Submicromolar concentrations of 4-hydroxynonenal induce glutamate cysteine ligase expression in HBE1 cells

Zhang, Hongqiao; Court, Nathalie

doi:10.1179/135100007x162266

Cited by 70 publications

(73 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our observations are consistent with prior reports that Nrf2 played a critical role in regulating expression of GCLc and GCLm. 67,68 Our results suggest that the elevation of intracellular redox status might be one of the mechanisms by which Plin5 inhibits HSC activation.…”

Section: Plin5 Restores Ld Formation In Hscmentioning

confidence: 88%

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Lin

Chen

2016

Laboratory Investigation

View full text Add to dashboard Cite

Hepatic stellate cells (HSC) are major effectors during hepatic fibrogenesis. The activation of HSC is coupled to the loss of lipid droplets (LDs), which are specialized organelles composed of neutral lipids surrounded by perilipins. LDs have emerged as a focal point of interest in understanding the metabolic regulation of intrahepatic lipids during lipid-mediated liver fibrogenesis. Perilipin 5 (Plin5) is a newly identified LD protein in the perilipin family, which plays a key role in regulating aspects of intracellular trafficking, signaling, and cytoskeletal organization in hepatocytes. Recent work in Plin5 knockout mice suggests a role in high fat diet-induced hepatic lipotoxicity. The current report is to evaluate the impact of Plin5 on HSC activation and to elucidate the underlying mechanisms. We now show that high fat diet-induced liver fibrosis is accompanied by an approximate 75% reduction in Plin5 in HSC, and that spontaneous activation of primary HSC produces temporally coincident loss of Plin5 expression and LD depletion. As modulating lipid content in HSC is a suggested strategy for inhibition of HSC activation and treatment of hepatic fibrosis, we asked whether exogenous Plin5 expression in primary HSC would reverse the activation phenotype and promote LD formation. Recombinant lentiviral Plin5 expression in primary mouse HSC restored the formation of LDs, increased lipid content by inducing expression of pro-lipogenic genes and suppressing expression of pro-lipolytic genes, and suppressed HSC activation (~two fold reduction in expression of procollagen and α-smooth muscle actin, two unique biomarkers for activated HSC). In addition, the expression of exogenous Plin5 in HSC attenuated cellular oxidative stress by reducing cellular reactive oxygen species, elevating cellular glutathione, and inducing gene expression of glutamate-cysteine ligase. Taken together, our results indicate that expression of Plin5 plays a critical role in the formation of LDs, the elevation of lipid content in HSC, and the inhibition of the activation of HSC.

show abstract

Section: Plin5 Restores Ld Formation In Hscmentioning

confidence: 88%

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Lin

Chen

2016

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…As low as 0.5 μM, HNE can induce transcription of glutamate cysteine ligase, the first enzyme of GSH synthesis, through activation of the Nrf2-EpRE signaling pathways (198). All these studies point to the potential signaling function of HNE in both physiological and pathological conditions.…”

Section: Signaling Pathways Activated By Hnementioning

confidence: 99%

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

Forman

Fukuto

Miller

et al. 2008

Archives of Biochemistry and Biophysics

Self Cite

217

165

View full text Add to dashboard Cite

During the past several years, major advances have been made in understanding how reactive oxygen species (ROS) and nitrogen species (RNS) participate in signal transduction. Identification of the specific targets and the chemical reactions involved still remains to be resolved with many of the signaling pathways in which the involvement of reactive species has been determined. Our understanding is that ROS and RNS have second messenger roles. While cysteine residues in the thiolate (ionized) form found in several classes of signaling proteins can be specific targets for reaction with H 2 O 2 and RNS, better understanding of the chemistry, particularly kinetics, suggests that for many signaling events in which ROS and RNS participate, enzymatic catalysis is more likely to be involved than non-enzymatic reaction. Due to increased interest in how oxidation products, particularly lipid peroxidation products, also are involved with signaling, a review of signaling by 4-hydroxy-2-nonenal (HNE) is included. This article focuses on the chemistry of signaling by ROS, RNS, and HNE and will describe reactions with selected target proteins as representatives of the mechanisms rather attempt to comprehensively review the many signaling pathways in which the reactive species are involved. Keywords signaling; glutathione; thioredoxin; oxidants; reactive oxygen species; thiols; peroxide; nitric oxide; peroxynitrite; 4-hydroxynonenal; cysteine; hydrogen peroxide; protein tyrosine phosphatase; reactive nitrogen species; eNOS; iNOS; nNOS; soluble guanylate cyclase; cGMP; tyrosine nitration; fatty acid nitration; NO-heme; NO-metal complexes; nitrite; protein kinase C; ERK; JNK; p38MAPK; tyrosine kinase receptors; calcium OVERVIEW OF SIGNALING BY REACTIVE SPECIESUnderstanding of the roles of reactive oxygen species (ROS), reactive nitrogen species (RNS) and the lipid peroxidation product, 4-hydroxy-2-nonenal (HNE) in signaling has evolved rapidly during the last decade. This has been markedly helped by identification of the specific targets in signaling pathways. In previous reviews, we defined how ROS, H 2 O 2 in particular,

show abstract

“…Stressdependent induction of Nrf2 signaling directly regulates the transcription of several antioxidant enzymes, including glutamate cysteine ligase (GCL; both GCLC and GCLM subunits), 25 glutathione S-transferase (GST ), 17 glutathione peroxidase (GPx), 17 glutathione reductase (GR), heme oxygenase-1 (HMOX1), and NADP(H) quinone oxidoreductase 1 (NQO1). GCL, GST, GPx, and GR are involved in glutathione (GSH) biosynthesis and its recycling.…”

Section: Nrf2 In Cellular Redox Homeostasismentioning

confidence: 99%

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

Swamy

Rajasekaran

Thannickal

2016

The American Journal of Pathology

View full text Add to dashboard Cite

Aging and age-related diseases have been associated with elevated oxidative stress, which may be related to increased production of reactive species and/or a deficiency in antioxidant defenses. The nuclear factor-erythroid-2erelated factor 2 (Nrf2)-mediated antioxidant response pathway maintains cellular reduction-oxidation homeostasis by inducing the transcription of an array of cytoprotective genes. However, there is evidence of impaired Nrf2 response in aging contributing to age-related fibrotic diseases. Herein, we review mechanisms for the dysregulation of Nrf2 signaling in aging. This understanding will pave the way for the design of novel therapeutic strategies that restore Nrf2 signaling to reestablish cellular homeostasis in aging and age-related fibrotic diseases.

show abstract

Submicromolar concentrations of 4-hydroxynonenal induce glutamate cysteine ligase expression in HBE1 cells

Cited by 70 publications

References 20 publications

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

Contact Info

Product

Resources

About