Fasting in α1-antitrypsin deficient liver: constitutive activation of autophagy

2002 ◽  
Vol 283 (5) ◽  
pp. G1156-G1165 ◽  
Author(s):  
Jeffrey H. Teckman ◽  
Jae-Koo An ◽  
Scott Loethen ◽  
David H. Perlmutter
Keyword(s):  
Liver Injury ◽  
Developmental State ◽  
Limited Information ◽  
Wild Type ◽  
Prolonged Fasting ◽  
Response To Stress ◽  
At Deficiency ◽  
Specific Increase ◽  
Altered Response ◽  
Physiological Stressor

α1-Antitrypsin (α1-AT) deficiency causes severe liver injury in a subgroup of patients. Liver injury is thought to be caused by retention of a polymerized mutant α1-ATZ molecule in the endoplasmic reticulum (ER) of hepatocytes and is associated with an intense autophagic response. However, there is limited information about what physiologic stressors might influence liver injury. In this study, we examined the effect of fasting in the PiZ mouse model of α1-AT deficiency, because fasting is a well-characterized physiological stressor and a known stimulus for autophagy. Results show that there is a marked increase in fat accumulation and in α1-AT-containing globules in the liver of the PiZ mouse induced by fasting. Although fasting induced a marked autophagic response in wild-type mice, the autophagic response was already activated in PiZ mice and did not further increase with fasting. PiZ mice also had a significantly decreased tolerance for prolonged fasting compared with wild-type mice (PiZ mice 0% survival of 72-h fast; wild-type 100% survivial). These results demonstrate an altered response to stress in the α1-AT-deficient liver, including inability to further increase an activated autophagic response, a developmental state-specific increase in α1-AT-containing globules, and increased mortality.

scholarly journals Stem cell factor and c-kit are involved in hepatic recovery after acetaminophen-induced liver injury in mice

2008 ◽  
Vol 295 (1) ◽  
pp. G45-G53 ◽  
Author(s):  
Bin Hu ◽  
Lisa M. Colletti
Keyword(s):  
Stem Cell ◽  
Liver Injury ◽  
Stem Cell Factor ◽  
Cellular Proliferation ◽  
Hepatocyte Proliferation ◽  
Mrna Levels ◽  
Wild Type ◽  
Hepatocyte Apoptosis ◽  
Large Reservoir ◽  
A Cell

Stem cell factor (SCF) and its receptor c-kit are important in hematopoiesis and cellular proliferation. c-kit has also been identified as a cell surface marker for progenitor cells. We have previously shown that there is a large reservoir of hepatic SCF, and this molecule plays a significant role in liver regeneration after 70% hepatectomy. In the current study, we further examined the expression of SCF and c-kit in acetaminophen (APAP)-induced liver injury in C57BL/6J mice or SCF-deficient sl-sld mice and their appropriate wild-type controls. Following APAP-induced liver injury, c-kit mRNA expression increased, with peak levels detected 48 h postinjury. Hepatic SCF mRNA levels after APAP injury were also increased, with peak levels seen 16 h post-APAP. The mortality rate in SCF-deficient mice treated with APAP was significantly higher than that of wild-type mice; furthermore, administration of exogenous SCF significantly reduced the mortality of APAP-treated wild-type mice. Bromodeoxyuridine incorporation experiments showed that SCF significantly increased hepatocyte proliferation at 48 and 72 h in APAP-treated mice. SCF inhibited APAP-induced hepatocyte apoptosis and increased Bcl-2 and Bcl-xL expression, suggesting that this decrease in hepatocyte apoptosis is mediated through Bcl-2 and Bcl-xL. In summary, SCF and c-kit expression was increased after APAP-induced liver injury. Administration of exogenous SCF reduces mortality in APAP-treated mice, increases hepatocyte proliferation, and prevents hepatocyte apoptosis induced by APAP, suggesting that these molecules are important in the liver's recovery from these injuries.

scholarly journals Defining dysfunction due to loss of MECP2 in Rett Patient Brain

2021 ◽  
Author(s):  
E Korsakova ◽  
A Morales ◽  
T McDaniel ◽  
A Lund ◽  
B Cooper ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Metabolic Pathways ◽  
Transcriptional Profiling ◽  
Childhood Development ◽  
Wild Type ◽  
Aberrant Expression ◽  
Metabolic Genes ◽  
Female Brain ◽  
Response To Stress

AbstractRett Syndrome is characterized by a postnatal loss of neurophysiological function and regression of childhood development. Because the syndrome is X-linked and males with MECP2 mutations generally do not survive birth, the study of this syndrome has been complicated by the fact that in female brain, a portion of neurons express wild type MECP2, and another portion express a non-functional allele of MECP2. Therefore, bulk-RNA-sequencing of Rett brain is confounded by the presence of chimerism of neurons for functional MECP2 in neurons. We developed an approach that allows for single-nuclei transcriptional profiling of individual neurons and a direct comparison between neurons that express functional MECP2 with those that express the disease-causing allele. We found that mutant neurons from Rett brain show patterns of aberrant expression of synaptic and metabolic genes, both of which can be detected in in vitro models of Rett Syndrome. We used these resources to identify a role for POU2F1/OCT1 transcription factor in mediating the response to stress due to loss of MECP2, highlighting a potential key molecular regulator of stress in Rett neurons. Together, our new sorting approach enables us to highlight defective molecular and metabolic pathways in Rett brain neurons and suggests that in vitro models could serve as valuable tools to further study this syndrome and potentially for development of novel therapeutics.

scholarly journals Phosphatidylcholine transfer protein/StarD2 promotes microvesicular steatosis and liver injury in murine experimental steatohepatitis

2017 ◽  
Vol 313 (1) ◽  
pp. G50-G61 ◽  
Author(s):  
Hayley T. Nicholls ◽  
Jason L. Hornick ◽  
David E. Cohen
Keyword(s):  
Liver Injury ◽  
Lipid Droplets ◽  
Plasma Concentrations ◽  
Fibroblast Growth Factor 21 ◽  
Wild Type ◽  
Hepatocellular Injury ◽  
Pathogenic Role ◽  
Deficient Diet ◽  
Transfer Protein ◽  
Phosphatidylcholine Transfer Protein

Mice fed a methionine- and choline-deficient (MCD) diet develop steatohepatitis that recapitulates key features of nonalcoholic steatohepatitis (NASH) in humans. Phosphatidylcholine is the most abundant phospholipid in the surfactant monolayer that coats and stabilizes lipid droplets within cells, and choline is required for its major biosynthetic pathway. Phosphatidylcholine-transfer protein (PC-TP), which exchanges phosphatidylcholines among membranes, is enriched in hepatocytes. PC-TP also regulates fatty acid metabolism through interactions with thioesterase superfamily member 2. We investigated the contribution of PC-TP to steatohepatitis induced by the MCD diet. Pctp−/− and wild-type control mice were fed the MCD diet for 5 wk and were then euthanized for histopathologic and biochemical analyses, as well as determinations of mRNA and protein expression. Whereas all mice developed steatohepatitis, plasma alanine aminotransferase and aspartate aminotransferase activities were only elevated in wild-type mice, indicating that Pctp−/− mice were protected from MCD diet-induced hepatocellular injury. Reduced hepatotoxicity due to the MCD diet in the absence of PC-TP expression was further evidenced by decreased activation of c-Jun and reduced plasma concentrations of fibroblast growth factor 21. Despite similar total hepatic concentrations of phosphatidylcholines and other lipids, the relative abundance of microvesicular lipid droplets within hepatocytes was reduced in Pctp−/− mice. Considering that the formation of larger lipid droplets may serve to protect against lipotoxicity in NASH, our findings suggest a pathogenic role for PC-TP that could be targeted in the management of this condition. NEW & NOTEWORTHY Phosphatidylcholine-transfer protein (PC-TP) is a highly specific phosphatidylcholine-binding protein that we previously showed to regulate hepatocellular nutrient metabolism through its interacting partner thioesterase superfamily member 2 (Them2). This study identifies a pathogenic role for PC-TP, independent of Them2, in the methionine- and choline-deficient diet model of experimental steatohepatitis. Our current observations suggest that PC-TP promotes liver injury by mediating the intermembrane transfer of phosphatidylcholines, thus stabilizing more pathogenic microvesicular lipid droplets.

Contribution of the TROLC gene to the regulation of tobacco growth in response to stress factors.

Biomics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 360-367
Author(s):  
B.R. Kuluev ◽  
Kh.G. Musin ◽  
E.A. Baimuhametova
Keyword(s):  
Transgenic Plants ◽  
Root Growth ◽  
Shoot Growth ◽  
Growth Parameters ◽  
Cadmium Acetate ◽  
Stress Factors ◽  
Wild Type ◽  
Abiotic Stress Factors ◽  
Negative Effect ◽  
Response To Stress

The trolC gene refers to plast genes that have entered the genome of Nicotiana tabacum as a probable result of horizontal transfer from Agrobacterium rhizogenes. It was shown that the trolC gene is expressed in young tissues of wild type tobacco; however, the physiological functions of the product of this gene remain largely unknown. The aim of our work was to obtain transgenic tobacco plants expressing a fragment of the trolC gene under the control of the 35SCaMV promoter in an antisense orientation and to assess the growth parameters of their roots under the action of abiotic stress factors. For morphometric analysis, 8 lines of transgenic plants were used. The analysis of root growth under the action of sodium chloride (100 mM), cadmium acetate (100 μM) and hypothermia (12°C) was conducted. Transgenic plants were characterized by improved shoot growth parameters under normal conditions. The roots of transgenic plants grew more slowly under normal conditions and under the action of cadmium and hypothermia than in wild type plants. The product of trolC gene has a negative effect on shoot growth, a positive effect on root growth, and also participates in the regulation and maintenance of root growth under the action of cadmium and hypothermia.

scholarly journals Spectrofluorometric Analysis of Autofluorescing Components of Crude Serum from a Rat Liver Model of Ischemia and Reperfusion

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1327 ◽  
Author(s):  
Anna C. Croce ◽  
Andrea Ferrigno ◽  
Clarissa Berardo ◽  
Giovanni Bottiroli ◽  
Mariapia Vairetti ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Liver Injury ◽  
Direct Detection ◽  
Ischemia Reperfusion ◽  
Cost Effective ◽  
Serum Samples ◽  
Spectral Parameters ◽  
Pure Compounds ◽  
Spectral Profiles ◽  
Response To Stress

Autofluorescence (AF) of crude serum was investigated with reference to the potential of its intrinsic AF biomarkers for the noninvasive diagnosis of liver injury. Spectral parameters of pure compounds representing retinol (vitamin A) and fluorescing free fatty acids were characterized by spectrofluorometry, to assess spectral parameters for the subsequent AF analysis of serum, collected from rats undergoing liver ischemia/reperfusion (I/R). Differences in AF spectral profiles detected between control and I/R were due to the increase in the AF components representing fatty acids in I/R serum samples. No significant changes occurred for retinol levels, consistently with the literature reporting that constant retinol levels are commonly observed in the blood, except for malnutrition or chronic severe liver disease. Conversely, fatty acids, in particular arachidonic and linoleic acid and their derivatives, act as modulating agents in inflammation, representing both a protective and damaging response to stress stimuli. The biometabolic and pathophysiological meaning of serum components and the possibility of their direct detection by AF spectrofluorometry open up interesting perspectives for the development of AF serum analysis, as a direct, cost effective, supportive tool to assess liver injury and related systemic metabolic alterations, for applications in experimental biomedicine and foreseen translation to the clinics.

scholarly journals Cell-specific regulatory effects of CXCR2 on cholestatic liver injury

2019 ◽  
Vol 317 (6) ◽  
pp. G773-G783 ◽  
Author(s):  
Takanori Konishi ◽  
Rebecca M. Schuster ◽  
Holly S. Goetzman ◽  
Charles C. Caldwell ◽  
Alex B. Lentsch
Keyword(s):  
Bile Duct ◽  
Liver Injury ◽  
Liver Damage ◽  
Chemokine Receptor ◽  
Therapeutic Target ◽  
Bile Duct Ligation ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Duct Ligation ◽  
Cholestatic Liver Injury

The CXC chemokine receptor 2 (CXCR2) is critical for neutrophil recruitment and hepatocellular viability but has not been studied in the context of cholestatic liver injury following bile duct ligation (BDL). The present study sought to elucidate the cell-specific roles of CXCR2 on acute liver injury after BDL. Wild-type and CXCR2−/− mice were subjected BDL. CXCR2 chimeric mice were created to assess the cell-specific role of CXCR2 on liver injury after BDL. SB225002, a selective CXCR2 antagonist, was administrated intraperitoneally after BDL to investigate the potential of pharmacological inhibition. CXCR2−/− mice had significantly less liver injury than wild-type mice at 3 and 14 days after BDL. There was no difference in biliary fibrosis among groups. The chemokines CXCL1 and CXCL2 were induced around areas of necrosis and biliary structures, respectively, both areas where neutrophils accumulated after BDL. CXCR2−/− mice showed significantly less neutrophil accumulation in those injured areas. CXCR2Liver+/Myeloid+ and CXCR2Liver−/Myeloid− mice recapitulated the wild-type and CXCR2-knockout phenotypes, respectively. CXCR2Liver+/Myeloid+ mice suffered higher liver injury than CXCR2Liver+/Myeloid− and CXCR2Liver−/Myeloid+; however, only those chimeras with knockout of myeloid CXCR2 (CXCR2Liver+/Myeloid− and CXCR2Liver−/Myeloid−) showed reduction of neutrophil accumulation around areas of necrosis. Daily administration of SB225002 starting after 3 days of BDL reduced established liver injury at 6 days. In conclusion, neutrophil CXCR2 guides the cell to the site of injury, while CXCR2 on liver cells affects liver damage independent of neutrophil accumulation. CXCR2 appears to be a viable therapeutic target for cholestatic liver injury. NEW & NOTEWORTHY This study is the first to reveal cell-specific roles of the chemokine receptor CXCR2 in cholestatic liver injury caused by bile duct ligation. CXCR2 on neutrophils facilitates neutrophil recruitment to the liver, while CXCR2 on liver cells contributes to liver damage independent of neutrophils. CXCR2 may represent a viable therapeutic target for cholestatic liver injury.

scholarly journals Ecto-Nucleotide Triphosphate Diphosphohydrolase-2 (NTPDase2) Deletion Increases Acetaminophen-Induced Hepatotoxicity

2020 ◽  
Vol 21 (17) ◽  
pp. 5998
Author(s):  
Linda Feldbrügge ◽  
Katrin Splith ◽  
Ines Kämmerer ◽  
Sandra Richter ◽  
Anna Riddermann ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Toxicity ◽  
Wild Type ◽  
Protective Properties ◽  
Hepatic Expression ◽  
Markers Of Inflammation ◽  
Acute Necrotizing ◽  
Portal Fibroblast ◽  
Portal Fibroblasts

Ecto-nucleotidase triphosphate diphosphohydrolase-2 (NTPDase2) is an ecto-enzyme that is expressed on portal fibroblasts in the liver that modulates P2 receptor signaling by regulating local concentrations of extracellular ATP and ADP. NTPDase2 has protective properties in liver fibrosis and may impact bile duct epithelial turnover. Here, we study the role of NTPDase2 in acute liver injury using an experimental model of acetaminophen (APAP) intoxication in mice with global deletion of NTPDase2. Acute liver toxicity was caused by administration of acetaminophen in wild type (WT) and NTPDase2-deficient (Entpd2 null) mice. The extent of liver injury was compared by histology and serum alanine transaminase (ALT). Markers of inflammation, regeneration and fibrosis were determined by qPCR). We found that Entpd2 expression is significantly upregulated after acetaminophen-induced hepatotoxicity. Entpd2 null mice showed significantly more necrosis and higher serum ALT compared to WT. Hepatic expression of IL-6 and PDGF-B are higher in Entpd2 null mice. Our data suggest inducible and protective roles of portal fibroblast-expressed NTPDase2 in acute necrotizing liver injury. Further studies should investigate the relevance of these purinergic pathways in hepatic periportal and sinusoidal biology as such advances in understanding might provide possible therapeutic targets.

The chemokine scavenging receptor D6 limits acute toxic liver injury in vivo

2009 ◽  
Vol 390 (10) ◽  
Author(s):  
Marie-Luise Berres ◽  
Christian Trautwein ◽  
Mirko Moreno Zaldivar ◽  
Petra Schmitz ◽  
Katrin Pauels ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Damage ◽  
Immune Modulation ◽  
Scavenger Receptor ◽  
Wild Type ◽  
Protein Levels ◽  
Inflammatory Chemokines ◽  
Toxic Liver Injury ◽  
Acute Toxic

Abstract The chemokine decoy receptor D6 is a promiscuous chemokine receptor lacking classical signaling functions. It negatively regulates inflammation by targeting CC chemokines to cellular internalization and degradation. Here we analyze the function of D6 in acute CCl4-induced liver damage in constitutive D6-/- and wild-type mice. The degree of liver injury was assessed by liver histology, serum transaminases, IL-6, and TNFα mRNA expression. Protein levels of D6 ligands (CCL2, CCL3, CCL5) and the non-D6-ligand CXCL9 within the livers were determined by ELISAs. The intrahepatic infiltration of immune cells was characterized by FACS. Genetic deletion of D6 led to prolonged liver damage after acute CCl4 administration. The augmented liver damage in D6-/- mice was associated with increased protein levels of intrahepatic inflammatory chemokines CCL2, CCL3, and CCL5 after 48 h, whereas CXCL9 was not different between knockout and wild-type mice. Functionally, increased intra-hepatic CC chemokine concentrations led to increased infiltration of CD45+ leukocytes, which were mainly identified as T and NK cells. In conclusion, the chemokine scavenger receptor D6 has a non-redundant role in acute toxic liver injury in vivo. These results support the importance of post-translational chemokine regulation and describe a new mechanism of immune modulation within the liver.

Sign in / Sign up

Export Citation Format

Share Document