Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease

Arndt, Stephanie; Wacker, Eva; Dorn, Christoph; Koch, Andreas; Saugspier, M; Thasler, Wolfgang E.; Hartmann, Arndt; Bosserhoff, Anja‐Katrin; Hellerbrand, Claus

doi:10.1136/gutjnl-2014-306968

Cited by 55 publications

(58 citation statements)

References 52 publications

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“…We also measured the expression of key regulators of iron metabolism in our mouse model. Hepatic Bmp6 gene expression was upregulated in MCD‐fed mice livers, which is consistent with the previous study 31 . MCD diet also induced upregulation of hepatic genes, Hamp1 and Hamp2 .…”

Section: Resultssupporting

confidence: 92%

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

Wang

Huang

et al. 2020

Liver International

188

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: 92%

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

Wang

Huang

et al. 2020

Liver International

188

120

View full text Add to dashboard Cite

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“…The key role of Cyp1b1 in the containment of oxidative stress in endothelia (Palenski et al, 2013, Tang et al, 2009), and the extensive effects of deletion on morphology and gene expression suggests that Bmp6 or endothelial-hepatocyte interactions are critically important. Bmp6 plays a key role not only in regulating Hepc , but also in coordinating iron regulation, stellate cells, and lipogenesis (Arndt et al, 2015). Bmp6 stimulates Bmpr1a/Bmpr2 receptors to signal through SMAD1/5/8 phosphorylation (Canali et al, 2017) (Figure 7) in partnership with the stimulation of transferrin receptors ( Trfc , Tfr2 ) by iron-transferrin complexes (Kautz et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Cyp1b1 deletion and retinol deficiency coordinately suppress mouse liver lipogenic genes and hepcidin expression during post-natal development

Maguire

Larsen

Foong

et al. 2017

Molecular and Cellular Endocrinology

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Cyp1b1 deletion and gestational vitamin A deficiency (GVAD) redirect adult liver gene expression. A matched sufficient pre- and post-natal diet, which has high carbohydrate and normal iron content (LF12), increased inflammatory gene expression markers in adult livers that were suppressed by GVAD and Cyp1b1 deletion. At birth on the LF12 diet, Cyp1b1 deletion and GVAD each suppress liver expression of the iron suppressor, hepcidin (Hepc), while increasing stellate cell activation markers and suppressing post-natal increases in lipogenesis. Hepc was less suppressed in Cyp1b1−/− pups with a standard breeder diet, but was restored by iron supplementation of the LF12 diet. Conclusions The LF12 diet delivered low post-natal iron and attenuated Hepc. Hepc decreases in Cyp1b1−/− and GVAD mice resulted in stellate activation and lipogenesis suppression. Endothelial BMP6, a Hepc stimulant, is a potential coordinator and Cyp1b1 target. These neonatal changes in Cyp1b1−/− mice link to diminished adult obesity and liver inflammation.

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“…BMP6 decifiency promotes hepatic inflammation and fibrosis in MCD plus high-fat diet-fed mice, but not in other non-NASH models, and recombinant BMP6 protein inhibits HSC activation [307]. …”

Section: Mechanisms Of Hsc Activationmentioning

confidence: 99%

Hepatic stellate cells as key target in liver fibrosis

Higashi

Friedman

Hoshida

2017

Advanced Drug Delivery Reviews

1,085

894

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Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.

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Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease

Cited by 55 publications

References 52 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

Cyp1b1 deletion and retinol deficiency coordinately suppress mouse liver lipogenic genes and hepcidin expression during post-natal development

Hepatic stellate cells as key target in liver fibrosis

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