Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury

Cheng, Ji; Kaplowitz, Neil

doi:10.3748/wjg.v10.i12.1699

Cited by 179 publications

(110 citation statements)

References 140 publications

Supporting

Mentioning

106

Contrasting

Unclassified

Order By: Relevance

“…Previously, we reported that homocysteine, a known ER stressor (11), which is elevated in DR (12), up-regulated VEGF expression through an endoplasmic reticulum stress response pathway that was dependent on activating transcription factor 4 (ATF4) (13). ATF4 protein levels increase in response to cellular stresses that cause global protein synthesis to be diminished.…”

Section: From the Department Of Biochemistry And Molecular Biology Umentioning

confidence: 99%

The Oxidative Stressor Arsenite Activates Vascular Endothelial Growth Factor mRNA Transcription by an ATF4-dependent Mechanism

Roybal

Hunsaker

Barbash

et al. 2005

Journal of Biological Chemistry

126

View full text Add to dashboard Cite

Aberrant retinal expression of vascular endothelial growth factor (VEGF) leading to neovascularization is a central feature of age-related macular degeneration and diabetic retinopathy, two leading causes of vision loss. Oxidative stress is suggested to occur in retinal tissue during age-related macular degeneration and diabetic retinopathy and is suspected in the mechanism of VEGF expression in these diseases. Arsenite, a thiol-reactive oxidative stressor, induces VEGF expression by a HIF-1␣-independent mechanism. Previously, we demonstrated that homocysteine, an endoplasmic reticulum stressor, increases VEGF transcription by a mechanism dependent upon activating transcription factor ATF4. Because ATF4 is expressed in response to oxidative stress, we hypothesized that ATF4 was also responsible for increased VEGF transcription in response to arsenite. We now show that arsenite increased steady state levels of VEGF mRNA and activated transcription from a VEGF promoter construct. Arsenite induced eIF2␣ phosphorylation, resulting in increased ATF4 protein levels. Inactivation or loss of ATF4 greatly diminished the VEGF response to arsenite treatment. Overexpression of ATF4 was sufficient to activate the VEGF promoter, and arsenite cooperated with exogenous ATF4 to further activate the promoter. A complex containing ATF4 binds a DNA element at ؉1767 bp relative to the VEGF transcription start site, and DNA binding activity is increased by arsenite treatment. In addition, the ability of a thiol antioxidant, N-acetylcysteine, to inhibit the effect of arsenite on VEGF expression coincided with its ability to inhibit phosphorylation of eIF2␣ and ATF4 protein expression. Thus, arsenite-induced up-regulation of VEGF gene transcription occurs by an ATF4-dependent mechanism.

show abstract

Section: From the Department Of Biochemistry And Molecular Biology Umentioning

confidence: 99%

The Oxidative Stressor Arsenite Activates Vascular Endothelial Growth Factor mRNA Transcription by an ATF4-dependent Mechanism

Roybal

Hunsaker

Barbash

et al. 2005

Journal of Biological Chemistry

126

View full text Add to dashboard Cite

show abstract

“…Within the methionine metabolic cycle, SAM has the properties of lowering homocysteine while increasing the levels of the antioxidant glutathione (GSH), and it also regulates DNA methylation and nucleotide composition (Halsted, 2004). Other studies, including our own, linked hyperhomocysteinemia and elevated S-adenosylhomocysteine (SAH) levels to hepatic endoplasmic reticulum (ER) stress mechanisms (Esfandiari et al, 2005;Ji and Kaplowitz, 2003), whereas hepatic lipid accumulation and hepatocellular apoptosis in ethanol-fed mice were prevented by betaine, a compound that corrects abnormal methionine metabolism by lowering homocysteine and SAH levels (Ji and Kaplowitz, 2004).…”

mentioning

confidence: 99%

S‐Adenosylmethionine Attenuates Hepatic Lipid Synthesis in Micropigs Fed Ethanol With a Folate‐Deficient Diet

Esfandiari

You

Villanueva

et al. 2007

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

Background: To demonstrate a causative role of abnormal methionine metabolism in the pathogenesis of alcoholic steatosis, we measured the effects on hepatic lipid synthesis of supplementing ethanol and folate-deficient diets with S-adenosylmethionine (SAM), a metabolite that regulates methionine metabolism.Methods: Yucatan micropigs were fed folate-deficient diets as control, with ethanol at 40% of kcal, and with ethanol supplemented with SAM at 0.4 g/1,000 kcal for 14 weeks. Histopathology, triglyceride levels and transcripts, and protein levels of the regulatory signals of hepatic lipid synthesis were measured in terminal omental adipose and liver samples.Results: Feeding ethanol at 40% of kcal with folate-deficient diets for 14 weeks increased and supplemental SAM maintained control levels of liver and plasma triglyceride. Serum adiponectin, liver transcripts of adiponectin receptor-1 (AdipoR1), and phosphorylated adenosine monophosphate kinase-b (p-AMPKb) were each reduced by ethanol feeding and were sustained at normal levels by SAM supplementation of the ethanol diets. Ethanol feeding activated and SAM supplementation maintained control levels of ER stress-induced transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) and its targeted transcripts of lipid synthesizing enzymes acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and glycerol-3-phosphate acyltransferase (GPAT).Conclusions: Ethanol feeding with a folate-deficient diet stimulates hepatic lipid synthesis by down-regulating adiponectin-mediated pathways of p-AMPK to increase the expression of nSREBP1c and its targeted lipogenic enzymes. Preventing abnormal hepatic methionine metabolism by supplementing ethanol diets with SAM reduces liver triglyceride levels by up-regulation of adiponectin-mediated pathways to decrease fatty acid and triglyceride synthesis. This study demonstrates that ethanol-induced hepatic lipid synthesis is mediated in part by abnormal methionine metabolism, and strengthens the concept that altered methionine metabolism plays an integral role in the pathogenesis of steatosis.

show abstract

“…Hyperhomocysteinemia may increase the myocardial wall dysfunction by excessive production of reactive oxygen species which is made evident by increased lipid peroxidation [22][23][24].…”

Section: Discussionmentioning

confidence: 99%

Effects of Acute Administration of D,L-Homocysteine Thiolactone on the Antioxidative Status of Rat Intestine and Liver

et al. 2016

View full text Add to dashboard Cite

Oxidative stress appears to play a role in the pathogenesis of several infl ammatory gastrointestinal diseases. Increased homocysteine levels may play a role in the pathogenesis of Chron's disease and ulcerative colitis. The aim of this study was to examine the infl uence of homocysteine on the antioxidant status of rat intestine and liver. The levels of thiobarbituric acid reactive substances (TBARS), activity of catalase (CAT) and total antioxidant status (TAS) were investigated in the isolated gut and liver of young male rats in the control group (8 rats) and after 3-hоur incubation in high doses of D, L-homocysteine thionolactone (Hcy) (10 μmol/L) (8 rats). Samples of duodenum, ileum, colon and liver were homogenized in sodium phosphate buffer (1:10). Homogenates were centrifuged at 10000 for 10 min at 4 0 C and the supernatant was taken for biochemical assays. Our results showed that high D, L-homocysteine thionolactone concentration reduced enzymatic catalase activity in homogenates of the isolated segments of duodenum (27.04%) p<0.01; ileum (37.27%), colon (34.17%) and liver (67.46%) p<0.001. Exposition to high D,L-homocysteine thiolactone concentration signifi cantly increased TBARS levels in the duodenum (106.05%), ileum (47.24%), colon (112.75%) and liver (32.07%) (p<0.01). Homocysteine also modifi ed the total antioxidant status of homogenates from the duodenum, ileum, colon and liver, increasing by 20.68% (duodenum), 24.74% (ileum), 14.88% (colon) and 19.35% (liver) (p<0.001). Homocysteine induced a consistent oxidative stress in rat's intestine and liver (reduced activity of catalase and increased level of TBARS), but the elevated activity of TAS in our experiments could be explained as an adaptive response to the generated free radicals which indicates the failure of the total antioxidant defense mechanism to protect the tissues from damage caused by homocysteine.

show abstract

Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury

Cited by 179 publications

References 140 publications

The Oxidative Stressor Arsenite Activates Vascular Endothelial Growth Factor mRNA Transcription by an ATF4-dependent Mechanism

The Oxidative Stressor Arsenite Activates Vascular Endothelial Growth Factor mRNA Transcription by an ATF4-dependent Mechanism

S‐Adenosylmethionine Attenuates Hepatic Lipid Synthesis in Micropigs Fed Ethanol With a Folate‐Deficient Diet

Effects of Acute Administration of D,L-Homocysteine Thiolactone on the Antioxidative Status of Rat Intestine and Liver

Contact Info

Product

Resources

About