Deregulated neddylation in liver fibrosis

Zubiete-Franco, Imanol; Fernández-Tussy, Pablo; Barbier-Torres, Lucía; Simón, Jorge; Fernández‐Ramos, David; Lopitz‐Otsoa, Fernando; Juan, Virginia Gutiérrez‐de; Davalillo, Sergio López de; Duce, Antonio Martín; Iruzubieta, Paula; Taibo, Daniel; Crespo, Javier; Caballería, Juan; Villa, Erica; Aurrekoetxea, Igor; Aspichueta, Patricia; Varela‐Rey, Marta; Lu, Shelly C.; Mato, José M.; Beraza, Naiara; Delgado, Teresa C.; Martínez‐Chantar, María Luz

doi:10.1002/hep.28933

Cited by 58 publications

(71 citation statements)

References 45 publications

(98 reference statements)

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“…In the pathology of liver fibrosis and in cholestatic liver injury different types of hepatic cells including hepatocytes, cholangiocytes, inflammatory macrophages (Kupffer cells) 16 and Natural Killer 7 , 17 – 19 cells, and hepatic stellate cells (HSC) 20 are known to mediate different effects, regulating the development and the progression of the disease. During initiation of fibrogenesis, hepatocyte apoptosis and cholangiocyte proliferation are the primary events driving disease progression 14 .…”

Section: Resultsmentioning

confidence: 99%

MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis

et al. 2018

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Glycine N-methyltransferase (GNMT) is the most abundant methyltransferase in the liver and a master regulator of the transmethylation flux. GNMT downregulation leads to loss of liver function progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Moreover, GNMT deficiency aggravates cholestasis-induced fibrogenesis. To date, little is known about the mechanisms underlying downregulation of GNMT levels in hepatic fibrosis and cirrhosis. On this basis, microRNAs are epigenetic regulatory elements that play important roles in liver pathology. In this work, we aim to study the regulation of GNMT by microRNAs during liver fibrosis and cirrhosis. Luciferase assay on the 3ʹUTR-Gnmt was used to confirm in silico analysis showing that GNMT is potentially targeted by the microRNA miR-873-5p. Correlation between GNMT and miR-873-5p in human cholestasis and cirrhosis together with miR-873-5p inhibition in vivo in different mouse models of liver cholestasis and fibrosis [bile duct ligation and Mdr2 (Abcb4)-/- mouse] were then assessed. The analysis of liver tissue from cirrhotic and cholestatic patients, as well as from the animal models, showed that miR-873-5p inversely correlated with the expression of GNMT. Importantly, high circulating miR-873-5p was also detected in cholestastic and cirrhotic patients. Preclinical studies with anti-miR-873-5p treatment in bile duct ligation and Mdr2-/- mice recovered GNMT levels in association with ameliorated inflammation and fibrosis mainly by counteracting hepatocyte apoptosis and cholangiocyte proliferation. In conclusion, miR-873-5p emerges as a novel marker for liver fibrosis, cholestasis, and cirrhosis and therapeutic approaches based on anti-miR-873-5p may be effective treatments for liver fibrosis and cholestatic liver disease.

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Section: Resultsmentioning

confidence: 99%

MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis

et al. 2018

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“…Furthermore, cirrhosis can also evolve to hepatocellular carcinoma (HCC) with poorer survival rates [13]. HCC is the most prevalent form of presentation (70%-85%) of liver cancer, which is the fifth most common cancer type in the world and the second cause of cancer-related death [14,15].…”

Section: Non-alcoholic Fatty Liver Disease and Derived Hepatocellularmentioning

confidence: 99%

“…Regarding their effect in the hepatocyte, both an upregulated A-SMase expression and ceramide content have been related to cell death [89] through activation of death receptors as fatty acid synthase (FAS) and TNFR1 [95]. The induction of necrosis in CCl 4 -treated mice, a fibrosis model widely studied [13,96], has been also correlated with an increase of ceramide content both in serum and liver [97]. Correlated with TNF, previously cited to deplete GSH levels in the cell during NASH, hepatocytes have been described to be more susceptible for cell death in that context [98,99].…”

Section: Ceramide and S1p Role In Fibrosis And Cirrhosis Developmentmentioning

confidence: 99%

Sphingolipids in Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma: Ceramide Turnover

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Ouro

Ala-Ibanibo

et al. 2019

IJMS

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Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the main causes of chronic liver disease worldwide. NAFLD comprises a group of conditions characterized by the accumulation of hepatic lipids that can eventually lead to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), the fifth most common cancer type with a poor survival rate. In this context, several works have pointed out perturbations in lipid metabolism and, particularly, changes in bioactive sphingolipids, as a hallmark of NAFLD and derived HCC. In the present work, we have reviewed existing literature about sphingolipids and the development of NAFLD and NAFLD-derived HCC. During metabolic syndrome, considered a risk factor for steatosis development, an increase in ceramide and sphigosine-1-phosphate (S1P) have been reported. Likewise, other reports have highlighted that increased sphingomyelin and ceramide content is observed during steatosis and NASH. Ceramide also plays a role in liver fibrosis and cirrhosis, acting synergistically with S1P. Finally, during HCC, metabolic fluxes are redirected to reduce cellular ceramide levels whilst increasing S1P to support tumor growth.

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“…Activation of NADPH oxidases (NOXs) induces HSCs activation ( Jiang et al, 2010 ), and inhibition of NOX1/NOX4 has been shown to suppress fibrogenesis in the bile duct ligation (BDL) and CCl 4 models ( Aoyama et al, 2012 ; Crosas-Molist and Fabregat, 2015 ). The immune response, that has multiple interactions with the fibrogenic process, may be also a candidate for therapy ( Pellicoro et al, 2014 ); thus, several strategies to block the TGF-β activity have shown efficacy ( Vogt et al, 2011 ; Rogler et al, 2017 ), and inhibition of chemokines and their receptors demonstrated antifibrotic effects in rodent models of liver fibrosis ( Zaldivar et al, 2010 ; Seifert et al, 2015 ; Zubiete-Franco et al, 2017 ).…”

Section: Mechanisms Involved In the Pathogenesis Of Liver Fibrosismentioning

confidence: 99%

Sphingosine 1-Phosphate Signaling as a Target in Hepatic Fibrosis Therapy

et al. 2017

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Liver fibrosis is an excess production of extracellular matrix proteins as a result of chronic liver disease which leads to cell death and organ dysfunction. The key cells involved in fibrogenesis are resident hepatic stellate cells (HSCs) which are termed myofibroblasts after activation, acquiring contractile, proliferative, migratory and secretory capability. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with well-established effects on angiogenesis, carcinogenesis and immunity. Accumulating evidence demonstrates that this metabolite is involved in the profibrotic inflammatory process through the regulation of pleiotropic cell responses, such as vascular permeability, leukocyte infiltration, cell survival, migration, proliferation and HSCs differentiation to myofibroblasts. S1P is synthesized by sphingosine kinases (SphKs) and many of its actions are mediated by S1P specific cell surface receptors (S1P1-5), although different intracellular targets of S1P have been identified. Modulation of SphKs/S1P/S1P receptors signaling is known to result in beneficial effects on various in vivo and in vitro models of liver fibrosis. Thus, a better knowledge of the molecular mechanisms involved in the modulation of the S1P pathway could help to improve liver fibrosis therapy. In this review, we analyze the effects of the S1P axis on the fibrogenic process, and the involvement of a range of inhibitors or approaches targeting enzymes related to S1P in the abrogation of pathological fibrogenesis. All in all, targeting this pathway offers therapeutic potential in the treatment of hepatic fibrosis.

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Deregulated neddylation in liver fibrosis

Cited by 58 publications

References 45 publications

MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis

MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis

Sphingolipids in Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma: Ceramide Turnover

Sphingosine 1-Phosphate Signaling as a Target in Hepatic Fibrosis Therapy

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