Downregulation of Hedgehog Ligands in Human Simple Steatosis May Protect Against Nonalcoholic Steatohepatitis: Is TAZ a Crucial Regulator? Zohreh Khajehahmadi 1 Sina Mohagheghi 2 Saman Nikeghbalian 3 Bita Geramizadeh 4 Iraj Khodadadi 1 Jamshid Karimi 1 Mohammad Ebrahim Ghaffari 5 Heidar Tavilani 1 * 1 Department of Clinical Biochemistry, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran 2 Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran 3 Shiraz Transplant Center, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran 4 Transplant Research Center, Pathology Department, Shiraz University of Medical Sciences, Shiraz, Iran 5 Dental Sciences Research Center, Faculty of Dentistry, Guilan University of Medical Sciences, Rasht, Iran Abstract The conversion of simple steatosis into nonalcoholic steatohepatitis (NASH) in patients with nonalcoholic fatty liver disease (NAFLD) has attracted many attentions in recent years. The role of the hedgehog (HH) pathway in the regulation of lipogenesis has been addressed in the literature. This study aimed to investigate the levels of the sonic hedge- hog (SHH) and Indian hedgehog (IHH) ligands and the correlation of these ligands with levels of proteins involved in the transforming growth factor-β1 (TGF-β1) pathway, as well as the evaluation of the transcrip- tional coactivator with PDZ binding motif (TAZ) expression in human simple steatosis, NASH cirrhosis, and controls. Patients were divided into two groups: the first group consisted of patients diagnosed with simple steatosis (n = 16) and the second group included those diagnosed with NASH cirrhosis (n = 15). As a control group, 18 histologically normal liver tissues were collected in this study. The expression of the TGF-β1path- way components and SHH and IHH ligands were analyzed by means of the quantitative real-time polymerase chain reaction and western blot analyses. A significant decrease was found in the hepatic expression of the SHH, IHH, and TGF-β1 pathways along with the expression of TAZ in tissue specimens with simple steatosis in comparison with patients affected by NASH cirrhosis and controls. Also, the levels of SHH and IHH proteins were significantly correlated with the expres- sion of proteins involved in the TGF-β1 pathway. Moreover, the expression of the HH pathway ligands was positively associated with the expression of TAZ, supporting the notion that TAZ may play a role in the activation of the HH pathway thereby regulating the expression of its ligands. It seems that in patients with NAFLD, the down- regulation of the HH pathway ligands may stem from steatosis; how- ever, at the same time, it may prevent the conversion of simple steatosis into NASH in patients with liver diseases. © 2019 IUBMB Life, 000(000):1–9, 2019 Keywords: non-alcoholic fatty liver disease; IHH protein; SHH protein; transforming growth factor β1 ABBREVIATIONS: NAFLD, nonalcoholic fatty liver disease; NASH, non- alcoholic steatohepatitis; HCC, hepatocellular carcinoma; HH, hedgehog; SHH, sonic hedgehog; IHH, Indian hedgehog; qRT-PCR, quantitative real- time polymerase chain reaction; Smo, smoothened; Gli, glioblastoma; TGF- β1, transforming growth factor-β1; TAZ, Transcriptional coactivator with PDZ binding motif; ER, endoplasmic reticulum; HSCs, hepatic stellate cells; MF, myofibroblasts © 2019 International Union of Biochemistry and Molecular Biology Volume 000, Number 000, Pages 1–9 *Address correspondence to: Heidar Tavilani, Department of Clinical Bio- chemistry, Faculty of Medicine, Hamadan University of Medical Sciences, Shahid Fahmideh Street, Hamadan, Iran. E-mail: tayebinia@umsha.ac.ir Zohreh Khajehahmadi and Sina Mohagheghi contributed equally to this work. Received 5 March 2019; Accepted 26 April 2019 DOI 10.1002/iub.2068 Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com) IUBMB Life 1 Research Communication