A5016679205- Adipose Tissue and Metabolism
- Diet and metabolism studies
- Metabolomics and Mass Spectrometry Studies
- Liver Disease Diagnosis and Treatment
- Lymphatic System and Diseases
- Pancreatic function and diabetes
- Adipokines, Inflammation, and Metabolic Diseases
- Cardiovascular Function and Risk Factors
- Muscle Physiology and Disorders
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Cardiovascular Disease and Adiposity
- Cancer, Hypoxia, and Metabolism
- Mitochondrial Function and Pathology
- Metabolism, Diabetes, and Cancer
- Lymphatic Disorders and Treatments
- Peroxisome Proliferator-Activated Receptors
- Metabolism and Genetic Disorders
- Lipid metabolism and biosynthesis
- Apelin-related biomedical research
- Hippo pathway signaling and YAP/TAZ
- Protein Tyrosine Phosphatases
- Atherosclerosis and Cardiovascular Diseases
- Cardiovascular Health and Disease Prevention
- Sympathectomy and Hyperhidrosis Treatments
- Endoplasmic Reticulum Stress and Disease
Pfizer (United States)
2019-2025
University of Massachusetts Chan Medical School
2010-2017
Yale University
2010-2014
Weatherford College
2010
Non-alcoholic fatty liver disease is prevalent in human obesity and type 2 diabetes, characterized by increases both hepatic triglyceride accumulation (denoted as steatosis) expression of pro-inflammatory cytokines such IL-1β. We report here that the development steatosis requires IL-1 signaling, which upregulates Fatty acid synthase to promote lipogenesis. Using clodronate liposomes selectively deplete Kupffer cells ob/ob mice, we observed remarkable amelioration obesity-induced reductions...
Abstract Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation progression. Here we demonstrate the Sterile-20-like mitogen-activated protein kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed ECs atherosclerotic plaques from mice humans. On basis of endothelial-specific MAP4K4 gene silencing ablation experiments Apoe −/− mice, show markedly promotes Western...
Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis poorly understood. The ability to assess genetic and pharmacologic interventions hampered by the lack of robust preclinical mouse models HFpEF. We developed a novel "two-hit" model, which combines obesity insulin resistance chronic pressure overload recapitulate clinical features C57Bl6/NJ mice fed high-fat diet (HFD) for > 10 weeks were administered an AAV8-driven vector resulting in...
The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity insulin resistance are highly associated nonalcoholic fatty disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. p38 mitogen-activated protein kinase (MAPK) c-Jun NH2-terminal (JNK) regulate metabolism. physiological contribution MAPK phosphatase 1 (MKP-1) as nuclear antagonist both JNK is unknown. Here we show that hepatic...
Proper regulation of energy storage in adipose tissue is crucial for maintaining insulin sensitivity and molecules contributing to this process have not been fully revealed. Here we show that type II transmembrane protein tenomodulin (TNMD) upregulated insulin-resistant versus insulin-sensitive individuals, who were matched body mass index (BMI). TNMD expression increases human preadipocytes during differentiation, whereas silencing blocks adipogenesis. Upon high-fat diet feeding, transgenic...
The lymphatic vasculature is involved in the pathogenesis of acute cardiac injuries, but little known about its role chronic dysfunction. Here, we demonstrate that angiotensin II infusion induced inflammation and fibrosis at 1 week caused dysfunction impaired transport 6 weeks mice, while co-administration VEGFCc156s improved these parameters. To identify novel mechanisms underlying this protection, RNA sequencing analysis distinct cell populations revealed specifically modulated II-induced...
Branched chain amino acid (BCAA) catabolic defects are implicated to be causal determinates of multiple diseases. This work aimed better understand how enhancing BCAA catabolism affected metabolic homeostasis as well the mechanisms underlying these improvements. The rate limiting step is irreversible decarboxylation by branched ketoacid dehydrogenase (BCKDH) enzyme complex, which post-translationally controlled through phosphorylation BCKDH kinase (BDK). study utilized BT2, a small molecule...
Branched chain amino acid (BCAA) catabolic impairments have been implicated in several diseases. ketoacid dehydrogenase (BCKDH) controls the rate limiting step BCAA degradation, activity of which is inhibited by BCKDH kinase (BDK)-mediated phosphorylation. Screening efforts to discover BDK inhibitors led identification thiophene PF-07208254, improved cardiometabolic endpoints mice. Structure-activity relationship studies a thiazole series inhibitors; however, these did not improve metabolism...
The integration of metabolic signals required for the regulation hepatic lipid homeostasis is complex. Previously, we showed that mice lacking expression mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) have increased fatty acid oxidation and are protected from development steatosis. Here, show leptin receptor-deficient (db/db) MKP-1 also resistant to Microarray analyses livers db/db suppression peroxisome proliferator-activated receptor γ (PPARγ) target genes. We identified...
Myeloperoxidase (MPO) is a highly abundant protein within the neutrophil that associated with lipoprotein oxidation, and increased plasma MPO levels are correlated poor prognosis after myocardial infarct. Thus, inhibitors have been developed for treatment of heart failure acute coronary syndrome in humans. 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide PF-06282999 recently described selective small molecule mechanism-based inactivator MPO. Here,...
The mammalian mitochondrial branched-chain ketoacid dehydrogenase (BCKD) complex is a multienzyme involved in the catabolism of amino acids. BCKD regulated by kinase, or BCKDK, which binds to E2 subunit BCKD, phosphorylates its E1 subunit, and inhibits enzymatic activity. Inhibition results increased levels acids ketoacids, this buildup has been associated with heart failure, type 2 diabetes mellitus, nonalcoholic fatty liver disease. To find BCKDK inhibitors for potential treatment these...
Parallel to major changes in fatty acid and glucose metabolism, defect branched-chain amino (BCAA) catabolism has also been recognized as a metabolic hallmark potential therapeutic target for heart failure. However, BCAA catabolic enzymes are ubiquitously expressed all cell types systemic is manifested disorder associated with obesity diabetes. Therefore, it remains be determined the cell-autonomous impact of cardiomyocytes intact hearts independent from its global effects. In this study, we...
In skeletal muscle, the mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a critical negative regulator of MAPKs. Since MAPKs have been reported to be both positive and for myogenesis, physiological role MKP-1 in muscle repair regeneration has remained unclear. Here, we show that plays an essential adult regenerative myogenesis. cardiotoxin-induced injury model, lack impaired regeneration. mdx mice, deficiency reduced body weight, mass, fiber cross-sectional area. addition,...
Inflammation induced by wound healing or infection activates local vascular endothelial cells to mediate leukocyte rolling, adhesion, and extravasation up-regulation of adhesion molecules such as E-selectin P-selectin. Obesity-associated adipose tissue inflammation has been suggested cause insulin resistance, but weight loss lipolysis also promote immune responses. While leukocyte-endothelial interactions are required for obesity-induced tissue, it is not known whether lipolysis-induced...
Adipose tissue relies on lipid droplet (LD) proteins in its role as a lipid-storing endocrine organ that controls whole body metabolism. Hypoxia-inducible Gene 2 (Hig2) is recently identified LD-associated protein hepatocytes promotes hepatic storage, but the adipocyte had not been investigated. Here we tested hypothesis Hig2 localization to LDs adipocytes adipose deposition and systemic glucose homeostasis.White brown adipocyte-deficient (Hig2fl/fl × Adiponection cre+) selective brown/beige...
Abstract Aims Two general phenotypes of heart failure (HF) are recognized: HF with reduced ejection fraction (HFrEF) and preserved EF (HFpEF). To develop phenotype‐specific approaches to treatment, distinguishing biomarkers needed. The goal this study was utilize quantitative metabolomics on a large, diverse population replicate extend existing knowledge the plasma metabolic signatures in human HF. Methods Plasma proteomics conducted 787 samples collected by Penn Medicine BioBank from...
Patients with metabolic syndrome and heart failure (HF) often have accompanying kidney dysfunction, which was recently defined as cardiovascular-kidney-metabolic (CKM) syndrome. Prior metabolomics profiling of patients identified a plasma branched chain amino acid (BCAA) signature, BCAAs themselves are elevated in the myocardium HF, potentially due to defect BCAA catabolic breakdown. The rate limiting step catabolism is decarboxylation by enzyme ketoacid dehydrogenase (BCKDH), negatively...
Myoblast differentiation into mature myotubes is a critical step in the development and repair of human skeletal muscle. Here we show that small interfering RNA (siRNA)-based silencing Ste20-like mitogen-activated protein 4 kinase (Map4k4) C2C12 myoblasts markedly enhances expression myogenic genes, myoblast fusion, myotube diameter. In contrast, adenovirus-mediated native Map4k4 cells attenuates each these processes, indicating negative regulator hypertrophy. Expression kinase-inactive...
Studies in vitro suggest that mitogen-activated protein kinase 4 (Map4k4) attenuates insulin signaling, but confirmation vivo is lacking since Map4k4 knockout lethal during embryogenesis. We thus generated mice with floxed alleles and a tamoxifen-inducible Cre/ERT2 recombinase under the control of ubiquitin C promoter to induce whole-body deletion after these animals reached maturity. Tamoxifen administration induced all tissues examined, causing decreased fasting blood glucose...
Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From starting point with potential idiosyncratic toxicity risk, modification benzothiophene core and discovery cryptic pocket allowed for improved potency 3-aryl substitution arrive at PF-07328948, which was largely devoid protein covalent binding liability. This BDK inhibitor shown also be degrader in cells vivo...
The molecular mechanisms underlying lymphatic vascular development and function are not well understood. Recent studies have suggested a role for endothelial cell (EC) mitogen-activated protein kinase 4 (Map4k4) in developmental angiogenesis atherosclerosis. Here, we show that constitutive loss of EC Map4k4 mice causes postnatal lethality due to chylothorax, suggesting is required normal function. Mice constitutively lacking displayed dilated capillaries, insufficient valves, impaired flow;...