Gene expression profile-based drug screen identifies SAHA as a novel treatment for NAFLD

Cheng, Zhujun; Wen, Yusong; Liang, Bowen; Chen, Siyang; Liu, Yujun; Wang, Zang; Cheng, Jiayu; Tang, Xiaoli; Xin, Hong‐Bo; Deng, Libin

doi:10.1039/c8mo00214b

Cited by 12 publications

(6 citation statements)

References 41 publications

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“…In addition, vorinostat ameliorated disease-induced cytotoxicity. Interestingly, in contrast to our results using vorinostat in the LAMPS model, recent reports show that vorinostat also reduced steatosis [64] and lipid metabolism pathways [65] in rat and HCC monoculture studies, respectively. These contrasting findings demonstrate the variability between animal models and simple cell culture models in assessing drug effects, highlighting the need for implementing all-human MPS model systems in drug testing platforms.…”

Section: Discussioncontrasting

confidence: 99%

A Quantitative Systems Pharmacology Platform Reveals NAFLD Pathophysiological States and Targeting Strategies

et al. 2022

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Non-alcoholic fatty liver disease (NAFLD) has a high global prevalence with a heterogeneous and complex pathophysiology that presents barriers to traditional targeted therapeutic approaches. We describe an integrated quantitative systems pharmacology (QSP) platform that comprehensively and unbiasedly defines disease states, in contrast to just individual genes or pathways, that promote NAFLD progression. The QSP platform can be used to predict drugs that normalize these disease states and experimentally test predictions in a human liver acinus microphysiology system (LAMPS) that recapitulates key aspects of NAFLD. Analysis of a 182 patient-derived hepatic RNA-sequencing dataset generated 12 gene signatures mirroring these states. Screening against the LINCS L1000 database led to the identification of drugs predicted to revert these signatures and corresponding disease states. A proof-of-concept study in LAMPS demonstrated mitigation of steatosis, inflammation, and fibrosis, especially with drug combinations. Mechanistically, several structurally diverse drugs were predicted to interact with a subnetwork of nuclear receptors, including pregnane X receptor (PXR; NR1I2), that has evolved to respond to both xenobiotic and endogenous ligands and is intrinsic to NAFLD-associated transcription dysregulation. In conjunction with iPSC-derived cells, this platform has the potential for developing personalized NAFLD therapeutic strategies, informing disease mechanisms, and defining optimal cohorts of patients for clinical trials.

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Section: Discussioncontrasting

confidence: 99%

A Quantitative Systems Pharmacology Platform Reveals NAFLD Pathophysiological States and Targeting Strategies

et al. 2022

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“…Lysine acetylation regulates the activity of intermediate metabolism enzymes of the FA pathways and of the TCA cycle 69 with emerging evidences on inflammation-associated metabolic diseases and aging supporting a multilayered lipid-epigenetic interplay [70][71][72] . Our findings are consistent with reports showing a decrease of LPS-induced cytokine expression after SAHA treatment in microglial cells, mixed glial cultures and macrophages 23,42,43,73 as well as with studies of lipid accumulation inhibition by SAHA in hepatic cells 74 and in cultured adipocytes 75 and by MS-275 (class I-specific HDAC inhibitor) in human macrophages 39 . A reduction in DG levels can sign a shift to a beneficial metabolic state since its generation is associated to inflammatory response as previously reported 61,64 .…”

Section: Discussionsupporting

confidence: 93%

LPS-induced lipid alterations in microglia revealed by MALDI mass spectrometry-based cell fingerprinting in neuroinflammation studies

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Enzlein

Hopf

2022

Sci Rep

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Pathological microglia activation can promote neuroinflammation in many neurodegenerative diseases, and it has therefore emerged as a potential therapeutic target. Increasing evidence suggests alterations in lipid metabolism as modulators and indicators in microglia activation and its effector functions. Yet, how lipid dynamics in activated microglia is affected by inflammatory stimuli demands additional investigation to allow development of more effective therapies. Here, we report an extensive matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) whole cell fingerprinting workflow to investigate inflammation-associated lipid patterns in SIM-A9 microglial cells. By combining a platform of three synergistic MALDI MS technologies we could detect substantial differences in lipid profiles of lipopolysaccharide (LPS)- stimulated and unstimulated microglia-like cells leading to the identification of 21 potential inflammation-associated lipid markers. LPS-induced lipids in SIM-A9 microglial cells include phosphatidylcholines, lysophosphatidylcholines (LysoPC), sphingolipids, diacylglycerols and triacylglycerols. Moreover, MALDI MS-based cell lipid fingerprinting of LPS-stimulated SIM-A9 microglial cells pre-treated with the non-selective histone deacetylase inhibitor suberoylanilide hydroxamic acid revealed specific modulation of LPS-induced-glycerolipids and LysoPC(18:0) with a significant reduction of microglial inflammation response. Our study introduces MALDI MS as a complementary technology for fast and label-free investigation of stimulus-dependent changes in lipid patterns and their modulation by pharmaceutical agents.

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“…Therefore, targeting the epigenetic factors may be one of the mechanisms for drug action to attenuate the onset of NAFLD, for example resveratrol and glucagon like peptide-1 receptor agonists (GLP-1RAs), as activators for SIRT1 alleviate the diet induced fatty liver in animal models [ 60 , 61 , 62 ]. Besides, vorinostat, an inhibitor of Histone deacetylase (HDAC) that inhibits the lipid synthesis in liver cells in vitro, can be a candidate drug in the treatment of NAFLD [ 63 ]. Epigenetic modifiers are being investigated as potential drug targets for NAFLD.…”

Section: Pathogenesis and Risk Factors Of Nafldmentioning

confidence: 99%

Deciphering the role of aberrant DNA methylation in NAFLD and NASH

Vachher¹,

Bansal²,

Kumar

et al. 2022

Heliyon

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Gene expression profile-based drug screen identifies SAHA as a novel treatment for NAFLD

Abstract: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide.

Cited by 12 publications

References 41 publications

A Quantitative Systems Pharmacology Platform Reveals NAFLD Pathophysiological States and Targeting Strategies

A Quantitative Systems Pharmacology Platform Reveals NAFLD Pathophysiological States and Targeting Strategies

LPS-induced lipid alterations in microglia revealed by MALDI mass spectrometry-based cell fingerprinting in neuroinflammation studies

Deciphering the role of aberrant DNA methylation in NAFLD and NASH

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