Steatohepatitis develops rapidly in transgenic mice overexpressingAbcb11and fed a methionine-choline-deficient diet

2005 ◽  
Vol 288 (6) ◽  
pp. G1321-G1327 ◽  
Author(s):  
Shikha S. Sundaram ◽  
Peter F. Whitington ◽  
Richard M. Green
Keyword(s):  
Transgenic Mice ◽  
Fatty Acid Synthase ◽  
Regulatory Element ◽  
Elevated Serum ◽  
The United States ◽  
Hepatic Triglyceride ◽  
Wild Type ◽  
Serum Aminotransferase ◽  
Tnf Α ◽  
Cytochrome P 450

Nonalcoholic fatty liver disease is the most common reason for abnormal liver chemistries in the United States. The factors that lead from benign steatosis to nonalcoholic steatohepatitis are poorly understood. Transthyretin- Abcb11 (TTR- Abcb11) transgenic mice overexpress the bile salt transporter Abcb11 and hypersecrete biliary lipids. Thus the aim of this study is to employ feeding of the methionine-choline-deficient (MCD) diet to TTR- Abcb11 transgenic mice to further determine the mechanisms responsible for the development of steatohepatitis. FVB/NJ and TTR- Abcb11 mice were fed control or MCD diets for up to 30 days. Serum aminotransferase levels, serum and hepatic triglyceride content, cytokines, markers of oxidative stress, and expression of selective genes were examined. MCD diet-fed TTR- Abcb11, but not wild-type, mice have elevated serum aminotransferase levels when compared after 7 days. They also have significantly lower hepatic triglyceride levels at all time points studied. After 14 days on the MCD diet, TTR- Abcb11 mice have 3-fold increases in TNF-α mRNA and 3.9-fold increases in IL-6 mRNA compared with FVB/NJ mice. TTR- Abcb11 mice also had a greater increase in cytochrome P-450 2E1 expression. A greater decrease in sterol regulatory element binding protein-1c and fatty acid synthase mRNA expression was also seen in TTR- Abcb11 compared with wild-type mice fed an MCD diet. They also have enhanced TNF-α, IL-6, and cytochrome P-450 2E1 expression. We conclude that TTR- Abcb11 mice develop a more rapid hepatitis with less steatosis.

Adenoviral E3-14.7K protein in LPS-induced lung inflammation

2000 ◽  
Vol 278 (4) ◽  
pp. L631-L639 ◽  
Author(s):  
Kevin S. Harrod ◽  
Amber D. Mounday ◽  
Jeffrey A. Whitsett
Keyword(s):  
Transgenic Mice ◽  
Lung Inflammation ◽  
Cell Injury ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Respiratory Epithelium ◽  
Wild Type ◽  
Intracellular Staining ◽  
Intratracheal Administration ◽  
Tnf Α

The adenoviral E3-14.7K protein is a cytoplasmic protein synthesized after adenoviral infection. To assess the contribution of E3-14.7K-sensitive pathways in the modulation of inflammation by the respiratory epithelium, inflammatory responses to intratracheal lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α were assessed in transgenic mice bearing the adenoviral E3-14.7K gene under the direction of the surfactant protein (SP) C promoter. When E3-14.7K transgenic mice were administered LPS intratracheally, lung inflammation as indicated by macrophage and neutrophil accumulation in bronchoalveolar lavage fluid was decreased compared with wild-type control mice. Lung inflammation and epithelial cell injury were decreased in E3-14.7K mice 24 and 48 h after LPS administration. Intracellular staining for surfactant proprotein (proSP) B, proSP-C, and SP-B was decreased and extracellular staining was markedly increased in wild-type mice after LPS administration, consistent with LPS-induced lung injury. In contrast, intense intracellular staining of proSP-B, proSP-C, and SP-B persisted in type II cells of E3-14.7K mice, whereas extracellular staining of proSP-B and proSP-C was absent. Inhibitory effects of intratracheal LPS on SP-C mRNA were ameliorated by expression of the E3-14.7Kgene. Similar to the response to LPS, lung inflammation after intratracheal administration of TNF-α was decreased in E3-14.7K transgenic mice. Levels of TNF-α after LPS administration were similar in wild-type and E3-14.7K-bearing mice. Cell-selective expression of E3-14.7K in the respiratory epithelium inhibited LPS- and TNF-α-mediated lung inflammation, demonstrating the critical role of respiratory epithelial cells in LPS- and TNF-α-induced lung inflammation.

scholarly journals Hyperactivity and Learning Deficits in Transgenic Mice Bearing a Human Mutant Thyroid Hormone β1 Receptor Gene

1998 ◽  
Vol 5 (4) ◽  
pp. 289-301 ◽  
Author(s):  
Michael P. McDonald ◽  
Rosemary Wong ◽  
Gregory Goldstein ◽  
Bruce Weintraub ◽  
Sheue-yann Cheng ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Transgenic Mice ◽  
Sustained Attention ◽  
Receptor Gene ◽  
Operant Chamber ◽  
Elevated Serum ◽  
Vigilance Task ◽  
Serum Levels ◽  
Wild Type ◽  
Wild Type Littermate

Resistance to thyroid hormone (RTH) is a human syndrome mapped to the thyroid receptor β(TRβ) gene on chromosome 3, representing a mutation of the ligandbinding domain of the TRβ gene. The syndrome is characterized by reduced tissue responsiveness to thyroid hormone and elevated serum levels of thyroid hormones. A common behavioral phenotype associated with RTH is attention deficit hyperactivity disorder (ADHD). To test the hypothesis that RTH produces attention deficits and/or hyperactivity, transgenic mice expressing a mutant TRβ gene were generated. The present experiment tested RTH transgenic mice from the PV kindred on behavioral tasks relevant to the primary features of ADHD: hyperactivity, sustained attention (vigilance), learning, and impulsivity. Male transgenic mice showed elevated locomotor activity in an open field compared to male wild-type littermate controls. Both male and female transgenic mice exhibited impaired learning of an autoshaping task, compared to wild-type controls. On a vigilance task in an operant chamber, there were no differences between transgenics and controls on the proportion of hits, response latency, or duration of stimulus tolerated. On an operant go/no-go task measuring sustained attention and impulsivity, there were no differences between controls and transgenics. These results indicate that transgenic mice bearing a mutant human TRβ gene demonstrate several behavioral characteristics of ADHD and may serve a valuable heuristic role in elucidating possible candidate genes in converging pathways for other causes of ADHD.

scholarly journals IκB overexpression in cardiomyocytes prevents NF-κB translocation and provides cardioprotection in trauma

2003 ◽  
Vol 284 (3) ◽  
pp. H804-H814 ◽  
Author(s):  
Deborah L. Carlson ◽  
D. Jean White ◽  
David L. Maass ◽  
Robin C. Nguyen ◽  
Brett Giroir ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Tissue ◽  
Nuclear Translocation ◽  
Total Body Surface Area ◽  
Nuclear Factor Κb ◽  
Cardiac Performance ◽  
Wild Type ◽  
Burn Trauma ◽  
Tnf Α ◽  
Cardiac Contractile Dysfunction

This study examined the effects of either IκBα overexpression (transgenic mice) or N-acetyl-leucinyl-leucinyl-norleucinal (ALLN) administration (proteosome inhibitor in wild-type mice) on cardiomyocyte secretion of tumor necrosis factor-α (TNF-α) and on cardiac performance after burn trauma. Transgenic mice were divided into four experimental groups. IκBα overexpressing mice were given a third-degree scald burn over 40% of the total body surface area or wild-type littermates were given either a scald or sham burn to provide appropriate controls. Pharmacological studies included ALLN (20 mg/kg) administration in either burned wild-type mice or wild-type shams. Burn trauma in wild-type mice promoted nuclear factor-κB (NF-κB) nuclear translocation, cardiomyocyte secretion of TNF-α, and impaired cardiac performance. IκBα overexpression or ALLN treatment of burn trauma prevented NF-κB activation in cardiac tissue, prevented cardiomyocyte secretion of TNF-α, and ablated burn-mediated cardiac contractile dysfunction. These data suggest that NF-κB activation and inflammatory cytokine secretion play a significant role in postburn myocardial abnormalities.

149 PRODUCTION OF KNOCK-DOWN MICE WITH shRNA CYTOCHROME P-450 4F16 GENE AND REDUCTION OF THE IMMUNE SYSTEM

2012 ◽  
Vol 24 (1) ◽  
pp. 187
Author(s):  
B. C. Yang ◽  
K. C. Hwang ◽  
K. W. Kim ◽  
H. C. Lee ◽  
H. J. Chung ◽  
...  
Keyword(s):  
Immune System ◽  
Interleukin 1 ◽  
Interleukin 10 ◽  
Wild Type ◽  
Knock Down ◽  
Tnf Α ◽  
C57bl Mice ◽  
Mrna And Protein Expression ◽  
Factor Α ◽  
Cytochrome P 450

The putative mouse homologue of cytochrome P-450 4F16 (Cyp4f16) is induced by interleukin-1 (Il-1), interleukin-6 (Il-6) and tumour necrosis factor-α (Tnf-α) and repressed by interleukin-10 (Il-10) and lipopolysaccharide (LPS). The Cyp4F16 is a subfamily of Cyp4F and it is also related to eicosanoids that are important mediators in the inflammatory cascade (Cui et al. 2001). To investigate the role of Cyp4F16, in the present study, we report the production of Cyp4f16 gene knock-down mice in 2 strains of mice, namely A/J and C57BL/6. The A/J is susceptible to infection and it is associated with Cyp4F16, whereas C57BL/6 is relatively resistant to infection. An shRNA-Cyp4F16 expression vector was microinjected into pronuclei of fertilized mouse oocytes and the embryos were transferred into pseudopregnant recipients. As a result, 25 and 50 mice were produced in the A/J and C57BL, respectively. Two mice in the A/J strain and 6 in the C57BL strain were confirmed by PCR as transgenic. Organs were collected in each of the lines produced by inbreeding and screened with real-time PCR for Cyp4f16 transcripts. The Cyp4f16 gene was expressed in a tissue-specific manner with high expression in the pancreas, spleen and lung and a lower level of transcription in the heart, muscle, thymus, kidney, testis and liver. In the spleen of transgenic Cyp4f16 knock-down mice, Cyp4f16 mRNA and protein expression levels were significantly lower than those of wild-type mice. The A/J Cyp4f16 knock-down mice suffered an inflammatory skin disease and tumours, but wild-type A/J mice and knock-down C57BL mice did not. Taken together, these results suggest that Cyp4f16 may play a regulatory role in the immune system and point to the use of the Cyp4f16 knock-down mouse as an experimental animal model for the study of the inflammatory process. This work was supported by a grant PJ0070762010 from BioGreen 21 Program, Rural Development Administration, Republic of Korea.

Recent Advances in Alcoholic Liver Disease IV. Dysregulated cytokine metabolism in alcoholic liver disease

2004 ◽  
Vol 287 (3) ◽  
pp. G497-G502 ◽  
Author(s):  
Craig J. McClain ◽  
Zhenyuan Song ◽  
Shirish S. Barve ◽  
Daniell B. Hill ◽  
Ion Deaciuc
Keyword(s):  
Liver Disease ◽  
Alcoholic Liver Disease ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Elevated Serum ◽  
Transforming Growth Factor Β ◽  
The United States ◽  
Etiologic Role ◽  
Tnf Α ◽  
New Strategies

Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the United States for which there is no FDA-approved therapy. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentration levels of TNF-α and TNF-α-inducible cytokines/chemokines, such as IL-6, -8, and -18, have been reported in patients with alcoholic hepatitis and/or cirrhosis, and levels correlated with markers of the acute phase response, liver function, and clinical outcome. Studies in animal models support an etiologic role for cytokines in the liver injury of ALD. Cytokines, such as transforming growth factor-β, play a critical role in the fibrosis of ALD. Multiple new strategies are under investigation to modulate cytokine metabolism as a form of therapy for ALD.

scholarly journals Combined Exposure to Fructose and Bisphenol A Exacerbates Abnormal Lipid Metabolism in Liver of Developmental Male Rats

2019 ◽  
Vol 16 (21) ◽  
pp. 4152 ◽  
Author(s):  
Ren Lin ◽  
Yue Jia ◽  
Fengjuan Wu ◽  
Yuan Meng ◽  
Qi Sun ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Bisphenol A ◽  
Fatty Acid Synthase ◽  
Regulatory Element ◽  
Hormone Sensitive Lipase ◽  
Male Rats ◽  
Exposure Group ◽  
Combined Exposure ◽  
Tnf Α ◽  
Abnormal Lipid Metabolism

The aim of this study was to investigate whether combined exposure to fructose and bisphenol A (BPA) has a synergistic effect on abnormal lipid metabolism in the liver of developmental male rats and its possible mechanism. Fifty weaned male Wistar rats were divided into five groups: the control, 13% fructose, 20% fructose, 1 µg/mL BPA, and 13% fructose + 1 µg/mL BPA (combined exposure). Rats were exposed to fructose and/or BPA through drinking water for eight weeks. Genes or proteins regulating lipid metabolism include sterol regulatory element binding protein 1 (SREBP1), adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS), zinc α 2 glycoprotein (ZAG) and estrogen receptor α (ERα), and the expression of proteins regulating inflammatory response, such as TLR4 and NF-κB, were determined. Serum total cholesterol (T-CHO), triglyceride (TG), low, high density lipoprotein cholesterol (LDL-C, HDL-C), blood glucose, insulin, IL-17 and TNF-α levels were also measured. Liver tissue morphology was observed by H&E staining. The results showed that the levels of gene and protein catalyzing lipogenesis were increased (SREBP1, ACC1 and FAS), while those catalyzing lipolysis were decreased (ATGL, HSL and ZAG), accompanied by dyslipidemia, insulin resistance and hepatic fat accumulation, and there were higher expression of TLR4 and NF-κB protein and lower expression of ERα protein in liver, and increased serum IL-17 and TNF-α levels in fructose and/or BPA exposed rats compared with controls. Moreover, the above indicators were more serious in combined exposure group than in single exposure group. Therefore, abnormal lipid metabolism in the liver of developmental rats could be exacerbated by combined exposed to fructose and BPA.

scholarly journals Innate and ozone-induced airway hyperresponsiveness in obese mice: role of TNF-α

2015 ◽  
Vol 308 (11) ◽  
pp. L1168-L1177 ◽  
Author(s):  
Alison Suzanne Williams ◽  
Joel Andrew Mathews ◽  
David Itiro Kasahara ◽  
Allison Patricia Wurmbrand ◽  
Lucas Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Systemic Inflammation ◽  
Airway Hyperresponsiveness ◽  
Elevated Serum ◽  
Airway Responsiveness ◽  
Ozone Exposure ◽  
Protein Carbonyls ◽  
Obese Mice ◽  
Wild Type ◽  
Tnf Α

Innate airway hyperresponsiveness (AHR) and augmented responses to ozone, an asthma trigger, are characteristics of obese mice. Systemic inflammation, a condition of increased circulating concentrations of inflammatory moieties, occurs in obesity. We hypothesized that TNF-α, via its effects as a master effector of this systemic inflammation, regulates innate AHR and augmented responses to ozone in obese mice. Therefore, we examined pulmonary inflammation and airway responsiveness in unexposed or ozone-exposed (2 ppm for 3 h) lean wild-type and obese Cpefatmice that were TNF-α sufficient or deficient. Cpefatmice lack carboxypeptidase E, which regulates satiety. Compared with wild type, Cpefatmice had elevated serum IL-17A, G-CSF, KC, MCP-1, IL-9, MIG, and leptin, indicating systemic inflammation. Despite reductions in most of these moieties in TNF-α-deficient vs. -sufficient Cpefatmice, we observed no substantial difference in airway responsiveness in these two groups of mice. Ozone-induced increases in bronchoalveolar lavage (BAL) neutrophils and macrophages were lower, but ozone-induced AHR and increases in BAL hyaluronan, osteopontin, IL-13, and protein carbonyls, a marker of oxidative stress, were augmented in TNF-α-deficient vs. -sufficient Cpefatmice. Our data indicate that TNF-α has an important role in promoting the systemic inflammation but not the innate AHR of obesity, suggesting that the systemic inflammation of obesity is not the major driver of this AHR. TNF-α is required for the augmented effects of acute ozone exposure on pulmonary inflammatory cell recruitment in obese mice, whereas TNF-α protects against ozone-induced AHR in obese mice, possibly by suppressing ozone-induced oxidative stress.

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