, which should be taken into account when consuming OLE-containing products with certain drugs, in particular those of narrow therapeutic window. SIGNIFICANCE STATEMENT: This study indicated that oleuropein, which belongs to the main constituents of the leaves and olive drupes of , induces the synthesis of the major cytochrome P450s (P450s) metabolizing the majority of prescribed drugs via activation of peroxisome proliferator-activated receptor α. This effect could modify the pharmacokinetic profile of co-administered drug substrates of the P450s, thus altering their therapeutic efficacy and toxicity.
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http://dx.doi.org/10.1124/dmd.120.000302DOI Listing
September 2021

Species Differences between Mouse and Human PPARα in Modulating the Hepatocarcinogenic Effects of Perinatal Exposure to a High-Affinity Human PPARα Agonist in Mice.

Toxicol Sci 2021 Aug;183(1):81-92

Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.

Evidence suggests that species differences exist between rodents and humans in their biological responses to ligand activation of PPARα. Moreover, neonatal/postnatal rodents may be more sensitive to the effects of activating PPARα. Thus, the present studies examined the effects of chronic ligand activation of PPARα initiated during early neonatal development and continued into adulthood on hepatocarcinogenesis in mice. Wild-type, Ppara-null, or PPARA-humanized mice were administered a potent, high-affinity human PPARα agonist GW7647, and cohorts of mice were examined over time. Activation of PPARα with GW7647 increased expression of known PPARα target genes in liver and was associated with hepatomegaly, increased hepatic cytotoxicity and necrosis, increased expression of hepatic MYC, and a high incidence of hepatocarcinogenesis in wild-type mice. These effects did not occur or were largely diminished in Ppara-null and PPARA-humanized mice, although background levels of hepatocarcinogenesis were also noted in both Ppara-null and PPARA-humanized mice. More fatty change (steatosis) was also observed in both Ppara-null and PPARA-humanized mice independent of GW7647 administration. Results from these studies indicate that the mouse PPARα is required to mediate hepatocarcinogenesis induced by GW7647 in mice and that activation of the human PPARα with GW7647 in PPARA-humanized mice are diminished compared with wild-type mice. Ppara-null and PPARA-humanized mice are valuable tools for examining species differences in the mechanisms of PPARα-induced hepatocarcinogenesis, but background levels of liver cancer observed in aged Ppara-null and PPARA-humanized mice must be considered when interpreting results from studies that use these models. These results also demonstrate that early life exposure to a potent human PPARα agonist does not enhance sensitivity to hepatocarcinogenesis.
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http://dx.doi.org/10.1093/toxsci/kfab068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404993PMC
August 2021

Diminished Hepatocarcinogenesis by a Potent, High-Affinity Human PPARα Agonist in PPARA-Humanized Mice.

Toxicol Sci 2021 Aug;183(1):70-80

Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.

Ppara-null and PPARA-humanized mice are refractory to hepatocarcinogenesis caused by the peroxisome proliferator-activated receptor-α (PPARα) agonist Wy-14,643. However, the duration of these earlier studies was limited to approximately 1 year of treatment, and the ligand used has a higher affinity for the mouse PPARα compared to the human PPARα. Thus, the present study examined the effect of long-term administration of a potent, high-affinity human PPARα agonist (GW7647) on hepatocarcinogenesis in wild-type, Ppara-null, or PPARA-humanized mice. In wild-type mice, GW7647 caused hepatic expression of known PPARα target genes, hepatomegaly, hepatic MYC expression, hepatic cytotoxicity, and a high incidence of hepatocarcinogenesis. By contrast, these effects were essentially absent in Ppara-null mice or diminished in PPARA-humanized mice, although hepatocarcinogenesis was observed in both genotypes. Enhanced fatty change (steatosis) was also observed in both Ppara-null and PPARA-humanized mice independent of GW7647. PPARA-humanized mice administered GW7647 also exhibited increased necrosis after 5 weeks of treatment. Results from these studies demonstrate that the mouse PPARα is required for hepatocarcinogenesis induced by GW7647 administered throughout adulthood. Results also indicate that a species difference exists between rodents and human PPARα in the response to ligand activation of PPARα. The hepatocarcinogenesis observed in control and treated Ppara-null mice is likely mediated in part by increased hepatic fatty change, whereas the hepatocarcinogenesis observed in PPARA-humanized mice may also be due to enhanced fatty change and cytotoxicity that could be influenced by the minimal activity of the human PPARα in this mouse line on downstream mouse PPARα target genes. The Ppara-null and PPARA-humanized mouse models are valuable tools for examining the mechanisms of PPARα-induced hepatocarcinogenesis, but the background level of liver cancer must be controlled for in the design and interpretation of studies that use these mice.
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http://dx.doi.org/10.1093/toxsci/kfab067DOI Listing
August 2021

Feeding-induced resistance to acute lethal sepsis is dependent on hepatic BMAL1 and FXR signalling.

Nat Commun 2021 05 12;12(1):2745. Epub 2021 May 12.

Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD, USA.

In mice, time of day strongly influences lethality in response to LPS, with survival greatest at the beginning compared to the end of the light cycle. Here we show that feeding, rather than light, controls time-of-day dependent LPS sensitivity. Mortality following LPS administration is independent of cytokine production and the clock regulator BMAL1 expressed in myeloid cells. In contrast, deletion of BMAL1 in hepatocytes globally disrupts the transcriptional response to the feeding cycle in the liver and results in constitutively high LPS sensitivity. Using RNAseq and functional validation studies we identify hepatic farnesoid X receptor (FXR) signalling as a BMAL1 and feeding-dependent regulator of LPS susceptibility. These results show that hepatocyte-intrinsic BMAL1 and FXR signalling integrate nutritional cues to regulate survival in response to innate immune stimuli. Understanding hepatic molecular programmes operational in response to these cues could identify novel pathways for targeting to enhance endotoxemia resistance.
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http://dx.doi.org/10.1038/s41467-021-22961-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115055PMC
May 2021

Suppressing the intestinal farnesoid X receptor/sphingomyelin phosphodiesterase 3 axis decreases atherosclerosis.

J Clin Invest 2021 05;131(9)

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.

Intestinal farnesoid X receptor (FXR) signaling is involved in the development of obesity, fatty liver disease, and type 2 diabetes. However, the role of intestinal FXR in atherosclerosis and its potential as a target for clinical treatment have not been explored. The serum levels of fibroblast growth factor 19 (FGF19), which is encoded by an FXR target gene, were much higher in patients with hypercholesterolemia than in control subjects and were positively related to circulating ceramide levels, indicating a link between intestinal FXR, ceramide metabolism, and atherosclerosis. Among ApoE-/- mice fed a high-cholesterol diet (HCD), intestinal FXR deficiency (in FxrΔIE ApoE-/- mice) or direct FXR inhibition (via treatment with the FXR antagonist glycoursodeoxycholic acid [GUDCA]) decreased atherosclerosis and reduced the levels of circulating ceramides and cholesterol. Sphingomyelin phosphodiesterase 3 (SMPD3), which is involved in ceramide synthesis in the intestine, was identified as an FXR target gene. SMPD3 overexpression or C16:0 ceramide supplementation eliminated the improvements in atherosclerosis in FxrΔIE ApoE-/- mice. Administration of GUDCA or GW4869, an SMPD3 inhibitor, elicited therapeutic effects on established atherosclerosis in ApoE-/- mice by decreasing circulating ceramide levels. This study identified an intestinal FXR/SMPD3 axis that is a potential target for atherosclerosis therapy.
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http://dx.doi.org/10.1172/JCI142865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087211PMC
May 2021

Manassantin B attenuates obesity by inhibiting adipogenesis and lipogenesis in an AMPK dependent manner.

FASEB J 2021 05;35(5):e21496

Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.

Saururus chinensis (S chinensis) has been used as an herb to treat edema, jaundice, and gonorrhea. Manassantin B (MNSB), a dineolignan isolated from S chinensis, was identified as a potent adipogenesis/lipogenesis inhibitor (IC  = 9.3 nM). To explore the underlying mechanism, both adipogenesis and lipogenesis were measured in differentiated 3T3-L1 preadipocytes, murine primary preadipocytes and adipose tissue explants upon MNSB treatment. Key regulators of adipogenesis/lipogenesis were downregulated by MNSB treatment, mainly resulting from increased phosphorylation of AMPK which was identified as a vital regulator of adipogenesis and lipogenesis. Moreover, MNSB did not increase AMPK phosphorylation in 3T3-L1 cells transfected with Prkaa1 (encoding protein kinase AMP-activated catalytic subunit alpha 1) siRNA or adipose tissue explants isolated from adipose-specific Prkaa1-disrupted mice (Prkaa1 ). In diet-induced obese C57BL/6N mice, MNSB displayed preventive and therapeutic effects on obesity accompanied by decreased adipocyte size. MNSB was also found to increase AMPK phosphorylation both in subcutaneous white adipose tissue and brown adipose tissue in vivo. These findings suggest that MNSB can be a new therapeutic agent for the prevention and treatment of obesity and other related metabolic disorders.
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http://dx.doi.org/10.1096/fj.202002126RRDOI Listing
May 2021

Myelocytomatosis-Protein Arginine N-Methyltransferase 5 Axis Defines the Tumorigenesis and Immune Response in Hepatocellular Carcinoma.

Hepatology 2021 Apr 25. Epub 2021 Apr 25.

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Background And Aims: HCC is a leading cause of cancer-related deaths globally with poor outcome and limited therapeutic options. Although the myelocytomatosis (MYC) oncogene is frequently dysregulated in HCC, it is thought to be undruggable. Thus, the current study aimed to identify the critical downstream metabolic network of MYC and develop therapies for MYC-driven HCC.

Approach And Results: Liver cancer was induced in mice with hepatocyte-specific disruption of Myc and control mice by administration of diethylnitrosamine. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses revealed that urinary dimethylarginine, especially symmetric dimethylarginine (SDMA), was increased in the HCC mouse model in an MYC-dependent manner. Analyses of human samples demonstrated a similar induction of SDMA in the urines from patients with HCC. Mechanistically, Prmt5, encoding protein arginine N-methyltransferase 5, which catalyzes SDMA formation from arginine, was highly induced in HCC and identified as a direct MYC target gene. Moreover, GSK3326595, a PRMT5 inhibitor, suppressed the growth of liver tumors in human MYC-overexpressing transgenic mice that spontaneously develop HCC. Inhibition of PRMT5 exhibited antiproliferative activity through up-regulation of the tumor suppressor gene Cdkn1b/p27, encoding cyclin-dependent kinase inhibitor 1B. In addition, GSK3326595 induced lymphocyte infiltration and major histocompatibility complex class II expression, which might contribute to the enhanced antitumor immune response. Combination of GSK3326595 with anti-programed cell death protein 1 (PD-1) immune checkpoint therapy (ICT) improved therapeutic efficacy in HCC.

Conclusions: This study reveals that PRMT5 is an epigenetic executer of MYC, leading to repression of the transcriptional regulation of downstream genes that promote hepatocellular carcinogenesis, highlights a mechanism-based therapeutic strategy for MYC-driven HCC by PRMT5 inhibition through synergistically suppressed proliferation and enhanced antitumor immunity, and finally provides an opportunity to mitigate the resistance of "immune-cold" tumor to ICT.
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http://dx.doi.org/10.1002/hep.31864DOI Listing
April 2021

The pathophysiological function of non-gastrointestinal farnesoid X receptor.

Pharmacol Ther 2021 Oct 22;226:107867. Epub 2021 Apr 22.

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States of America. Electronic address:

Farnesoid X receptor (FXR) influences bile acid homeostasis and the progression of various diseases. While the roles of hepatic and intestinal FXR in enterohepatic transport of bile acids and metabolic diseases were reviewed previously, the pathophysiological functions of FXR in non-gastrointestinal cells and tissues have received little attention. Thus, the roles of FXR in the liver, immune system, nervous system, cardiovascular system, kidney, and pancreas beyond the gastrointestinal system are reviewed herein. Gain of FXR function studies in non-gastrointestinal tissues reveal that FXR signaling improves various experimentally-induced metabolic and immune diseases, including non-alcoholic fatty liver disease, type 2 diabetes, primary biliary cholangitis, sepsis, autoimmune diseases, multiple sclerosis, and diabetic nephropathy, while loss of FXR promotes regulatory T cells production, protects the brain against ischemic injury, atherosclerosis, and inhibits pancreatic tumor progression. The downstream pathways regulated by FXR are diverse and tissue/cell-specific, and FXR has both ligand-dependent and ligand-independent activities, all of which may explain why activation and inhibition of FXR signaling could produce paradoxical or even opposite effects in some experimental disease models. FXR signaling is frequently compromised by diseases, especially during the progressive stage, and rescuing FXR expression may provide a promising strategy for boosting the therapeutic effect of FXR agonists. Tissue/cell-specific modulation of non-gastrointestinal FXR could influence the treatment of various diseases. This review provides a guide for drug discovery and clinical use of FXR modulators.
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http://dx.doi.org/10.1016/j.pharmthera.2021.107867DOI Listing
October 2021

Hypoxia via ERK Signaling Inhibits Hepatic PPARα to Promote Fatty Liver.

Cell Mol Gastroenterol Hepatol 2021 30;12(2):585-597. Epub 2021 Mar 30.

Department of Molecular and Integrative Physiology, Internal Medicine, University of Michigan, Ann Arbor, Michigan. Electronic address:

Background & Aims: Fatty liver or nonalcoholic fatty liver disease (NAFLD) is the most common liver disease associated with comorbidities such as insulin resistance and cardiovascular and metabolic diseases. Chronic activation of hypoxic signaling, in particular, hypoxia-inducible factor (HIF)2α, promotes NAFLD progression by repressing genes involved in fatty acid β-oxidation through unclear mechanisms. Therefore, we assessed the precise mechanism by which HIF2α promotes fatty liver and its physiological relevance in metabolic homeostasis.

Methods: Primary hepatocytes from VHL (Vhl) and PPARα (Ppara-null) knockout mice that were loaded with fatty acids, murine dietary protocols to induce hepatic steatosis, and fasting-refeeding dietary regimen approaches were used to test our hypothesis.

Results: Inhibiting autophagy using chloroquine did not decrease lipid contents in Vhl primary hepatocytes. Inhibition of ERK using MEK inhibitor decreased lipid contents in primary hepatocytes from a genetic model of constitutive HIF activation and primary hepatocytes loaded with free fatty acids. Moreover, MEK-ERK inhibition potentiated ligand-dependent activation of PPARα. We also show that MEK-ERK inhibition improved diet-induced hepatic steatosis, which is associated with the induction of PPARα target genes. During fasting, fatty acid β-oxidation is induced by PPARα, and refeeding inhibits β-oxidation. Our data show that ERK is involved in the post-prandial repression of hepatic PPARα signaling.

Conclusions: Overall, our results demonstrate that ERK activated by hypoxia signaling plays a crucial role in fatty acid β-oxidation genes by repressing hepatocyte PPARα signaling.
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http://dx.doi.org/10.1016/j.jcmgh.2021.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258975PMC
March 2021

Constitutive androstane receptor induced-hepatomegaly and liver regeneration is partially yes-associated protein activation.

Acta Pharm Sin B 2021 Mar 28;11(3):727-737. Epub 2020 Nov 28.

Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

The constitutive androstane receptor (CAR, NR3I1) belongs to nuclear receptor superfamily. It was reported that CAR agonist TCPOBOP induces hepatomegaly but the underlying mechanism remains largely unknown. Yes-associated protein (YAP) is a potent regulator of organ size. The aim of this study is to explore the role of YAP in CAR activation-induced hepatomegaly and liver regeneration. TCPOBOP-induced CAR activation on hepatomegaly and liver regeneration was evaluated in wild-type (WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy (PHx) mice. The results demonstrate that TCPOBOP can increase the liver-to-body weight ratio in wild-type mice and PHx mice. Hepatocytes enlargement around central vein (CV) area was observed, meanwhile hepatocytes proliferation was promoted as evidenced by the increased number of KI67 cells around portal vein (PV) area. The protein levels of YAP and its downstream targets were upregulated in TCPOBOP-treated mice and YAP translocation can be induced by CAR activation. Co-immunoprecipitation results suggested a potential protein-protein interaction of CAR and YAP. However, CAR activation-induced hepatomegaly can still be observed in liver-specific YAP-deficient ( ) mice. In summary, CAR activation promotes hepatomegaly and liver regeneration partially by inducing YAP translocation and interaction with YAP signaling pathway, which provides new insights to further understand the physiological functions of CAR.
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http://dx.doi.org/10.1016/j.apsb.2020.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982502PMC
March 2021

Testosterone Metabolite 6β-Hydroxytestosterone Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysms in Male Mice.

J Am Heart Assoc 2021 04 15;10(7):e018536. Epub 2021 Mar 15.

Department of Pharmacology Addiction Science and Toxicology College of Medicine University of Tennessee Health Science Center Memphis TN.

Background Sex is a prominent risk factor for abdominal aortic aneurysms (AAAs), and angiotensin II (Ang II) induces AAA formation to a greater degree in male than in female mice. We previously reported that cytochrome P450 1B1 contributes to the development of hypertension, as well as AAAs, in male mice. We also found that a cytochrome P450 1B1-generated metabolite of testosterone, 6β-hydroxytestosterone (6β-OHT), contributes to Ang II-induced hypertension and associated cardiovascular and renal pathogenesis in male mice. The current study was conducted to determine the contribution of 6β-OHT to Ang II-induced AAA development in male mice. Methods and Results Intact or castrated and male mice were infused with Ang II or its vehicle for 28 days, and administered 6β-OHT every third day for the duration of the experiment. Abdominal aortas were then evaluated for development of AAAs. We observed a significant increase in the incidence and severity of AAAs in intact Ang II-infused mice, compared with vehicle-treated mice, which were minimized in castrated and intact mice infused with Ang II. Treatment with 6β-OHT significantly restored the incidence and severity of AAAs in Ang II-infused castrated and intact mice. However, administration of testosterone failed to increase AAA incidence and severity in Ang II-infused intact mice. Conclusions Our results indicate that the testosterone-cytochrome P450 1B1-generated metabolite 6β-OHT contributes to Ang II-induced AAA development in male mice.
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http://dx.doi.org/10.1161/JAHA.120.018536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174379PMC
April 2021

Analytical methodologies for sensing catechol--methyltransferase activity and their applications.

J Pharm Anal 2021 Feb 7;11(1):15-27. Epub 2020 Apr 7.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.

Mammalian catechol--methyltransferases (COMT) are an important class of conjugative enzymes, which play a key role in the metabolism and inactivation of catechol neurotransmitters, catechol estrogens and a wide range of endobiotics and xenobiotics that bear the catechol group. Currently, COMT inhibitors are used in combination with levodopa for the treatment of Parkinson's disease in clinical practice. The crucial role of COMT in human health has raised great interest in the development of more practical assays for highly selective and sensitive detection of COMT activity in real samples, as well as for rapid screening and characterization of COMT inhibitors as drug candidates. This review summarizes recent advances in analytical methodologies for sensing COMT activity and their applications. Several lists of biochemical assays for measuring COMT activity, including the probe substrates, along with their analytical conditions and kinetic parameters, are presented. Finally, the challenges and future perspectives in the field, such as visualization of COMT activity in vivo and in situ, are highlighted. Collectively, this review article overviews the practical assays for measuring COMT activities in complex biological samples, which will strongly facilitate the investigations on the relevance of COMT to human diseases and promote the discovery of COMT inhibitors via high-throughput screening.
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http://dx.doi.org/10.1016/j.jpha.2020.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930641PMC
February 2021

FXR-Deoxycholic Acid-TNF-α Axis Modulates Acetaminophen-Induced Hepatotoxicity.

Toxicol Sci 2021 05;181(2):273-284

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, China.

The idiosyncratic characteristics and severity of acetaminophen (APAP) overdose-induced hepatotoxicity render identifying the predisposing factors and mechanisms of APAP-induced liver toxicity necessary and urgent. Farnesoid X receptor (FXR) controls bile acid homeostasis and modulates the progression of various liver diseases. Although global FXR deficiency in mice enhances APAP intoxication, the mechanism remains elusive. In this study, an increased sensitivity to APAP-induced toxicity was found in global Fxr-null (Fxr-/-) mice, but was not observed in hepatocyte-specific or macrophage-specific Fxr-null mice, suggesting that global FXR deficiency enhances APAP hepatotoxicity via disruption of systematic bile acid homeostasis. Indeed, more bile acid accumulation was found in global Fxr-/- mice, while 2% cholestyramine diet feeding decreased serum bile acids and alleviated APAP hepatotoxicity in global Fxr-/- mice, suggesting that bile acid accumulation contributes to APAP toxicity. Bile acids were suspected to induce macrophage to release tumor necrosis factor-α (TNF-α), which is known to enhance the APAP hepatotoxicity. In vitro, deoxycholic acid (DCA), a secondary bile acid metabolite, significantly induced Tnfa mRNA and dose-dependently enhanced TNF-α release from macrophage, while the same dose of DCA did not directly potentiate APAP toxicity in cultured primary hepatocytes. In vivo, DCA enhanced TNF-α release and potentiated APAP toxicity, both of which were abolished by the specific TNF-α antagonist infliximab. These results reveal an FXR-DCA-TNF-α axis that potentiates APAP hepatotoxicity, which could guide the clinical safe use of APAP.
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http://dx.doi.org/10.1093/toxsci/kfab027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163055PMC
May 2021

Targeting Xenobiotic Nuclear Receptors PXR and CAR to Prevent Cobicistat Hepatotoxicity.

Toxicol Sci 2021 04;181(1):58-67

Center for Pharmacogenetics, Department of Pharmaceutical Sciences.

Liver-related diseases including drug-induced liver injury are becoming increasingly prominent in AIDS patients. Cobicistat (COBI) is the backbone of multiple regimens for antiretroviral therapy. The current work investigated the mechanisms of adverse drug-drug interactions associated with COBI that lead to liver damage. For individuals co-infected with HIV and tuberculosis (TB), the World Health Organization recommends the initiation of TB treatment followed by antiretroviral therapy. Rifampicin (RIF), a first line anti-TB drug, is a human specific activator of pregnane X receptor (PXR). Using PXR-humanized mice, we found that RIF-mediated PXR activation potentiates COBI hepatotoxicity. In contrast, rifabutin, a PXR-neutral analog of RIF, has no impact on COBI hepatotoxicity. Because of the crosstalk between PXR and the constitutive androstane receptor (CAR), the role of CAR in COBI hepatotoxicity was also investigated. Similar to PXR, ligand-dependent activation of CAR also potentiates COBI hepatotoxicity. Our further studies illustrated that PXR and CAR modulate COBI hepatotoxicity through the CYP3A4-dependent pathways. In summary, the current work determined PXR and CAR as key modulators of COBI hepatotoxicity. Given the fact that many prescription drugs and herbal supplements can activate PXR and CAR, these two receptors should be considered as targets to prevent COBI hepatotoxicity in the clinic.
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http://dx.doi.org/10.1093/toxsci/kfab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081023PMC
April 2021

Novel Strategy for Mining and Identification of Acylcarnitines Using Data-Independent-Acquisition-Based Retention Time Prediction Modeling and Pseudo-Characteristic Fragmentation Ion Matching.

J Proteome Res 2021 03 24;20(3):1602-1611. Epub 2021 Feb 24.

School of Public Health/ MOE Key Lab for Public Health, Fudan University, Shanghai 200032, China.

It is a challenging work to screen, identify, and quantify acylcarnitines in complex biological samples. A method, based on the retention time (RT) prediction and data-independent acquisition strategies, was proposed for the large-scale identification of acylcarnitines using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS). Relative cumulative eluotropic strength was introduced as a novel descriptor in building a linear prediction model, which not only solves the problem that acylcarnitines with long carbon chains cannot be well predicted in traditional models but also proves its robustness and transferability across instruments in two data sets that were acquired in distinct chromatography conditions. The accessibility of both predictive RT and MS spectra of suspect features effectively reduced about 30% false-positive results, and consequently, 150 and 186 acylcarnitines were identified in the rat liver and human plasma (NIST SRM 1950), respectively. This method provides a new approach in large-scale analysis of acylcarnitine in lipidomic studies and can also be extended to the analysis of other lipids.
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http://dx.doi.org/10.1021/acs.jproteome.0c00810DOI Listing
March 2021

Political uncertainty moderates neural evaluation of incongruent policy positions.

Philos Trans R Soc Lond B Biol Sci 2021 04 22;376(1822):20200138. Epub 2021 Feb 22.

School of Government and Public Policy, University of Arizona, Tucson, AZ, USA.

Uncertainty has been shown to impact political evaluation, yet the exact mechanisms by which uncertainty affects the minds of citizens remain unclear. This experiment examines the neural underpinnings of uncertainty in political evaluation using functional magnetic resonance imaging (fMRI). During fMRI, participants completed an experimental task where they evaluated policy positions attributed to hypothetical political candidates. Policy positions were either congruent or incongruent with candidates' political party affiliation and presented with varying levels of certainty. Neural activity was modelled as a function of uncertainty and incongruence. Analyses suggest that neural activity in brain regions previously implicated in affective and evaluative processing (anterior cingulate cortex, insular cortex) differed as a function of the interaction between uncertainty and incongruence, such that activation in these areas was greatest when information was both certain and incongruent, and uncertainty influenced processing differently as a function of the valence of the attached information. These findings suggest that individuals are attuned to uncertainty in the stated issue positions of politicians, and that the neural processing of this uncertainty is dependent on congruence of these positions with expectations based on political party identification. Implications for the study of emotion and politics and political cognition are discussed. This article is part of the theme issue 'The political brain: neurocognitive and computational mechanisms'.
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http://dx.doi.org/10.1098/rstb.2020.0138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935043PMC
April 2021

Withaferin A alleviates fulminant hepatitis by targeting macrophage and NLRP3.

Cell Death Dis 2021 02 11;12(2):174. Epub 2021 Feb 11.

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Fulminant hepatitis (FH) is an incurable clinical syndrome where novel therapeutics are warranted. Withaferin A (WA), isolated from herb Withania Somnifera, is a hepatoprotective agent. Whether and how WA improves D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced FH is unknown. This study was to evaluate the hepatoprotective role and mechanism of WA in GalN/LPS-induced FH. To determine the preventive and therapeutic effects of WA, wild-type mice were dosed with WA 0.5 h before or 2 h after GalN treatment, followed by LPS 30 min later, and then killed 6 h after LPS treatment. To explore the mechanism of the protective effect, the macrophage scavenger clodronate, autophagy inhibitor 3-methyladenine, or gene knockout mouse lines NLR family pyrin domain containing 3 (Nlrp3)-null, nuclear factor-erythroid 2-related factor 2 (Nrf2)-null, liver-specific AMP-activated protein kinase (Ampk)a1 knockout (Ampka1) and liver-specific inhibitor of KB kinase β (Ikkb) knockout (Ikkb) mice were subjected to GalN/LPS-induced FH. In wild-type mice, WA potently prevented GalN/LPS-induced FH and inhibited hepatic NLRP3 inflammasome activation, and upregulated NRF2 and autophagy signaling. Studies with Nrf2-null, Ampka1, and Ikkb mice demonstrated that the hepatoprotective effect was independent of NRF2, hepatic AMPKα1, and IκκB. Similarly, 3-methyladenine cotreatment failed to abolish the hepatoprotective effect of WA. The hepatoprotective effect of WA against GalN/LPS-induced FH was abolished after macrophage depletion, and partially reduced in Nlrp3-null mice. Consistently, WA alleviated LPS-induced inflammation partially dependent on the presence of NLRP3 in primary macrophage in vitro. Notably, WA potently and therapeutically attenuated GalN/LPS-induced hepatotoxicity. In conclusion, WA improves GalN/LPS-induced hepatotoxicity by targeting macrophage partially dependent on NLRP3 antagonism, while largely independent of NRF2 signaling, autophagy induction, and hepatic AMPKα1 and IκκB. These results support the concept of treating FH by pharmacologically targeting macrophage and suggest that WA has the potential to be repurposed for clinically treating FH as an immunoregulator.
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http://dx.doi.org/10.1038/s41419-020-03243-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878893PMC
February 2021

The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer.

Nat Rev Gastroenterol Hepatol 2021 05 10;18(5):335-347. Epub 2021 Feb 10.

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

Farnesoid X receptor (FXR) is a ligand-activated transcription factor involved in the control of bile acid (BA) synthesis and enterohepatic circulation. FXR can influence glucose and lipid homeostasis. Hepatic FXR activation by obeticholic acid is currently used to treat primary biliary cholangitis. Late-stage clinical trials investigating the use of obeticholic acid in the treatment of nonalcoholic steatohepatitis are underway. Mouse models of metabolic disease have demonstrated that inhibition of intestinal FXR signalling reduces obesity, insulin resistance and fatty liver disease by modulation of hepatic and gut bacteria-mediated BA metabolism, and intestinal ceramide synthesis. FXR also has a role in the pathogenesis of gastrointestinal and liver cancers. Studies using tissue-specific and global Fxr-null mice have revealed that FXR acts as a suppressor of hepatocellular carcinoma, mainly through regulating BA homeostasis. Loss of whole-body FXR potentiates progression of spontaneous colorectal cancer, and obesity-induced BA imbalance promotes intestinal stem cell proliferation by suppressing intestinal FXR in Apc mice. Owing to altered gut microbiota and FXR signalling, changes in overall BA levels and specific BA metabolites probably contribute to enterohepatic tumorigenesis. Modulating intestinal FXR signalling and altering BA metabolites are potential strategies for gastrointestinal and liver cancer prevention and treatment. In this Review, studies on the role of FXR in metabolic diseases and gastrointestinal and liver cancer are discussed, and the potential for development of targeted drugs are summarized.
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http://dx.doi.org/10.1038/s41575-020-00404-2DOI Listing
May 2021
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