MCD diet-induced steatohepatitis is associated with alterations in asymmetric dimethylarginine (ADMA) and its transporters

Pasqua, Laura Giuseppina Di; Berardo, Clarissa; Rizzo, Vittoria; Richelmi, Plinio; Croce, Anna Cleta; Vairetti, Mariapia; Ferrigno, Andrea

doi:10.1007/s11010-016-2758-2

Cited by 11 publications

(7 citation statements)

References 42 publications

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“…To demonstrate lipid accumulation more clearly, we used Oil Red O to stain LDs in the liver. As reported recently, MCD‐diet resulted in generation of giant LDs in mouse livers, 32 which was significantly suppressed by Fer‐1 treatment (Figure 5D). To elucidate whether reduced LD size is correlated with a decrease in total amount of neutral lipid, we measured the content of hepatic triglyceride, one of the major component of LDs.…”

Section: Resultssupporting

confidence: 81%

Targeting ferroptosis alleviates methionine‐choline deficient (MCD)‐diet induced NASH by suppressing liver lipotoxicity

Wang

Huang

et al. 2020

Liver International

170

120

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Abbreviations: AA, arachidonic acid; Abhd5, abhydrolase domain containing 5; Ace, angiotensin I converting enzyme; Acsl4, Long-chain fatty-acid-CoA ligase 4; AdA, adrenic acid;Alox5ap, arachidonate 5-lipoxygenase-activating protein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATCC, American Type Culture Collection; CoQ, coenzyme Q; Cyp, cytochrome P450; DFO, deferoxamine; Elovl6, elongation of very long chain fatty acids protein 6; Fer-1, Ferrostatin-1; FSP1, ferroptosis suppressor protein 1; GPX4, glutathione peroxidase 4; HCC, hepatocellular carcinoma; HE, hematoxylin and eosin; Hmox1, heme oxygenase-1; Hsl, hormone-sensitive lipase; IRPs, iron regulatory proteins; KEGG, Kyoto Encyclopedia of Genes; LDs, lipid droplets; Lip-1, Liprostatin-1; Lpcat2, lysophosphatidylcholine acyltransferase 2; MCD, methionine-and choline-deficient; MCDM, methionine-and choline-deficient medium; Mcp-1, monocyte chemoattractant protein-1; NAFLD, nonalcoholic fatty liver disease; NAS score, non-alcoholic steatohepatitis score; NASH, nonalcoholic steatohepatitis; Nox2, NADPH oxidase 2; PBS, phosphate buffer solution; PE, phosphatidylethanolamine; PI, propidium iodide; Pla2g4a, phospholipase A2, group IVA; Pnpla2, patatin like phospholipase domain containing 2; PPAR, peroxisome proliferator-activator receptor; Ptgs1/2, prostaglandin-endoperoxide synthase 1/2; PUFAs, polyunsaturated fatty acids;RNA-seq, RNA-sequencing; ROS, reactive oxygen species; RTA, radical trapping agent; RT-PCR, real-time polymerase chain reaction; shRNA, short hairpin RNA; Srebp1c, sterol regulatory element-binding protein 1c; TEM, transmission electron microscopy; Tgfβ, transforming growth factor-β; Tnf-α, tumor necrosis factor-α; VLDL, very-low-density lipoprotein. Abstract Background: NASH is one of the fastest growing liver diseases that leads to severe steatosis, inflammation and ultimately liver injury. However, the pathophysiological mechanisms of NASH remain unclear and pharmacological treatment against the disease is unavailable currently. Ferroptosis is a non-apoptotic form of cell death induced by iron-dependent lipid peroxidation. Since NASH progression is accompanied by massive lipid accumulation, which generates lipotoxic species, we investigated the role of ferroptosis in NASH progression. Method: Mice were fed on MCD-diet to mimic NASH progression and gene expression in liver was analysed by RNA-seq. The occurrence of hepatic ferroptosis was measured by lipid ROS level, electron microscopy and in vivo PI staining. The beneficial effects of ferroptosis inhibitors on NASH was evaluated by liver pathology analysis. The mechanism of lipid ROS induced lipid droplets accumulation was investigated by in vitro cell culture. Results: RNA-seq analysis suggested that elevated arachidonic acid metabolism promotes ferroptosis in MCD-diet fed mouse livers, which was further demonstrated by lipid ROS accumulation, morphological change of mitochondria and increased cell death. Iron accumulation was detected in the liver and the serum of MCD-f...

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Section: Resultssupporting

confidence: 81%

Targeting ferroptosis alleviates methionine‐choline deficient (MCD)‐diet induced NASH by suppressing liver lipotoxicity

Wang

Huang

et al. 2020

Liver International

170

120

View full text Add to dashboard Cite

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“…Blots were incubated for 1 h with secondary antibodies (peroxidase-coupled anti-mouse and anti-rabbit, Biorad) diluted 1:2000 with PBS. Immunostaining was revealed by ECL using a Chemidoc XRS Plus (Biorad Laboratories Inc., Hercules, CA, USA) [ 42 ].…”

Section: Methodsmentioning

confidence: 99%

Selective Blockade of the Metabotropic Glutamate Receptor mGluR5 Protects Mouse Livers in In Vitro and Ex Vivo Models of Ischemia Reperfusion Injury

Ferrigno

Berardo

Pasqua

et al. 2018

IJMS

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2-Methyl-6-(phenylethynyl)pyridine (MPEP), a negative allosteric modulator of the metabotropic glutamate receptor (mGluR) 5, protects hepatocytes from ischemic injury. In astrocytes and microglia, MPEP depletes ATP. These findings seem to be self-contradictory, since ATP depletion is a fundamental stressor in ischemia. This study attempted to reconstruct the mechanism of MPEP-mediated ATP depletion and the consequences of ATP depletion on protection against ischemic injury. We compared the effects of MPEP and other mGluR5 negative modulators on ATP concentration when measured in rat hepatocytes and acellular solutions. We also evaluated the effects of mGluR5 blockade on viability in rat hepatocytes exposed to hypoxia. Furthermore, we studied the effects of MPEP treatment on mouse livers subjected to cold ischemia and warm ischemia reperfusion. We found that MPEP and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) deplete ATP in hepatocytes and acellular solutions, unlike fenobam. This finding suggests that mGluR5s may not be involved, contrary to previous reports. MPEP, as well as MTEP and fenobam, improved hypoxic hepatocyte viability, suggesting that protection against ischemic injury is independent of ATP depletion. Significantly, MPEP protected mouse livers in two different ex vivo models of ischemia reperfusion injury, suggesting its possible protective deployment in the treatment of hepatic inflammatory conditions.

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“…For instance, methionine deficiency causes reduced serum concentrations of ADMA and cysteine, products of transmethylation and transsulfuration respectively. 45 , 46 , 47 , 48 In this single time point observational study we used serum concentrations of ADMA and cysteine as proxy measures of one-carbon metabolism synthetic activity. ADMA was lower in kwashiorkor ( P < 0·0001) and marasmic-kwashiorkor ( P = 0·00032), relative to marasmus ( Figure 2 and Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

One-carbon metabolism in children with marasmus and kwashiorkor

et al. 2022

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Background Kwashiorkor is a childhood syndrome of edematous malnutrition. Its precise nutritional precipitants remain uncertain despite nine decades of study. Remarkably, kwashiorkor's disturbances resemble the effects of experimental diets that are deficient in one-carbon nutrients. This similarity suggests that kwashiorkor may represent a nutritionally mediated syndrome of acute one-carbon metabolism dysfunction. Here we report findings from a cross-sectional exploration of serum one-carbon metabolites in Malawian children.Methods Blood was collected from children aged 12À60 months before nutritional rehabilitation: kwashiorkor (N = 94), marasmic-kwashiorkor (N = 43) marasmus (N = 118), moderate acute malnutrition (N = 56) and controls (N = 46). Serum concentrations of 16 one-carbon metabolites were quantified using LC/MS techniques, and then compared across participant groups.Findings Twelve of 16 measured one-carbon metabolites differed significantly between participant groups. Measured outputs of one-carbon metabolism, asymmetric dimethylarginine (ADMA) and cysteine, were lower in marasmic-kwashiorkor (median µmol/L ( § SD): 0¢549 ( § 0¢217) P = 0¢00045 & 90 ( § 40) P < 0¢0001, respectively) and kwashiorkor (0¢557 ( § 0¢195) P < 0¢0001 & 115 ( § 50) P < 0¢0001), relative to marasmus (0¢698 ( § 0¢212) & 153 ( § 42)). ADMA and cysteine were well correlated with methionine in both kwashiorkor and marasmic-kwashiorkor.Interpretation Kwashiorkor and marasmic-kwashiorkor were distinguished by evidence of one-carbon metabolism dysfunction. Correlative observations suggest that methionine deficiency drives this dysfunction, which is implicated in the syndrome's pathogenesis. The hypothesis that kwashiorkor can be prevented by fortifying low quality diets with methionine, along with nutrients that support efficient methionine use, such as choline, requires further investigation.

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MCD diet-induced steatohepatitis is associated with alterations in asymmetric dimethylarginine (ADMA) and its transporters

Cited by 11 publications

References 42 publications

Targeting ferroptosis alleviates methionine‐choline deficient (MCD)‐diet induced NASH by suppressing liver lipotoxicity

Targeting ferroptosis alleviates methionine‐choline deficient (MCD)‐diet induced NASH by suppressing liver lipotoxicity

Selective Blockade of the Metabotropic Glutamate Receptor mGluR5 Protects Mouse Livers in In Vitro and Ex Vivo Models of Ischemia Reperfusion Injury

One-carbon metabolism in children with marasmus and kwashiorkor

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