Naringin attenuates fructose-induced NAFLD progression in rats through reducing endogenous triglyceride synthesis and activating the Nrf2/ HO-1 pathway Sirinat Pengnet 1 , Phinsuda Sumarithum 2 , Nuttaphong Phongnu 2 , Sakdina Prommaouan 2 , Napapas Kantip 2 , Ittipon Phoungpetchara 3 and Wachirawadee Malakul 2,4 * 1 Division of Physiology, School of Medical Sciences, University of Phayao, Phayao, Thailand, 2 Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand, 3 Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand, 4 Centre of Excellence in Medical Biotechnology, Naresuan University, Phitsanulok, Thailand Background: Excessive fructose consumption causes hepatic lipid accumulation via increased triglyceride (TG) synthesis, leading to the development and progression of non-alcoholic fatty liver disease (NALFD). Naringin, a flavanone glycoside found in citrus fruit, has antioxidant and hypolipidemic properties. Therefore, the aim of this study was to investigate the effect of naringin on fructose-induced NAFLD in rats and the possible underlying mechanism. Methods: Male Sprague Dawley rats were given 10% (w/v) fructose in drinking water for 12 weeks. Naringin (100 mg/kg/day) was administered orally to rats for the last 4 weeks of fructose overload. After 12 weeks of treatment, the hepatic lipid content was determined. In addition, the expression of proteins involved in de novo lipogenesis (DNL) and TG synthesis as well as antioxidant and inflammatory mediators in the liver were examined by western blot analysis. Results: Treatment of fructose-fed rats with naringin significantly decreased the hepatic TG and cholesterol content as well as serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. Naringin treatment also decreased the hepatic expression of carbohydrate response element binding protein (ChREBP), sterol regulatory element-binding protein-1c (SREBP-1c) and nuclear SREBP-1c (nSREBP-1c) as well as enzymes involved in DNL (acetyl CoA carboxylase [ACC] and fatty acid synthase [FAS]) and an enzyme involved in TG synthesis (glycerol-3-phosphate acyltransferase 1 [GPAT-1] and diacylglycerol acyltransferase2 [DGAT2]) in fructose-fed rats. In addition, naringin induced a significant decrease in the hepatic expression of nuclear factor kappa B (NF-κB) OPEN ACCESS EDITED BY Guoxun Chen, The University of Tennessee, Knoxville, United States REVIEWED BY Hanqing Chen, Guangzhou First People’s Hospital, China Fares E. M. Ali, Al-Azhar University, Egypt *CORRESPONDENCE Wachirawadee Malakul, wachirawadeema@nu.ac.th SPECIALTY SECTION This article was submitted to Gastrointestinal and Hepatic Pharmacology, a section of the journal Frontiers in Pharmacology RECEIVED 21 September 2022 ACCEPTED 06 December 2022 PUBLISHED 15 December 2022 CITATION Pengnet S, Sumarithum P, Phongnu N, Prommaouan S, Kantip N, Phoungpetchara I and Malakul W (2022), Naringin attenuates fructose-induced NAFLD progression in rats through reducing endogenous triglyceride synthesis and activating the Nrf2/HO- 1 pathway. Front. Pharmacol. 13:1049818. doi: 10.3389/fphar.2022.1049818 COPYRIGHT © 2022 Pengnet, Sumarithum, Phongnu, Prommaouan, Kantip, Phoungpetchara and Malakul. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Pharmacology frontiersin.org 01 TYPE Original Research PUBLISHED 15 December 2022 DOI 10.3389/fphar.2022.1049818