Comparison of Gene Expression Patterns Between Mouse Models of Nonalcoholic Fatty Liver Disease and Liver Tissues From Patients

Teufel, Andreas; Itzel, Timo; Erhart, Wiebke; Brosch, Mario; Wang, Xiaoyu; Kim, Yong Oock; Schönfels, Witigo von; Herrmann, Alexander; Brückner, Stefan; Stickel, Felix; Dufour, Jean–François; Chavakis, Triantafyllos; Hellerbrand, Claus; Spang, Rainer; Maass, T; Becker, Thomas; Schreiber, Stefan; Schafmayer, Clemens; Schuppan, Detlef; Hampe, Jochen

doi:10.1053/j.gastro.2016.05.051

Cited by 192 publications

(239 citation statements)

References 36 publications

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“…Our combined analysis, as well as a more limited study (68), demonstrated DPT upregulation in the liver of NASH patients. This finding was not confirmed in a recent cross-species transcriptomic study, which relied on a cohort stratification based on the composite NAS score; this score does not isolate the fibrosis component of the disease (69) and therefore precludes the detection of altered Dpt expression (Supplemental Figure 9). In order to gain further insight in the potential novel role of DPT suggested by the human gene expression data analysis, further studies were conducted in preclinical models.…”

Section: Discussionmentioning

confidence: 84%

Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin

et al. 2017

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Section: Discussionmentioning

confidence: 84%

Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin

et al. 2017

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“…A systems biology weighted gene co-expression network analysis of 16 human NASH, 10 NAFLD, and 19 normal liver samples identified a highly significant module ( p < 2 × 10 −6 ) associated with RNA processing (86). These changes are not in all datasets, however, as a German study in 45 morbidly obese subjects with NAFLD or NASH did not show alterations in splicing factor expression (87, 88). Studies in mice have shown similar changes in the expression of splicing factors in diet-induced obesity and NASH models (79, 85, 88, 89).…”

Section: Alternative Splicing and Fatty Livermentioning

confidence: 86%

“…These changes are not in all datasets, however, as a German study in 45 morbidly obese subjects with NAFLD or NASH did not show alterations in splicing factor expression (87, 88). Studies in mice have shown similar changes in the expression of splicing factors in diet-induced obesity and NASH models (79, 85, 88, 89). So NAFLD and NASH are associated with changes in RNA splicing factor expression in the liver, and this likely contributes to alterations in RNA splicing.…”

Section: Alternative Splicing and Fatty Livermentioning

confidence: 86%

Alternative RNA Splicing in the Pathogenesis of Liver Disease

Webster

2017

Front. Endocrinol.

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Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent due to the worldwide obesity epidemic and currently affects one-third of adults or about one billion people worldwide. NAFLD is predicted to affect over 50% of the world’s population by the end of the next decade. It is the most common form of liver disease and is associated with increased risk for progression to a more severe form non-alcoholic steatohepatitis, as well as insulin resistance, type 2 diabetes mellitus, cirrhosis, and eventually hepatocellular carcinoma. This review article will focus on the role of alternative splicing in normal liver physiology and dysregulation in liver disease.

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“…The approach of characterizing gene expression in NAFLD and NASH has long been utilized to better understand the molecular basis of disease development [16, 17]. For example, in humans, gene expression patterns clearly separated steatohepatitis from steatosis and normal liver [18], mild fibrosis and septal fibrosis [19], and low versus high levels of steatosis [20].…”

Section: Introductionmentioning

confidence: 99%

Altered expression of MALAT1 lncRNA in nonalcoholic steatohepatitis fibrosis regulates CXCL5 in hepatic stellate cells

Leti

Legendre

Still

et al. 2017

Translational Research

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In the present study, we sought to identify lncRNA expression profiles in NASH patients with histological evidence of lobular inflammation and advanced fibrosis. We profiled lncRNA expression using RNA-sequencing of wedge liver biopsies from 24 NAFLD patients with normal liver histology, 53 NAFLD patients with lobular inflammation, and 65 NAFLD patients with advanced fibrosis. Transcript profiling identified 4432 and 4057 differentially expressed lncRNAs in comparisons of normal tissue with lobular inflammation and fibrosis samples, respectively. Functional enrichment analysis revealed lncRNA participation in TGFB1 and TNF signaling, insulin resistance, and extracellular matrix maintenance. Several lncRNAs were highly expressed in fibrosis relative to normal tissue, including nuclear paraspeckle assembly transcript 1 (NEAT1), hepatocellular carcinoma upregulated lncRNA (HULC), and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). Two potential target mRNAs, syndecan 4 (SDC4) and C-X-C motif chemokine ligand 5 (CXCL5) were identified for HULC and MALAT1, respectively, but only CXCL5 showed differential expression among the different histological classes. Knockdown of MALAT1 expression reduced CXCL5 transcript and protein levels by 50% and 30%, respectively, in HepG2 cells. Expression of MALAT1 and CXCL5 was upregulated in activated hepatic stellate (LX-2) cells compared to cells in the quiescent state, and MALAT1 expression was regulated by hyperglycemia and insulin in HepG2 cells, but only by insulin in LX-2 cells. Dysregulated lncRNA expression is associated with inflammation and fibrosis in NASH. Functionally relevant differences in MALAT1 expression may contribute to the development of fibrosis in NASH through mechanisms involving inflammatory chemokines.

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Comparison of Gene Expression Patterns Between Mouse Models of Nonalcoholic Fatty Liver Disease and Liver Tissues From Patients

Cited by 192 publications

References 36 publications

Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin

Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin

Alternative RNA Splicing in the Pathogenesis of Liver Disease

Altered expression of MALAT1 lncRNA in nonalcoholic steatohepatitis fibrosis regulates CXCL5 in hepatic stellate cells

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