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Article ; Online: Non-steroidal FXR agonist cilofexor improves cholestatic liver injury in the

Fuchs, Claudia D / Sroda, Natalie / Scharnagl, Hubert / Gupta, Ruchi / Minto, Wesley / Stojakovic, Tatjana / Liles, John T / Budas, Grant / Hollenback, David / Trauner, Michael

JHEP reports : innovation in hepatology

2023 Volume 5, Issue 11, Page(s) 100874

Abstract: Background & aims: The nuclear receptor farnesoid X receptor (FXR) is a key regulator of hepatic bile acid (BA) and lipid metabolism, inflammation and fibrosis. Here, we aimed to explore the potential of cilofexor (GS-9674), a non-steroidal FXR agonist, ...

Abstract	Background & aims: The nuclear receptor farnesoid X receptor (FXR) is a key regulator of hepatic bile acid (BA) and lipid metabolism, inflammation and fibrosis. Here, we aimed to explore the potential of cilofexor (GS-9674), a non-steroidal FXR agonist, as a therapeutic approach for counteracting features of cholestatic liver injury by evaluating its efficacy and mechanisms in the Methods: FVB/N wild-type and Results: Cilofexor treatment improved serum levels of aspartate aminotransferase, alkaline phosphatase as well as BAs in Conclusion: Collectively the current data show that cilofexor treatment improves cholestatic liver injury and decreases hepatic fibrosis in the Impact and implications: Treatment with cilofexor, a non-steroidal farnesoid X receptor (FXR) agonist, improved histological features of sclerosing cholangitis, cholestasis and hepatic fibrosis in the
Language	English
Publishing date	2023-08-03
Publishing country	Netherlands
Document type	Journal Article
ISSN	2589-5559
ISSN (online)	2589-5559
DOI	10.1016/j.jhepr.2023.100874
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Article ; Online: Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice.

Martins, Bárbara B / Hösch, Natália G / Alcantara, Queren A / Budas, Grant R / Chen, Che-Hong / Mochly-Rosen, Daria / Ferreira, Julio C B / Zambelli, Vanessa O

Biomolecules

2021 Volume 11, Issue 12

Abstract: Protein kinase Cε (PKCε) is highly expressed in nociceptor neurons and its activation has been reported as pro-nociceptive. Intriguingly, we previously demonstrated that activation of the mitochondrial PKCε substrate aldehyde dehydrogenase-2 (ALDH2) ... ...

Abstract	Protein kinase Cε (PKCε) is highly expressed in nociceptor neurons and its activation has been reported as pro-nociceptive. Intriguingly, we previously demonstrated that activation of the mitochondrial PKCε substrate aldehyde dehydrogenase-2 (ALDH2) results in anti-nociceptive effects. ALDH2 is a major enzyme responsible for the clearance of 4-hydroxy-2-nonenal (4-HNE), an oxidative stress byproduct accumulated in inflammatory conditions and sufficient to induce pain hypersensitivity in rodents. Here we determined the contribution of the PKCε-ALDH2 axis during 4-HNE-induced mechanical hypersensitivity. Using knockout mice, we demonstrated that PKCε is essential for the nociception recovery during 4-HNE-induced hypersensitivity. We also found that ALDH2 deficient knockin mice display increased 4-HNE-induced nociceptive behavior. As proof of concept, the use of a selective peptide activator of PKCε (ΨεHSP90), which favors PKCε translocation to mitochondria and activation of PKCε-ALDH2 axis, was sufficient to block 4-HNE-induced hypersensitivity in WT, but not in ALDH2-deficient mice. Similarly, ΨεHSP90 administration prevented mechanical hypersensitivity induced by endogenous production of 4-HNE after carrageenan injection. These findings provide evidence that selective activation of mitochondrial PKCε-ALDH2 axis is important to mitigate aldehyde-mediated pain in rodents, suggesting that ΨεHSP90 and small molecules that mimic it may be a potential treatment for patients with pain.
MeSH term(s)	Aldehyde Dehydrogenase, Mitochondrial/genetics ; Aldehyde Dehydrogenase, Mitochondrial/metabolism ; Aldehydes/adverse effects ; Animals ; Carrageenan/adverse effects ; Disease Models, Animal ; Gene Knock-In Techniques ; Gene Knockout Techniques ; Male ; Mice ; Mitochondria/metabolism ; Pain/chemically induced ; Pain/metabolism ; Protein Kinase C-epsilon/metabolism ; Protein Transport
Chemical Substances	Aldehydes ; Carrageenan (9000-07-1) ; ALDH2 protein, mouse (EC 1.2.1.3) ; Aldehyde Dehydrogenase, Mitochondrial (EC 1.2.1.3) ; Prkce protein, mouse (EC 2.7.1.-) ; Protein Kinase C-epsilon (EC 2.7.11.13) ; 4-hydroxy-2-nonenal (K1CVM13F96)
Language	English
Publishing date	2021-11-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom11121798
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Article: Apoptosis signal-regulating kinase 1 inhibition in

Wilson, Kathryn S / Buist, Hanna / Suveizdyte, Kornelija / Liles, John T / Budas, Grant R / Hughes, Colin / MacLean, Margaret R / Johnson, Martin / Church, Alistair C / Peacock, Andrew J / Welsh, David J

Pulmonary circulation

2020 Volume 10, Issue 2, Page(s) 2045894020922810

Abstract: Pulmonary arterial hypertension, group 1 of the pulmonary hypertension disease family, involves pulmonary vascular remodelling, right ventricular dysfunction and cardiac failure. Oxidative stress, through activation of mitogen-activated protein kinases ... ...

Abstract	Pulmonary arterial hypertension, group 1 of the pulmonary hypertension disease family, involves pulmonary vascular remodelling, right ventricular dysfunction and cardiac failure. Oxidative stress, through activation of mitogen-activated protein kinases is implicated in these changes. Inhibition of apoptosis signal-regulating kinase 1, an apical mitogen-activated protein kinase, prevented pulmonary arterial hypertension developing in rodent models. Here, we investigate apoptosis signal-regulating kinase 1 in pulmonary arterial hypertension by examining the impact that its inhibition has on the molecular and cellular signalling in established disease. Apoptosis signal-regulating kinase 1 inhibition was investigated in
Language	English
Publishing date	2020-05-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2638089-4
ISSN	2045-8940 ; 2045-8932
ISSN (online)	2045-8940
ISSN	2045-8932
DOI	10.1177/2045894020922810
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Article ; Online: ASK1/ p38 axis inhibition blocks the release of mitochondrial "danger signals" from hepatocytes and suppresses progression to cirrhosis and liver cancer.

Hepatology (Baltimore, Md.)

2024

Abstract: Background and aims: Apoptosis Signal-regulating Kinase 1 (ASK1) is activated by various pathological stimuli and induces cell apoptosis through downstream p38 activation. We studied the effect of pharmacological ASK1 inhibition on cirrhosis and its ... ...

Abstract	Background and aims: Apoptosis Signal-regulating Kinase 1 (ASK1) is activated by various pathological stimuli and induces cell apoptosis through downstream p38 activation. We studied the effect of pharmacological ASK1 inhibition on cirrhosis and its sequelae using comprehensive preclinical in vivo and in vitro systems. Approach and results: Short-term (4-6 wk) and long-term (24-44 wk) ASK1 inhibition using small molecule GS-444217 was tested in thioacetamide-induced and BALB/c. Mdr2-/- murine models of cirrhosis and HCC, and in vitro using primary hepatocyte cell death assays. Short-term GS-444217 therapy in both models strongly reduced phosphorylated p38, hepatocyte death, and fibrosis by up to 50%. Profibrogenic release of mitochondrial DAMP mitochondrial deoxyribonucleic acid from dying hepatocytes was blocked by ASK1 or p38 inhibition. Long-term (24 wk) therapy in BALBc.Mdr2 - / - model resulted in a moderate 25% reduction in bridging fibrosis, but not in net collagen deposition. Despite this, the development of cirrhosis was effectively prevented, with strongly reduced p21 + hepatocyte staining (by 72%), serum ammonia levels (by 46%), and portal pressure (average 6.07 vs. 8.53 mm Hg in controls). Extended ASK1 inhibition for 44 wk in aged BALB/c. Mdr2-/- mice resulted in markedly reduced tumor number and size by ~50% compared to the control group. Conclusions: ASK1 inhibition suppresses the profibrogenic release of mitochondrial deoxyribonucleic acid from dying hepatocytes in a p38-dependent manner and protects from liver fibrosis. Long-term ASK1 targeting resulted in diminished net antifibrotic effect, but the progression to liver cirrhosis and cancer in BALBc/ Mdr2- / - mice was effectively inhibited. These data support the clinical evaluation of ASK1 inhibitors in fibrotic liver diseases.
Language	English
Publishing date	2024-02-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1097/HEP.0000000000000801
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Article: The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model.

Schwabl, Philipp / Hambruch, Eva / Budas, Grant R / Supper, Paul / Burnet, Michael / Liles, John T / Birkel, Manfred / Brusilovskaya, Ksenia / Königshofer, Philipp / Peck-Radosavljevic, Markus / Watkins, William J / Trauner, Michael / Breckenridge, David G / Kremoser, Claus / Reiberger, Thomas

Biomedicines

2021 Volume 9, Issue 1

Abstract: Background: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on ... ...

Abstract	Background: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on portal pressure and fibrosis in experimental NASH. Methods: NASH was induced in Wistar rats using a choline-deficient high-fat diet plus intraperitoneal sodium nitrite injections. First, a dose-finding study was performed with 10 mg/kg and 30 mg/kg of cilofexor, focusing on histological readouts. Liver fibrosis was assessed by Picro-Sirius-Red, desmin staining and hepatic hydroxyproline content. Gene expression was determined by RT-PCR. In a subsequent hemodynamic study, rats received 30 mg/kg cilofexor with or without propranolol (25 mg/kg). Portal pressure, systemic hemodynamics and splanchnic blood flow were measured. Results: Cilofexor dose-dependently induced FXR target genes Conclusion: The non-steroidal FXR agonist cilofexor decreased portal hypertension and reduced liver fibrosis in NASH rats. While cilofexor seems to primarily decrease sinusoidal resistance in cirrhotic portal hypertension, the combination with propranolol additionally reduced mesenteric hyperperfusion.
Language	English
Publishing date	2021-01-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines9010060
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Article ; Online: The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model

Philipp Schwabl / Eva Hambruch / Grant R. Budas / Paul Supper / Michael Burnet / John T. Liles / Manfred Birkel / Ksenia Brusilovskaya / Philipp Königshofer / Markus Peck-Radosavljevic / William J. Watkins / Michael Trauner / David G. Breckenridge / Claus Kremoser / Thomas Reiberger

Biomedicines, Vol 9, Iss 1, p

2021 Volume 60

Abstract	Background: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on portal pressure and fibrosis in experimental NASH. Methods: NASH was induced in Wistar rats using a choline-deficient high-fat diet plus intraperitoneal sodium nitrite injections. First, a dose-finding study was performed with 10 mg/kg and 30 mg/kg of cilofexor, focusing on histological readouts. Liver fibrosis was assessed by Picro-Sirius-Red, desmin staining and hepatic hydroxyproline content. Gene expression was determined by RT-PCR. In a subsequent hemodynamic study, rats received 30 mg/kg cilofexor with or without propranolol (25 mg/kg). Portal pressure, systemic hemodynamics and splanchnic blood flow were measured. Results: Cilofexor dose-dependently induced FXR target genes shp, cyp7a1 and fgf15 in hepatic and ileal tissues, paralleled by a dose-dependent reduction in liver fibrosis area (Picro-Sirius-Red) of −41% (10 mg/kg) and −69% (30 mg/kg), respectively. The 30 mg/kg cilofexor dose significantly reduced hepatic hydroxyproline content (−41%), expression of col1a1 (−37%) and pdgfr-β (−36%), as well as desmin area (−42%) in NASH rats. Importantly, cilofexor decreased portal pressure (11.9 ± 2.1 vs. 8.9 ± 2.2 mmHg; p = 0.020) without affecting splanchnic blood-flow or systemic hemodynamics. The addition of propranolol to cilofexor additionally reduced splanchnic inflow (−28%) but also mean arterial pressure (−25%) and heart rate (−37%). Conclusion: The non-steroidal FXR agonist cilofexor decreased portal hypertension and reduced liver fibrosis in NASH rats. While cilofexor seems to primarily decrease sinusoidal resistance in cirrhotic portal hypertension, the combination with propranolol additionally reduced mesenteric hyperperfusion.
Keywords	NASH ; FXR ; cilofexor ; portal hypertension ; fibrosis ; rats ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Aldehyde dehydrogenase 2 in cardiac protection: a new therapeutic target?

Budas, Grant R / Disatnik, Marie-Hélène / Mochly-Rosen, Daria

Trends in cardiovascular medicine

2009 Volume 19, Issue 5, Page(s) 158–164

Abstract: Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is emerging as a key enzyme involved in cytoprotection in the heart. ALDH2 mediates both the detoxification of reactive aldehydes such as acetaldehyde and 4-hydroxy-2-nonenal and the bioactivation of ... ...

Abstract	Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is emerging as a key enzyme involved in cytoprotection in the heart. ALDH2 mediates both the detoxification of reactive aldehydes such as acetaldehyde and 4-hydroxy-2-nonenal and the bioactivation of nitroglycerin to nitric oxide. In addition, chronic nitrate treatment results in ALDH2 inhibition and contributes to nitrate tolerance. Our laboratory recently identified ALDH2 to be a key mediator of endogenous cytoprotection. We reported that ALDH2 is phosphorylated and activated by the survival kinase protein kinase C epsilon and found a strong inverse correlation between ALDH2 activity and infarct size. We also identified a small molecule ALDH2 activator which reduces myocardial infarct size induced by ischemia/reperfusion in vivo. In this review, we discuss evidence that ALDH2 is a key mediator of endogenous survival signaling in the heart, suggest possible cardioprotective mechanisms mediated by ALDH2 and discuss potential clinical implications of these findings.
MeSH term(s)	Aldehyde Dehydrogenase/genetics ; Aldehyde Dehydrogenase/metabolism ; Aldehyde Dehydrogenase, Mitochondrial ; Animals ; Cytoprotection ; Humans ; Ischemic Preconditioning, Myocardial ; Myocardial Infarction/enzymology ; Myocardial Reperfusion Injury/enzymology ; Myocardium/enzymology ; Phosphorylation ; Protein Kinase C/metabolism ; Signal Transduction
Chemical Substances	ALDH2 protein, human (EC 1.2.1.3) ; Aldehyde Dehydrogenase (EC 1.2.1.3) ; Aldehyde Dehydrogenase, Mitochondrial (EC 1.2.1.3) ; Protein Kinase C (EC 2.7.11.13)
Language	English
Publishing date	2009-12-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1097434-9
ISSN	1873-2615 ; 1050-1738
ISSN (online)	1873-2615
ISSN	1050-1738
DOI	10.1016/j.tcm.2009.09.003
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Article: Cardioprotective mechanisms of PKC isozyme-selective activators and inhibitors in the treatment of ischemia-reperfusion injury.

Budas, Grant R / Churchill, Eric N / Mochly-Rosen, Daria

Pharmacological research

2007 Volume 55, Issue 6, Page(s) 523–536

Abstract: Current treatment for acute myocardial infarction (AMI) is aimed at limiting the duration of ischemia by either mechanical (balloon catheters) or enzymatic (thrombolytics) means to disrupt the occlusion. While these treatments are effective in limiting ... ...

Abstract	Current treatment for acute myocardial infarction (AMI) is aimed at limiting the duration of ischemia by either mechanical (balloon catheters) or enzymatic (thrombolytics) means to disrupt the occlusion. While these treatments are effective in limiting the duration of ischemia, no therapeutic treatment is currently available to prevent ischemic injury and to reduce reperfusion injury, which occurs after these interventions. The development of rationally designed PKC isozyme-selective regulator peptides has permitted investigation into the role of specific PKC isozymes in ischemia-reperfusion (IR) injury. Based on these studies, it is now evident that epsilon and deltaPKC have distinct temporal and opposing roles in regulating myocardial damage induced by IR. Activation of epsilonPKC before ischemia protects the heart by mimicking preconditioning, whereas inhibition of deltaPKC during reperfusion protects the heart from reperfusion-induced damage. These cardioprotective effects have been observed in isolated cardiomyocytes, isolated perfused hearts and in vivo in all species tested including mouse, rat and pig and may provide the basis for future therapeutic agents. Having established the efficacy of PKC isozyme-specific regulators in reducing IR injury, the next challenge is to outline the molecular mechanisms regulated by delta and epsilonPKC isozymes that result in enhanced tolerance to IR. In this review, we discuss progress that has been made in establishing cytoprotective mechanisms, which arise as a consequence of epsilonPKC activation or deltaPKC inhibition, and how they may lead to protection in the setting of myocardial ischemia reperfusion.
MeSH term(s)	Animals ; Apoptosis ; Cardiotonic Agents/pharmacology ; Cardiotonic Agents/therapeutic use ; Cytoprotection ; Enzyme Activation ; Enzyme Activators/pharmacology ; Enzyme Activators/therapeutic use ; Isoenzymes/antagonists & inhibitors ; Isoenzymes/chemistry ; Isoenzymes/metabolism ; Myocardial Reperfusion Injury/drug therapy ; Myocardial Reperfusion Injury/enzymology ; Myocardial Reperfusion Injury/pathology ; Protein Kinase C-delta/antagonists & inhibitors ; Protein Kinase C-delta/chemistry ; Protein Kinase C-delta/metabolism ; Protein Kinase C-epsilon/chemistry ; Protein Kinase C-epsilon/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Reactive Oxygen Species/metabolism
Chemical Substances	Cardiotonic Agents ; Enzyme Activators ; Isoenzymes ; Protein Kinase Inhibitors ; Reactive Oxygen Species ; Protein Kinase C-delta (EC 2.7.11.13) ; Protein Kinase C-epsilon (EC 2.7.11.13)
Language	English
Publishing date	2007-04-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1003347-6
ISSN	1096-1186 ; 1043-6618 ; 0031-6989
ISSN (online)	1096-1186
ISSN	1043-6618 ; 0031-6989
DOI	10.1016/j.phrs.2007.04.005
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Zs.A 721: Show issues

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Article ; Online: ASK1 Inhibition Halts Disease Progression in Preclinical Models of Pulmonary Arterial Hypertension.

Budas, Grant R / Boehm, Mario / Kojonazarov, Baktybek / Viswanathan, Gayathri / Tian, Xia / Veeroju, Swathi / Novoyatleva, Tatyana / Grimminger, Friedrich / Hinojosa-Kirschenbaum, Ford / Ghofrani, Hossein A / Weissmann, Norbert / Seeger, Werner / Liles, John T / Schermuly, Ralph T

American journal of respiratory and critical care medicine

2017 Volume 197, Issue 3, Page(s) 373–385

Abstract: Rationale: Progression of pulmonary arterial hypertension (PAH) is associated with pathological remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of MAPKs (mitogen- ... ...

Abstract	Rationale: Progression of pulmonary arterial hypertension (PAH) is associated with pathological remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of MAPKs (mitogen-activated protein kinases), which stimulate apoptosis, inflammation, and fibrosis. Objectives: We investigated whether pharmacological inhibition of the redox-sensitive apical MAPK, ASK1 (apoptosis signal-regulating kinase 1), can halt the progression of pulmonary vascular and RV remodeling. Methods: A selective, orally available ASK1 inhibitor, GS-444217, was administered to two preclinical rat models of PAH (monocrotaline and Sugen/hypoxia), a murine model of RV pressure overload induced by pulmonary artery banding, and cellular models. Measurements and main results: Oral administration of GS-444217 dose dependently reduced pulmonary arterial pressure and reduced RV hypertrophy in PAH models. The therapeutic efficacy of GS-444217 was associated with reduced ASK1 phosphorylation, reduced muscularization of the pulmonary arteries, and reduced fibrotic gene expression in the RV. Importantly, efficacy was observed when GS-444217 was administered to animals with established disease and also directly reduced cardiac fibrosis and improved cardiac function in a model of isolated RV pressure overload. In cellular models, GS-444217 reduced phosphorylation of p38 and JNK (c-Jun N-terminal kinase) induced by adenoviral overexpression of ASK1 in rat cardiomyocytes and reduced activation/migration of primary mouse cardiac fibroblasts and human pulmonary adventitial fibroblasts derived from patients with PAH. Conclusions: ASK1 inhibition reduced pathological remodeling of the pulmonary vasculature and the right ventricle and halted progression of pulmonary hypertension in rodent models. These preclinical data inform the first description of a causal role of ASK1 in PAH disease pathogenesis.
MeSH term(s)	Animals ; Biopsy, Needle ; Cardiotonic Agents ; Cells, Cultured ; Disease Models, Animal ; Fibroblasts/cytology ; Fibroblasts/drug effects ; Hemodynamics/physiology ; Hypertension, Pulmonary/drug therapy ; Hypertension, Pulmonary/pathology ; Hypertrophy, Right Ventricular/prevention & control ; Immunohistochemistry ; MAP Kinase Kinase Kinase 5/administration & dosage ; MAP Kinase Kinase Kinase 5/antagonists & inhibitors ; Mice ; Pulmonary Artery/drug effects ; Random Allocation ; Rats ; Risk Assessment
Chemical Substances	Cardiotonic Agents ; MAP Kinase Kinase Kinase 5 (EC 2.7.11.25)
Language	English
Publishing date	2017-09-14
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.201703-0502OC
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Article ; Online: Peptide-based urinary monitoring of fibrotic nonalcoholic steatohepatitis by mass-barcoded activity-based sensors.

Cazanave, Sophie C / Warren, Andrew D / Pacula, Maciej / Touti, Fayçal / Zagorska, Anna / Gural, Nil / Huang, Eric K / Sherman, Sarah / Cheema, Mehar / Ibarra, Sabrina / Bates, Jamie / Billin, Andrew N / Liles, John T / Budas, Grant R / Breckenridge, David G / Tiniakos, Dina / Ratziu, Vlad / Daly, Ann K / Govaere, Olivier /

Anstee, Quentin M / Gelrud, Louis / Luther, Jay / Chung, Raymond T / Corey, Kathleen E / Winckler, Wendy / Bhatia, Sangeeta / Kwong, Gabriel A

Science translational medicine

2021 Volume 13, Issue 616, Page(s) eabe8939

Abstract: Noninvasive detection of nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease, promises to improve patient screening, accelerate drug trials, and reduce health care costs. On the basis of protease dysregulation of ...

Abstract	Noninvasive detection of nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease, promises to improve patient screening, accelerate drug trials, and reduce health care costs. On the basis of protease dysregulation of the biological pathways of fibrotic NASH, we developed the Glympse Bio Test System (GBTS) for multiplexed quantification of liver protease activity. GBTS-NASH comprises a mixture of 19 mass-barcoded PEGylated peptides that is administered intravenously and senses liver protease activity by releasing mass-barcoded reporters into urine for analysis by mass spectrometry. To identify a protease signature of NASH, transcriptomic analysis of 355 human liver biopsies identified a 13-protease panel that discriminated clinically relevant NASH ≥F2 fibrosis from F0-F1 with high classification accuracy across two independent patient datasets. We screened 159 candidate substrates to identify a panel of 19 peptides that exhibited high activity for our 13-protease panel. In the choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) mouse model, binary classifiers trained on urine samples discriminated fibrotic NASH from simple steatosis and healthy controls across a range of nondisease conditions and indicated disease regression upon diet change [area under receiver operating characteristics (AUROCs) > 0.97]. Using a hepatoprotective triple combination treatment (FXR agonist, ACC and ASK1 inhibitors) in a rat model of NASH, urinary classification distinguished F0-F1 from ≥F2 animals and indicated therapeutic response as early as 1 week on treatment (AUROCs >0.91). Our results support GBTS-NASH to diagnose fibrotic NASH via an infusion of peptides, monitor changes in disease severity, and indicate early treatment response.
MeSH term(s)	Fibrosis ; Humans ; Non-alcoholic Fatty Liver Disease ; Peptides
Chemical Substances	Peptides
Language	English
Publishing date	2021-10-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.abe8939
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