Gene Expression Predicts Histological Severity and Reveals Distinct Molecular Profiles of Nonalcoholic Fatty Liver Disease

Hoang, Stephen A.; Oseini, Abdul M.; Feaver, Ryan E.; Cole, Banumathi K.; Asgharpour, Amon; Vincent, Robert; Siddiqui, Mohammad Shadab; Lawson, Mark; Day, Nathan; Taylor, Justin M.; Wamhoff, Brian R.; Mirshahi, Faridoddin; Contos, Melissa J.; Idowu, Michael O.; Sanyal, Arun J.

doi:10.1038/s41598-019-48746-5

Cited by 129 publications

(155 citation statements)

References 44 publications

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“…Finally, among tesamorelin-treated participants, we assessed relationships between changes in hepatic expression of differentially regulated gene sets and change in fibrosis-related gene score based on the hepatic expression of 18 genes previously shown to correlate with fibrosis ( 7 ). Among our overall sample at baseline, we found a strong association between fibrosis-related gene score and histologic fibrosis stage ( P = 0.0009; post-ANOVA test for linear trend P = 0.0001), which validated our use of this gene set as a proxy for hepatic fibrosis ( Supplemental Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD

Fourman¹,

Billingsley²,

Agyapong³

et al. 2020

JCI Insight

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Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity among people living with HIV that has a more aggressive course than NAFLD among the general population. In a recent randomized placebo-controlled trial, we demonstrated that the growth hormone–releasing hormone analog tesamorelin reduced liver fat and prevented fibrosis progression in HIV-associated NAFLD over 1 year. As such, tesamorelin is the first strategy that has shown to be effective against NAFLD among the population with HIV. The current study leveraged paired liver biopsy specimens from this trial to identify hepatic gene pathways that are differentially modulated by tesamorelin versus placebo. Using gene set enrichment analysis, we found that tesamorelin increased hepatic expression of hallmark gene sets involved in oxidative phosphorylation and decreased hepatic expression of gene sets contributing to inflammation, tissue repair, and cell division. Tesamorelin also reciprocally up- and downregulated curated gene sets associated with favorable and poor hepatocellular carcinoma prognosis, respectively. Notably, among tesamorelin-treated participants, these changes in hepatic expression correlated with improved fibrosis-related gene score. Our findings inform our knowledge of the biology of pulsatile growth hormone action and provide a mechanistic basis for the observed clinical effects of tesamorelin on the liver.

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Section: Resultsmentioning

confidence: 99%

Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD

Fourman¹,

Billingsley²,

Agyapong³

et al. 2020

JCI Insight

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“…(4) Modern multiomics approaches confirm the relevance of histologic observations by demonstrating a correlation between genetic predictors of progression and histologic assessment of the NAS. (5) Here, we discuss the key molecular and cellular mechanisms that form the underpinnings of the observed histologic changes and global transcriptomics changes in NAFLD.…”

Section: Pathogenesis Of Nonalcoholic Steatohepatitis: An Overviewmentioning

confidence: 99%

“…However, there is considerable heterogeneity in NAFLD progression and NASH development, and only a subset of NAFLD develops NASH. Potential explanations for this variability include differences in etiopathogenic drivers, dynamic multiphasic progression, or that they represent distinct diseases. Alcohol is a well‐recognized disease modifier.…”

Section: Steatosis and Lipotoxicitymentioning

confidence: 99%

“…Subject to the caveat that there is significant collinearity between the NAFLD activity score (NAS) and fibrosis, fibrosis is the only histologic factor associated with mortality . Modern multiomics approaches confirm the relevance of histologic observations by demonstrating a correlation between genetic predictors of progression and histologic assessment of the NAS . Here, we discuss the key molecular and cellular mechanisms that form the underpinnings of the observed histologic changes and global transcriptomics changes in NAFLD.…”

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confidence: 93%

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Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

2020

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Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous group of liver diseases characterized by the accumulation of fat in the liver. The heterogeneity of NAFLD is reflected in a clinical and histologic spectrum where some patients develop isolated steatosis of the liver, termed nonalcoholic fatty liver, whereas others develop hepatocyte injury, ballooning, inflammation, and consequent fibrosis, termed nonalcoholic steatohepatitis (NASH). Systemic insulin resistance is a major driver of hepatic steatosis in NAFLD. Lipotoxicity of accumulated lipids along with activation of the innate immune system are major drivers of NASH. Lipid‐induced sublethal and lethal stress culminates in the activation of inflammatory processes, such as the release of proinflammatory extracellular vesicles and cell death. Innate and adaptive immune mechanisms involving macrophages, dendritic cells, and lymphocytes are central drivers of inflammation that recognize damage‐ and pathogen‐associated molecular patterns and contribute to the progression of the inflammatory cascade. While the activation of the innate immune system and the recruitment of proinflammatory monocytes into the liver in NASH are well known, the exact signals that lead to this remain less well defined. Further, the contribution of other immune cell types, such as neutrophils and B cells, is an area of intense research. Many host factors, such as the microbiome and gut–liver axis, modify individual susceptibility to NASH. In this review, we discuss lipotoxicity, inflammation, and the contribution of interorgan crosstalk in NASH pathogenesis.

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“…To elucidate the transcriptional changes that are associated with human NAFLD, we procured publicly available human NAFLD/NASH transcriptome data from the Gene Expression Omnibus (GEO) and subjected them to Ingenuity Pathway Analysis for the prediction of changes in upstream factors ( Table 2 ). Predictions were based on two GEO datasets with strong power analysis ( Table 2 ) as well as a previously published Ingenuity Pathway Analysis (IPA)-based prediction analysis [ 7 , 205 , 206 ]. The activation of PPARγ was the only consistent prediction for simple steatosis, whereas the onset of fibrosis was associated with changes in a larger number of transcription factors, which were consistent in at least half of the datasets.…”

Section: Prediction Of Transcriptional Regulators By Database Analmentioning

confidence: 99%

Transcriptional Regulation in Non-Alcoholic Fatty Liver Disease

2020

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Obesity is the primary risk factor for the pathogenesis of non-alcoholic fatty liver disease (NAFLD), the worldwide prevalence of which continues to increase dramatically. The liver plays a pivotal role in the maintenance of whole-body lipid and glucose homeostasis. This is mainly mediated by the transcriptional activation of hepatic pathways that promote glucose and lipid production or utilization in response to the nutritional state of the body. However, in the setting of chronic excessive nutrition, the dysregulation of hepatic transcriptional machinery promotes lipid accumulation, inflammation, metabolic stress, and fibrosis, which culminate in NAFLD. In this review, we provide our current understanding of the transcription factors that have been linked to the pathogenesis and progression of NAFLD. Using publicly available transcriptomic data, we outline the altered activity of transcription factors among humans with NAFLD. By expanding this analysis to common experimental mouse models of NAFLD, we outline the relevance of mouse models to the human pathophysiology at the transcriptional level.

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Gene Expression Predicts Histological Severity and Reveals Distinct Molecular Profiles of Nonalcoholic Fatty Liver Disease

Cited by 129 publications

References 44 publications

Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD

Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

Transcriptional Regulation in Non-Alcoholic Fatty Liver Disease

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