Nonalcoholic fatty liver disease: Biomarkers support decisions around pharmacological intervention
Authors: Silvia Sookoian, Carlos J. Pirola
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. This study was partially supported by grants PICT2010‐0441, PICT 2014‐0432, and PICT 2014‐1816 (Agencia Nacional de Promoción Científica y Tecnológica, FONCyT). S.S. and C.J.P. belong to Consejo Nacional de Investigaciones Científicas (CONICET). TO THE EDITOR: We read with great interest the article of Ajmera et al.1 reporting on the relationship between biomarkers and the histological disease spectrum of nonalcoholic fatty liver disease (NAFLD) in a large population of well‐characterized patients from the Nonalcoholic Steatohepatitis Clinical Research Network. The researchers found a significant association between circulating levels of total plasminogen activator inhibitor 1 (tPAI1) and the presence of nonalcoholic steatohepatitis, which was independent of clinical confounding factors.1 The clinical value of this result should be highlighted, also having important implications for tailoring pharmacological interventions. We have previously observed in a case‐control study (215 individuals) that patients with NAFLD have increased levels of biomarkers of atherosclerosis, including PAI1, soluble intercellular adhesion molecule 1, and sCD40L; to extend these observations, we measured, by immunohistochemistry, their hepatic protein expression.2 We found that liver PAI1 immunoreactivity was significantly associated with disease severity; PAI1 was expressed in hepatocytes as well as in the inflammatory infiltrate.2 To further evaluate the effect of losartan, an angiotensin II type 1 receptor (AT1R) antagonist, and telmisartan, an AT1R‐blocker with insulin‐sensitizing properties, on hepatic expression of PAI1 (Serpine1), we used a rat model of NAFLD. We found that both drugs reverted fatty liver, but only 12 weeks of losartan strongly reduced hepatic Serpine1 gene expression.3 A previous study showed that tumor necrosis factor alpha, which is overexpressed in NAFLD, and renin‐angiotensin system coordinately stimulate PAI1 production in hepatocytes.4 Together, these results suggest that losartan has potential not only in the treatment of NAFLD, but also the associated cardiovascular outcomes, including PAI1 overexpression. Table 1 illustrates a full list of pharmacological agents under current investigation targeting PAI1 not only in the treatment of NAFLD, but also related conditions, including obstructive sleep apnea.5 Collectively, as shown in the work of Ajmera et al.1 NAFLD pathogenesis involves highly interconnected mechanisms, of which the molecular taxonomy is more complex than the mere accumulation of fat in the liver. In fact, as in many metabolic syndrome components, the pathways involved reflect a low‐to‐moderate degree of inflammation as simply shown by an increased leukocyte count. Therefore, it is reasonable to assume that NAFLD requires not only precision diagnosis, but also precision treatment. Table 1 - Pharmacological Targets of SERPINE1 (PAI1) Drug Name/ Status* Drug Bank No. and Description Role/Medical Use Mechanism/s of Action Condition (ClinicalTrials.gov Identifier No.) Urokinase/approved DB00013 Low‐molecular‐weight form of human urokinase Activator (target)/treatment of embolism, coronary artery thrombosis, and venous and arterial blood clots Acts on the endogenous fibrinolytic system, cleaving the Arg‐Val bond in plasminogen to produce active plasmin Cholelithiasis Associated With Common Bile Duct Stones (NCT01687959) Alteplase/approved DB00009 Purified human tissue plasminogen activator Target/glycosylated, 527 residues purified from CHO cells The protease domain cleaves the Arg‐Val bond in plasminogen to form plasmin. Myocardial Infarction (NCT02182011) Coronary Artery Disease (NCT00868855) Cholelithiasis Associated With Common Bile Duct Stones (NCT01687959) Ischemic Stroke (NCT02572336) Stroke, Acute (NCT01957774) Cardiovascular Risk in Pediatric Cancer (NCT02010190) Obstructive Sleep Apnea (NCT02202811 and NCT00936481) Atherosclerotic Disease (NCT02176941) Tenecteplase/ Approved DB00031 527 amino acid glycoprotein Target/treatment of myocardial infarction and lysis of intracoronary emboli Binds to fibrin‐rich clots through the fibronectin finger‐like domain and the Kringle 2 domain Myocardial Infarction (NCT02182011) Candesartan/ Approved DB00796 Class of organic compounds known as biphenyltetrazoles and derivatives Antagonist Angiotensin II receptor 1 (AT1) antagonist Coronary artery disease; Cardiopulmonary bypass; Fibrinolysis; Inflammation (NCT00607672) Losartan/ Approved DB00678 Class of organic compounds known as biphenyltetrazoles and derivatives Antagonist Angiotensin II receptor 1 (AT1) antagonist NAFLD in children (NCT01913470) The list of compounds is based on drugs that specifically target SERPINE1 (Serpin Family E Member 1, PAI‐1) either as antagonist or inhibitors, and of which there are current registered clinical trials that include primary and /or secondary outcomes specifically focused on interfering/ acting or targeting PAI1.Status (*): stands for FDA‐approved drugs; #Clinical Trials.gov Identifier extracted from https://clinicaltrials.gov. Drug bank number and description extracted from http://www.drugbank.ca/drugs/.