Clinical Science (London, England : 1979)最新文献

{"title":"MKP2 suppresses TGF-β1-induced epithelial-to-mesenchymal transition through JNK inhibition.","authors":"Ivonne Loeffler","doi":"10.1042/CS20180881","DOIUrl":"https://doi.org/10.1042/CS20180881","url":null,"abstract":"<p><p>Interstitial fibrosis is a typical feature of end-stage renal diseases, regardless of the initial cause of kidney injury. Epithelial-to-mesenchymal transition (EMT) is a mechanism that is thought to play a role in generating the interstitial matrix-producing myofibroblasts and is prominently induced by the transforming growth factor-β 1 (TGF-β1). TGF-β1 signals through a variety of Smad and non-Smad signaling pathways, including the mitogen-activated protein kinase (MAPK) pathways. In a study published in a recent issue of <i>Clinical Science</i> (Clin. Sci. (2018) 132(21),2339-2355), Li et al. investigated the potential role of the Mitogen-activated protein kinase phosphatase 2 (MKP2), also known as Dusp4, in the control of EMT and renal fibrosis. Based on results obtained with an animal model of kidney fibrosis and a proximal tubular epithelial cell line system, the authors put forward a role for MKP2 as a negative feedback regulator of TGF-β1-induced EMT and fibrosis in the kidney. Intriguingly, MKP2 is found to down-regulate activity of c-Jun, but not that of other MAPKs, extracellular signal-regulated kinases or p38, implying a role for c-Jun N-terminal kinase-dependent signaling in renal fibrosis. In this commentary, I discuss the findings of Li and co-workers in the context of the recent literature placing a focus on potential clinical/therapeutic implications.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"545-550"},"PeriodicalIF":6.0,"publicationDate":"2019-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1042/CS20180881","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36555152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elafibranor interrupts adipose dysfunction-mediated gut and liver injury in mice with alcoholic steatohepatitis.","authors":"Tzu-Hao Li,&nbsp;Ying-Ying Yang,&nbsp;Chia-Chang Huang,&nbsp;Chih-Wei Liu,&nbsp;Hung-Cheng Tsai,&nbsp;Ming-Wei Lin,&nbsp;Chang-Youh Tsai,&nbsp;Shiang-Fen Huang,&nbsp;Ying-Wen Wang,&nbsp;Tzung-Yan Lee,&nbsp;Yi-Hsiang Huang,&nbsp;Ming-Chih Hou,&nbsp;Han-Chieh Lin","doi":"10.1042/CS20180873","DOIUrl":"https://doi.org/10.1042/CS20180873","url":null,"abstract":"<p><p><b>Background:</b> Reversal of alcohol-induced peroxisome proliferator-activated receptor (PPAR) α (PPARα) and PPARδ dysfunction has been reported to decrease the severity of alcoholic steatohepatitis (ASH). Autophagy is essential for cell survival and tissue energy homeostasis. Emerging evidence indicates that alcohol-induced adipose tissue (AT) autophagy dysfunction contributes to injury in the intestine, liver, and AT of ASH. <b>Methods:</b> The effects and mechanisms of dual PPARα/δ agonist elafibranor on autophagy stimulation were investigated using mice with ASH. <b>Results:</b> C57BL/6 mice on ethanol diet showed AT dysfunction, disrupted intestinal barrier, and ASH, which was accompanied by alcohol-mediated decrease in PPARα, PPARδ, and autophagy levels in intestine, liver, and AT. Chronic treatment with elafibranor attenuated AT apoptosis and inflammation by restoration of tissue PPARα, PPARδ, and autophagy levels. In ASH mice, alcohol-induced AT dysfunction along with increased fatty acid (FA) uptake and decreased free FA (FFA) release from AT was inhibited by elafibranor. The improvement of AT autophagy dysfunction by elafibranor alleviated inflammation and apoptosis-mediated intestinal epithelial disruption in ASH mice. Acute elafibranor incubation inhibited ethanol-induced ASH-mice-sera-enhanced autophagy dysfunction, apoptosis, barrier disruption, and intracellular steatosis in Caco-2 cells and primary hepatocytes (PHs). <b>Conclusion<i>:</i></b> Altogether, these findings demonstrated that the PPARα/δ agonist, elafibranor, decreased the severity of liver injury by restoration of alcohol-suppressed AT autophagy function and by decreasing the release of apoptotic markers, inflammatory cytokines, and FFA, thereby reducing intestinal epithelium disruption and liver inflammation/apoptosis/steatosis in ASH mice. These data suggest that dual PPAR agonists can serve as potential therapeutic agents for the management of ASH.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"531-544"},"PeriodicalIF":6.0,"publicationDate":"2019-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1042/CS20180873","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36827730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging awareness on the importance of skeletal muscle in liver diseases: time to dig deeper into mechanisms!","authors":"Maxime Nachit,&nbsp;Isabelle A Leclercq","doi":"10.1042/CS20180421","DOIUrl":"https://doi.org/10.1042/CS20180421","url":null,"abstract":"<p><p>Skeletal muscle is a tissue that represents 30-40% of total body mass in healthy humans and contains up to 75% of total body proteins. It is thus the largest organ in non-obese subjects. The past few years have seen increasing awareness of the prognostic value of appreciating changes in skeletal muscle compartment in various chronic diseases. Hence, a low muscle mass, a low muscle function and muscle fatty infiltration are linked with poor outcomes in many pathological conditions. In particular, an affluent body of evidence links the severity, the complications and mortality of chronic liver disease (CLD) with skeletal muscle depletion. Yet it is still not clear whether low muscle mass is a cause, an aggravating factor, a consequence of the ongoing disease, or an epiphenomenon reflecting general alteration in the critically ill patient. The mechanisms by which the muscle compartment influences disease prognosis are still largely unknown. In addition, whether muscle alterations contribute to liver disease progression is an unanswered question. Here, we first review basic knowledge about muscle compartment to draw a conceptual framework for interpreting skeletal muscle alteration in CLD. We next describe recent literature on muscle wasting in cirrhosis and liver transplantation. We then discuss the implication of skeletal muscle compartment in non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), focusing on plausible metabolic disruption in muscle compartment that might participate in NAFLD progression. Finally, we discuss shortcomings and challenges we need to address in the near future prior to designate the muscle compartment as a therapeutic target in CLD.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"465-481"},"PeriodicalIF":6.0,"publicationDate":"2019-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1042/CS20180421","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36960576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Omeprazole prevents CDX2 and SOX9 expression by inhibiting hedgehog signaling in Barrett's esophagus cells.","authors":"Jiao Huang,&nbsp;Hua Liu,&nbsp;Tiantian Sun,&nbsp;Jing-Yuan Fang,&nbsp;Jilin Wang,&nbsp;Hua Xiong","doi":"10.1042/CS20180828","DOIUrl":"https://doi.org/10.1042/CS20180828","url":null,"abstract":"Activation of hedgehog (Hh) signaling contributes to the progression of Barrett's esophagus (BE), which increases the risk of esophageal adenocarcinoma. Recent clinical studies revealed that proton-pump inhibitors (PPIs) but not H2 receptor antagonists (H2RAs) were associated with a decreased risk of esophageal adenocarcinoma. We would like to know whether PPIs interfere with BE progression during BE treatment. Here, we explored the role of omeprazole on Hh signaling and expression of two crucial biomarkers of BE, SOX9 and CDX2. We demonstrated that bile acids elevated expression of Hh pathway target genes, such as GLI1 and PTCH1, and induced SOX9 and CDX2 up-regulation in both CP-A and CP-B cells. Omeprazole, but not famotidine, down-regulated these genes induced by bile acids. In addition, omeprazole-induced down-regulation of SOX9 and CDX2 was mediated by Hh signaling. To explore the mechanisms by which omeprazole inhibits Hh signaling, we performed luciferase assay but did not find any effects of omeprazole on the activity of GLI1 promoter, the critical transcription factor of Hh signaling. Therefore, we used miRNA sequencing and a bioinformatics tool in our study to identify the differently expressed miRNAs in BE organoids treated with or without omeprazole, and we identified miR-2116-3p was involved in omeprazole-mediated inhibition of Hh signaling and subsequent down-regulation of SOX9 and CDX2. Collectively, our data indicate omeprazole inhibits Hh signaling and subsequent SOX9 and CDX2 expression via up-regulating miR-2116-3p. We have demonstrated a novel acid-independent mechanism of omeprazole that might yield valuable insight into clinical management of BE progression, irrespective of acid reflux symptoms.","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"483-495"},"PeriodicalIF":6.0,"publicationDate":"2019-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1042/CS20180828","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36917760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Involvement of serum amyloid A1 in the rupture of fetal membranes through induction of collagen I degradation.","authors":"Wang-Sheng Wang,&nbsp;Wen-Jiao Li,&nbsp;Ya-Wei Wang,&nbsp;Lu-Yao Wang,&nbsp;Ya-Bing Mi,&nbsp;Jiang-Wen Lu,&nbsp;Yi Lu,&nbsp;Chu-Yue Zhang,&nbsp;Kang Sun","doi":"10.1042/CS20180950","DOIUrl":"https://doi.org/10.1042/CS20180950","url":null,"abstract":"<p><p>The <i>de novo</i> synthesis of serum amyloid A1 (SAA1) is augmented in human fetal membranes at parturition. However, its role in parturition remains largely unknown. Here, we investigated whether SAA1 was involved in the rupture of fetal membranes, a crucial event in parturition accompanied with extensive degradation of collagens. Results showed that SAA1 decreased both intracellular and extracellular COL1A1 and COL1A2 abundance, the two subunits of collagen I, without affecting their mRNA levels in human amnion fibroblasts. These reductions were completely blocked only with inhibition of both matrix metalloproteases (MMPs) and autophagy. Consistently, SAA1 increased MMP-2/9 abundance and the markers for autophagic activation including autophagy related (ATG) 7 (ATG7) and the microtubule-associated protein light chain 3 β (LC3B) II/I ratio with the formation of LC3 punctas and autophagic vacuoles in the fibroblasts. Moreover, the autophagic degradation of COL1A1/COL1A2 and activation of MMP-2/9 by SAA1 were blocked by inhibitors for the toll-like receptors 2/4 (TLR2/4) or NF-κB. Finally, reciprocal corresponding changes of SAA1 and collagen I were observed in the amnion following spontaneous rupture of membranes (ROM) at parturition. Conclusively, SAA1 may participate in membrane rupture at parturition by degradating collagen I via both autophagic and MMP pathways. These effects of SAA1 appear to be mediated by the TLR2/4 receptors and the NF-κB pathway.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"515-530"},"PeriodicalIF":6.0,"publicationDate":"2019-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1042/CS20180950","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36897752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Balancing mitochondrial dynamics via increasing mitochondrial fusion attenuates infarct size and left ventricular dysfunction in rats with cardiac ischemia/reperfusion injury.","authors":"Chayodom Maneechote, Siripong Palee, Sasiwan Kerdphoo, Thidarat Jaiwongkam, Siriporn C Chattipakorn, Nipon Chattipakorn","doi":"10.1042/CS20190014","DOIUrl":"10.1042/CS20190014","url":null,"abstract":"<p><p>An uncontrolled balance of mitochondrial dynamics has been shown to contribute to cardiac dysfunction during ischemia/reperfusion (I/R) injury. Although inhibition of mitochondrial fission could ameliorate cardiac dysfunction, modulation of mitochondrial fusion by giving a fusion promoter at different time-points during cardiac I/R injury has never been investigated. We hypothesized that giving of a mitochondrial fusion promoter at different time-points exerts cardioprotection with different levels of efficacy in rats with cardiac I/R injury. Forty male Wistar rats were subjected to a 30-min ischemia by coronary occlusion, followed by a 120-min reperfusion. The rats were then randomly divided into control and three treated groups: pre-ischemia, during-ischemia, and onset of reperfusion. A pharmacological mitochondrial fusion promoter-M1 (2 mg/kg) was used for intervention. Reduced mitochondrial fusion protein was observed after cardiac I/R injury. M1 administered prior to ischemia exerted the highest level of cardioprotection by improving both cardiac mitochondrial function and dynamics regulation, attenuating incidence of arrhythmia, reducing infarct size and cardiac apoptosis, which led to the preservation of cardiac function and decreased mortality. M1 given during ischemia and on the onset of reperfusion also exerted cardioprotection, but with a lower efficacy than when given at the pre-ischemia time-point. Attenuating a reduction in mitochondrial fusion proteins during myocardial ischemia and at the onset of reperfusion exerted cardioprotection by attenuating mitochondrial dysfunction and dynamic imbalance, thus reducing infarct size and improving cardiac function. These findings indicate that it could be a promising intervention with the potential to afford cardioprotection in the clinical setting of acute myocardial infarction.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"497-513"},"PeriodicalIF":0.0,"publicationDate":"2019-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36917761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The first identified heterozygous nonsense mutations in podocalyxin offer new perspectives on the biology of podocytopathies.","authors":"Ido Refaeli,&nbsp;Michael R Hughes,&nbsp;Kelly M McNagny","doi":"10.1042/CS20181067","DOIUrl":"https://doi.org/10.1042/CS20181067","url":null,"abstract":"<p><p>In the last two decades, our understanding of the genetic underpinnings of inherited podocytopathies has advanced immensely. By sequencing the genomes of a large pool of families affected by focal segmental glomerulosclerosis (FSGS), researchers have identified a common theme: familial podocytopathies are frequently caused by genes selectively expressed in podocytes. Podocalyxin is a podocyte-specific surface sialomucin that has long been known to play important roles in podocyte morphogenesis and function. Few studies, however, have shown a conclusive link between mutations in the gene and FSGS complemented by functional evidence. In a fascinating new paper published in <i>Clinical Science</i>, Lin et al. identify two unrelated pedigrees in which dominant loss-of-function mutations in <i>PODXL</i> lead to adult-onset FSGS. Nonsense-mediated decay of the mutated <i>PODXL</i> transcripts leads to protein insufficiency, which in turn cause podocyte dysfunction through defects in motility and cytoskeletal organization. This is the first study to date that demonstrates, mechanistically, how autosomal dominant mutations in podocalyxin can lead to FSGS and renal insufficiency. Here, we summarize the experimental findings of this manuscript and propose, perhaps, a more controversial hypothesis: down-regulation of podocalyxin protein expression from podocytes is a critical turning point in the progression of most podocytopathies and may be mechanistically relevant to glomerulopathies in which podocyte damage is not necessarily induced by genetic lesions.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"443-447"},"PeriodicalIF":6.0,"publicationDate":"2019-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1042/CS20181067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36944685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of G protein-coupled estrogen receptor protects intestine from ischemia/reperfusion injury in mice by protecting the crypt cell proliferation.","authors":"Shiquan Chai,&nbsp;Kaixuan Liu,&nbsp;Wanbing Feng,&nbsp;Tiantian Liu,&nbsp;Qian Wang,&nbsp;Rong Zhou,&nbsp;Shiming Chen,&nbsp;Liyan Wang,&nbsp;Guanyu Chen,&nbsp;Tian Ming,&nbsp;Jiandong Zhao,&nbsp;Chuanyong Liu,&nbsp;Bing Xue","doi":"10.1042/CS20180919","DOIUrl":"https://doi.org/10.1042/CS20180919","url":null,"abstract":"<p><p>The intestinal ischemia/reperfusion (I/R) injury is a common clinical event related with high mortality in patients undergoing surgery or trauma. Estrogen exerts salutary effect on intestinal I/R injury, but the receptor type is not totally understood. We aimed to identify whether the G protein-coupled estrogen receptor (GPER) could protect the intestine against I/R injury and explored the mechanism. Adult male C57BL/6 mice were subjected to intestinal I/R injury by clamping (45 min) of the superior mesenteric artery followed by 4 h of intestinal reperfusion. Our results revealed that the selective GPER blocker abolished the protective effect of estrogen on intestinal I/R injury. Selective GPER agonist G-1 significantly alleviated I/R-induced intestinal mucosal damage, neutrophil infiltration, up-regulation of TNF-α and cyclooxygenase-2 (Cox-2) expression, and restored impaired intestinal barrier function. G-1 could ameliorate the impaired crypt cell proliferation ability induced by I/R and restore the decrease in villus height and crypt depth. The up-regulation of inducible nitric oxide synthase (iNOS) expression after I/R treatment was attenuated by G-1 administration. Moreover, selective iNOS inhibitor had a similar effect with G-1 on promoting the proliferation of crypt cells in the intestinal I/R model. Both GPER and iNOS were expressed in leucine-rich repeat containing G-protein coupled receptor 5 (Lgr5) positive stem cells in crypt. Together, these findings demonstrate that GPER activation can prompt epithelial cell repair following intestinal injury, which occurred at least in part by inhibiting the iNOS expression in intestinal stem cells (ISCs). GPER may be a novel therapeutic target for intestinal I/R injury.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"449-464"},"PeriodicalIF":6.0,"publicationDate":"2019-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1042/CS20180919","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36917762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Local cyclical compression modulates macrophage function <i>in situ</i> and alleviates immobilization-induced muscle atrophy.","authors":"","doi":"10.1042/CS-20180432_COR","DOIUrl":"https://doi.org/10.1042/CS-20180432_COR","url":null,"abstract":"Clinical Science (2018) 132(19), 2147-2161; https://doi.org/10.1042/CS20180432\u0000\u0000Corrections to Figures 1–3 of the original article have been made online. These corrections are described and explained below.\u0000\u00001. Micrographs (micrographic images) of control samples for Figure 1B …","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"407"},"PeriodicalIF":6.0,"publicationDate":"2019-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1042/CS-20180432_COR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36921634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatic accumulation of S-adenosylmethionine in hamsters with non-alcoholic fatty liver disease associated with metabolic syndrome under selenium and vitamin E deficiency.","authors":"Josep Maria Del Bas,&nbsp;Benjamín Rodríguez,&nbsp;Francesc Puiggròs,&nbsp;Silvia Mariné,&nbsp;Miguel Angel Rodríguez,&nbsp;David Moriña,&nbsp;Lluís Armengol,&nbsp;Antoni Caimari,&nbsp;Lluís Arola","doi":"10.1042/CS20171039","DOIUrl":"https://doi.org/10.1042/CS20171039","url":null,"abstract":"<p><p>Progression of non-alcoholic fatty liver disease (NAFLD) in the context of metabolic syndrome (MetS) is only partially explored due to the lack of preclinical models. In order to study the alterations in hepatic metabolism that accompany this condition, we developed a model of MetS accompanied by the onset of steatohepatitis (NASH) by challenging golden hamsters with a high-fat diet low in vitamin E and selenium (HFD), since combined deficiency results in hepatic necroinflammation in rodents. Metabolomics and transcriptomics integrated analyses of livers revealed an unexpected accumulation of hepatic S-Adenosylmethionine (SAM) when compared with healthy livers likely due to diminished methylation reactions and repression of GNMT. SAM plays a key role in the maintenance of cellular homeostasis and cell cycle control. In agreement, analysis of over-represented transcription factors revealed a central role of c-myc and c-Jun pathways accompanied by negative correlations between SAM concentration, MYC expression and AMPK phosphorylation. These findings point to a drift of cell cycle control toward senescence in livers of HFD animals, which could explain the onset of NASH in this model. In contrast, hamsters with NAFLD induced by a conventional high-fat diet did not show SAM accumulation, suggesting a key role of selenium and vitamin E in SAM homeostasis. In conclusion, our results suggest that progression of NAFLD in the context of MetS can take place even in a situation of hepatic SAM excess and that selenium and vitamin E status might be considered in current therapies against NASH based on SAM supplementation.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"409-423"},"PeriodicalIF":6.0,"publicationDate":"2019-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1042/CS20171039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35594131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}