Zhengtong Pei - Academia.edu (original) (raw)

Papers by Zhengtong Pei

Journal of gastrointestinal oncology, 2015

We report a case of a 71-year-old Caucasian male presenting with an exfoliative skin rash all ove... more We report a case of a 71-year-old Caucasian male presenting with an exfoliative skin rash all over his body. The patient was also found to have a huge gall bladder mass extending into the liver that turned out to be adenocarcinoma of the gall bladder on biopsy. Gall bladder cancer usually presents with abdominal pain, swelling or jaundice. We report only the second case in literature of a gall bladder adenocarcinoma presenting with exfoliative erythroderma as its paraneoplastic presentation.

The Journal of biological chemistry, Jan 13, 2007

Fatty acid transport protein 4 (FATP4) is a fatty acyl-CoA synthetase that preferentially activat... more Fatty acid transport protein 4 (FATP4) is a fatty acyl-CoA synthetase that preferentially activates very long chain fatty acid substrates, such as C24:0, to their CoA derivatives. To gain better insight into the physiological functions of FATP4, we established dermal fibroblast cell lines from FATP4-deficient wrinkle-free mice and wild type (w.t.) mice. FATP4 -/- fibroblasts had no detectable FATP4 protein by Western blot. Compared with w.t. fibroblasts, cells lacking FATP4 had an 83% decrease in C24:0 activation. Peroxisomal degradation of C24:0 was reduced by 58%, and rates of C24:0 incorporation into major phospholipid species (54-64% decrease), triacylglycerol (64% decrease), and cholesterol esters (58% decrease) were significantly diminished. Because these lipid metabolic processes take place in different subcellular organelles, we used immunofluorescence and Western blotting of subcellular fractions to investigate the distribution of FATP4 protein and measured enzyme activity ...

The second member of the human and murine bubblegum family is a testis- and brainstem-specific acyl-CoA synthetase

The Journal of biological chemistry, Jan 10, 2006

Acyl-CoA synthetases that activate fatty acids to their CoA derivatives play a central role in fa... more Acyl-CoA synthetases that activate fatty acids to their CoA derivatives play a central role in fatty acid metabolism. ACSBG1, an acyl-CoA synthetase originally identified in the fruit fly mutant bubblegum, was hypothesized to contribute to the biochemical pathology of X-linked adrenoleukodystrophy. We looked for homologous proteins and identified ACSBG2 in humans, mice, and rats. Human ACSBG1 and ACSBG2 amino acid sequences are 50% identical. ACSBG2 expression was confined to the testis and brainstem. Immunohistochemistry and in situ hybridization studies further localized ACSBG2 expression to testicular Sertoli cells and large motoneurons in the medulla oblongata and cervical spinal cord. Full-length cDNA encoding human and mouse ACSBG2 was cloned. In transfected COS-1 cells, both human and murine ACSBG2 were detected as 75- to 80-kDa proteins by Western blot. Cells overexpressing ACSBG2 had increased ability to activate oleic acid (C18:1omega9) and linoleic acid (C18:2omega6) but ...

Expression of ERCC1, TYMS, RRM1, TUBB3, non-muscle myosin II, myoglobin and MyoD1 in lung adenocarcinoma pleural effusions predicts survival in patients receiving platinum-based chemotherapy

Molecular Medicine Reports, 2014

The association between the expression of excision repair cross‑complementing gene 1 (ERCC1), thy... more The association between the expression of excision repair cross‑complementing gene 1 (ERCC1), thymidylate synthase (TYMS), ribonuleotide reductase M1 (RRM1), βIII‑tubulin (TUBB3), non‑muscle myosin II, myoglobin and MyoD1 in metastatic lung adenocarcinoma, and clinical outcomes with platinum‑based chemotherapy treatment is not well‑established. Recently, increasing attention has been focused on the involvement of ERCC1, TYMS, RRM1 and TUBB3 in the development of drug resistance. There has been less research into the role of muscle myosin II, myoglobin and MyoD1 in the pathogenesis of lung cancer, although these genes are known to have important functions within tumor cells. In the current study, malignant pleural effusion from 116 patients with untreated lung adenocarcinoma diagnosed between 2011 and 2012, were collected. The protein expression levels of ERCC1, TYMS, RRM1 and TUBB3 were evaluated with immunocytochemistry and western blot analysis. The expression levels of non‑muscle myosin II, myoglobin and MyoD1 were measured in a subset of 50 patients, treated with platinum‑based chemotherapy. The association of each of these seven factors with one another, as well as with patient survival were analyzed. Immunohistochemistry demonstrated that the percentage of pleural fluid samples from patients with lung adenocarcinoma expressing ERCC1, TYMS, RRM1 and TUBB3 was 37, 36.2, 82.7 and 69.8%, respectively. In the subset of 50 patients in whom the remaining factors were analyzed, the percentage expressing non‑muscle myosin II was 48%, for myoglobin the figure was 40% and for MyoD1 it was 38%. There was a positive correlation between each pair of the above seven molecules with the exception of TYMS and RRM1. Expression of ERCC1, TYMS, TUBB3, non‑muscle myosin II, myoglobin and MyoD1 genes was associated with decreased survival in patients with metastatic lung adenocarcinoma. Expression of ERCC1, TYMS, TUBB3, non‑muscle myosin II, myoglobin and MyoD1 was also associated with decreased survival rates of patients with lung adenocarcinoma treated with platinum‑based chemotherapy. These factors may be used as clinical biomarkers to predict the biological behavior and chemoresistance of tumor cells, and the survival of patients with lung carcinoma.

PLoS Pathogens, 2013

All positive strand (+RNA) viruses of eukaryotes replicate their genomes in association with memb... more All positive strand (+RNA) viruses of eukaryotes replicate their genomes in association with membranes. The mechanisms of membrane remodeling in infected cells represent attractive targets for designing future therapeutics, but our understanding of this process is very limited. Elements of autophagy and/or the secretory pathway were proposed to be hijacked for building of picornavirus replication organelles. However, even closely related viruses differ significantly in their requirements for components of these pathways. We demonstrate here that infection with diverse picornaviruses rapidly activates import of long chain fatty acids. While in non-infected cells the imported fatty acids are channeled to lipid droplets, in infected cells the synthesis of neutral lipids is shut down and the fatty acids are utilized in highly up-regulated phosphatidylcholine synthesis. Thus the replication organelles are likely built from de novo synthesized membrane material, rather than from the remodeled pre-existing membranes. We show that activation of fatty acid import is linked to the upregulation of cellular long chain acyl-CoA synthetase activity and identify the long chain acyl-CoA syntheatse3 (Acsl3) as a novel host factor required for polio replication. Poliovirus protein 2A is required to trigger the activation of import of fatty acids independent of its protease activity. Shift in fatty acid import preferences by infected cells results in synthesis of phosphatidylcholines different from those in uninfected cells, arguing that the viral replication organelles possess unique properties compared to the pre-existing membranes. Our data show how poliovirus can change the overall cellular membrane homeostasis by targeting one critical process. They explain earlier observations of increased phospholipid synthesis in infected cells and suggest a simple model of the structural development of the membranous scaffold of replication complexes of picorna-like viruses, that may be relevant for other (+)RNA viruses as well.

PLoS ONE, 2013

Lung cancer is the leading cause of cancer deaths worldwide. In the United States, only one in si... more Lung cancer is the leading cause of cancer deaths worldwide. In the United States, only one in six lung cancer patients survives five years after diagnosis. These statistics may improve if new therapeutic targets are identified. We previously reported that an enzyme of fatty acid metabolism, very long-chain acyl-CoA synthetase 3 (ACSVL3), is overexpressed in malignant glioma, and that depleting glioblastoma cells of ACSVL3 diminishes their malignant properties. To determine whether ACSVL3 expression was also increased in lung cancer, we studied tumor histologic sections and lung cancer cell lines. Immunohistochemical analysis of normal human lung showed moderate ACSVL3 expression only in bronchial epithelial cells. In contrast, all of 69 different lung tumors tested, including adeno-, squamous cell, large cell, and small cell carcinomas, had robustly elevated ACSVL3 levels. Western blot analysis of lung cancer cell lines derived from these tumor types also had significantly increased ACSVL3 protein compared to normal bronchial epithelial cells. Decreasing the growth rate of lung cancer cell lines did not change ACSVL3 expression. However, knocking down ACSVL3 expression by RNA interference reduced cell growth rates in culture by 65-76%, and the ability of tumor cells to form colonies in soft agar suspension by 65-80%. We also conducted studies to gain a better understanding of the biochemical properties of human ACSVL3. ACSVL3 mRNA was detected in many human tissues, but the expression pattern differed somewhat from that of the mouse. The enzyme activated long-and very long-chain saturated fatty acid substrates, as well as long-chain mono-and polyunsaturated fatty acids to their respective coenzyme A derivatives. Endogenous human ACSVL3 protein was found in a punctate subcellular compartment that partially colocalized with mitochondria as determined by immunofluorescence microscopy and subcellular fractionation. From these studies, we conclude that ACSVL3 is a promising new therapeutic target in lung cancer.

X-linked adrenoleukodystrophy: role of very long-chain acyl-CoA synthetases

Molecular Genetics and Metabolism, 2004

The principal biochemical abnormality in the neurodegenerative disorder X-linked adrenoleukodystr... more The principal biochemical abnormality in the neurodegenerative disorder X-linked adrenoleukodystrophy (X-ALD) is elevated plasma and tissue levels of very long-chain fatty acids (VLCFA). Enzymes with very long-chain acyl-CoA synthetase (VLACS) activity are required for VLCFA metabolism, including degradation by peroxisomal beta-oxidation or incorporation into complex lipids, and may also participate in VLCFA synthesis. Two enzymes with VLACS activity, ACSVL1 and BG1, were investigated for their potential role in X-ALD biochemical pathology. Skin fibroblast mRNA levels for ACSVL1, an enzyme previously shown to be in peroxisomes and to participate in VLCFA beta-oxidation, were not significantly different between normal controls, patients with childhood cerebral X-ALD, and patients with adrenomyeloneuropathy. Similar results were obtained with mRNA for BG1, a non-peroxisomal enzyme that is highly expressed in nervous system, adrenal gland, and testis, the principal tissues pathologically affected in X-ALD. No significant differences in the immunohistochemical staining patterns of tissues expressing either ACSVL1 or BG1 were observed when wild-type and X-ALD mice were compared. Western blot analysis of BG1 protein levels showed no differences between fibroblasts from controls, cerebral X-ALD, or adrenomyeloneuropathy patients. BG1 protein levels were similar in wild-type and X-ALD mouse brain, spinal cord, testis, and adrenal gland. We hypothesized that one function of BG1 was to direct VLCFA into the cholesterol ester synthesis pathway. However, BG1 depletion in Neuro2a cells using RNA interference did not decrease incorporation of labeled VLCFA into cholesterol esters. We conclude that the role, if any, of ACSVL1 and BG1 in X-ALD biochemical pathology is indirect.

Molecular Genetics and Metabolism, 2011

Long-chain fatty acids are an important source of energy in muscle and heart where the acyl-CoA d... more Long-chain fatty acids are an important source of energy in muscle and heart where the acyl-CoA dehydrogenases (ACADs) participate in consecutive cycles of β-oxidation to generate acetyl-CoA and reducing equivalents for generating energy. However, the role of long-chain fatty acid oxidation in the brain and other tissues that do not rely on fat for energy is poorly understood. Here we characterize two new ACADs, ACAD10 and ACAD11, both with significant expression in human brain. ACAD11 utilizes substrates with primary carbon chain lengths between 20 and 26, with optimal activity towards C22CoA. The combination of ACAD11 with the newly characterized ACAD9 accommodates the full spectrum of long chain fatty acid substrates presented to mitochondrial β-oxidation in human cerebellum. ACAD10 has significant activity towards the branched-chain substrates R and S, 2 methyl-C15-CoA and is highly expressed in fetal but not adult brain. This pattern of expression is similar to that of LCAD, another ACAD previously shown to be involved in long branched chain fatty acid metabolism. Interestingly, the ACADs in human cerebellum were found to have restricted cellular distribution. ACAD9 was most highly expressed in the granular layer, ACAD11 in the white matter, and MCAD in the molecular layer and axons of specific neurons. This compartmentalization of ACADs in the human central nerve system, suggests that β-oxidation in cerebellum participates in different functions other than generating energy, for example, the synthesis and/or degradation of unique cellular lipids and catabolism of aromatic amino acids, compounds that are vital to neuronal function.

Laboratory Investigation, 2007

X-linked adreno-leukodystrophy is a progressive, systemic peroxisomal disorder that primarily aff... more X-linked adreno-leukodystrophy is a progressive, systemic peroxisomal disorder that primarily affects the adrenal cortex, as well as myelin and axons of the central nervous system. Marked phenotypic heterogeneity does not correlate with disease-causing mutations in ABCD1, which encodes a peroxisomal membrane protein that is a member of the ABC transmembrane transporter proteins. The precise physiological functions of ABCD1 and ABCD2, a closely related peroxisomal membrane half-transporter, are unknown. The abcd1 knockout mouse does not develop the inflammatory demyelination so typical and devastating in adreno-leukodystrophy, but it does display the same lamellae and lipid profiles in adrenocortical cells under the electron microscope as the human patients. The adrenocortical cells in the mouse also exhibit immunohistochemical evidence of oxidative stress at 12 weeks but no evidence of oxidative damage. To better understand the pathogenesis of this complex disease, we evaluate the adrenal lesion of the abcd1 knockout mouse as a function of normal aging, dietary or therapeutic manipulations, and abcd genotype. The loss of abcd2 causes oxidative stress in the adrenal at 12 weeks, as judged by increased immunoreactivity for the mitochondrial manganese superoxide dismutase, in both the inner cortex and medulla. The loss of abcd2 (n ¼ 20), but not abcd1 (n ¼ 27), results in the spontaneous and premature deposition of ceroid, a known end-product of oxidative damage, predominantly in adrenal medullary cells. These data indicate that the loss of abcd2 results in greater oxidative stress in murine adrenal cells than the loss of abcd1, providing a clue to its cellular function. We also find that the adrenocortical lesion of the abcd1 knockout mouse does not produce functional impairment at ten to nineteen months or overt hypocortisolism at any age, nor does it progress histologically; these and other data align this mouse model closer to human female heterozygotes than to male ALD or AMN hemizygotes.

Journal of Hepatology, 2006

The Acyl-CoA Synthetase "Bubblegum" (Lipidosin): FURTHER CHARACTERIZATION AND ROLE IN NEURONAL FATTY ACID -OXIDATION

Journal of Biological Chemistry, 2003

Acyl-CoA synthetases play a pivotal role in fatty acid metabolism, providing activated substrates... more Acyl-CoA synthetases play a pivotal role in fatty acid metabolism, providing activated substrates for fatty acid catabolic and anabolic pathways. Acyl-CoA synthetases comprise numerous proteins with diverse substrate specificities, tissue expression patterns, and subcellular localizations, suggesting that each enzyme directs fatty acids toward a specific metabolic fate. We reported that hBG1, the human homolog of the acyl-CoA synthetase mutated in the Drosophila mutant &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;bubblegum,&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; belongs to a previously unidentified enzyme family and is capable of activating both long- and very long-chain fatty acid substrates. We now report that when overexpressed, hBG1 can activate diverse saturated, monosaturated, and polyunsaturated fatty acids. Using in situ hybridization and immunohistochemistry, we detected expression of mBG1, the mouse homolog of hBG1, in cerebral cortical and cerebellar neurons and in steroidogenic cells of the adrenal gland, testis, and ovary. The expression pattern and ability of BG1 to activate very long-chain fatty acids implicates this enzyme in the pathogenesis of X-linked adrenoleukodystrophy. In neuron-derived Neuro2a cells, mBG1 co-sedimented with mitochondria and was found in small vesicular structures located in close proximity to mitochondria. RNA interference was used to decrease mBG1 expression in Neuro2a cells and led to a 30-35% decrease in activation and beta-oxidation of the long-chain fatty acid, palmitate. These results suggest that in Neuro2a cells, mBG1-activated long-chain fatty acids are directed toward mitochondrial degradation. mBG1 appears to play a minor role in very long-chain fatty acid activation in these cells, indicating that other acyl-CoA synthetases are necessary for very long-chain fatty acid metabolism in Neuro2a cells.

Mouse Very Long-chain Acyl-CoA Synthetase 3/Fatty Acid Transport Protein 3 Catalyzes Fatty Acid Activation but Not Fatty Acid Transport in MA-10 Cells

Journal of Biological Chemistry, 2004

The family of proteins that includes very long-chain acyl-CoA synthetases (ACSVL) consists of six... more The family of proteins that includes very long-chain acyl-CoA synthetases (ACSVL) consists of six members. These enzymes have also been designated fatty acid transport proteins. We cloned full-length mouse Acsvl3 cDNA and characterized its protein product ACSVL3/fatty acid transport protein 3. The predicted amino acid sequence contains two highly conserved motifs characteristic of acyl-CoA synthetases. Northern blot analysis revealed that the mouse Acsvl3 mRNA is highly expressed in adrenal gland, testis, and ovary, with lower expression in the brain of adult mice. A developmental Northern blot revealed that Acsvl3 mRNA levels were significantly higher in embryonic mouse brain (embryonic days 12-14) than in newborn or adult mice, suggesting a possible role in nervous system development. Immunohistochemistry revealed high ACSVL3 expression in adrenal cortical cells, spermatocytes and interstitial cells of the testis, theca cells of the ovary, cerebral cortical neurons, and cerebellar Purkinje cells. Endogenous ACSVL3 was found primarily in mitochondria of MA-10 and Neuro2a cells by both Western blot analysis of subcellular fractions and immunofluorescence analysis. In MA-10 cells, loss-of-function studies using RNA interference confirmed that endogenous ACSVL3 is an acyl-CoA synthetase capable of activating both long-chain (C16:0) and very long-chain (C24:0) fatty acids. However, despite decreased acyl-CoA synthetase activity, initial rates of fatty acid uptake were unaffected by knockdown of Acsvl3 expression in MA-10 cells. These studies cast doubt on the designation of ACSVL3 as a fatty acid transport protein.

Acyl-CoA Synthetase VL3 Knockdown Inhibits Human Glioma Cell Proliferation and Tumorigenicity

Cancer Research, 2009

The contribution of lipid metabolic pathways to malignancy is poorly understood. Expression of th... more The contribution of lipid metabolic pathways to malignancy is poorly understood. Expression of the fatty acyl-CoA synthetase ACSVL3 was found to be markedly elevated in clinical malignant glioma specimens but nearly undetectable in normal glia. ACSVL3 levels correlated with the malignant behavior of human glioma cell lines and glioma cells propagated as xenografts. ACSVL3 expression was induced by the activation of oncogenic receptor tyrosine kinases (RTK) c-Met and epidermal growth factor receptor. Inhibiting c-Met activation with neutralizing anti-hepatocyte growth factor monoclonal antibodies reduced ACSVL3 expression concurrent with tumor growth inhibition in vivo. ACSVL3 expression knockdown using RNA interference, which decreased long-chain fatty acid activation, inhibited anchorage-dependent and anchorage-independent glioma cell growth by approximately 70% and approximately 90%, respectively. ACSVL3-depleted cells were less tumorigenic than control cells, and subcutaneous xenografts grew approximately 60% slower than control tumors. Orthotopic xenografts produced by ACSVL3-depleted cells were 82% to 86% smaller than control xenografts. ACSVL3 knockdown disrupted Akt function as evidenced by RTK-induced transient decreases in total and phosphorylated Akt, as well as glycogen synthase kinase 3beta, via a caspase-dependent mechanism. Expressing constitutively active myr-Akt rescued cells from the anchorage-dependent and anchorage-independent growth inhibitory effects of ACSVL3 depletion. These studies show that ACSVL3 maintains oncogenic properties of malignant glioma cells via a mechanism that involves, in part, the regulation of Akt function.

Neuroendocrinology, 2009

Background-The dopamine (DA) D 2 receptor (D2R) agonist bromocriptine (BC) decreases body fat in ... more Background-The dopamine (DA) D 2 receptor (D2R) agonist bromocriptine (BC) decreases body fat in animal and human models and increases lean muscle mass, improves glucose intolerance and insulin resistance, and reduces triglycerides and free fatty acids. We have previously shown a negative correlation between D2R and body weight in obese individuals and in rodents, and that chronic food restriction increases D2R binding in genetically obese rats. The purpose of this study was to assess whether the antiobesity and metabolic effects of BC are related to changes in midbrain DA and D2R activity by measuring D2R and DA transporter (DAT) binding in a genetic (leptin-receptor-deficient) and environmental (diet-induced) rodent obesity model.