Identification of a potent NAFLD drug candidate for controlling T2DM-mediated inflammation and secondary damage in vitro and in vivo

Md Samsuzzaman; Jae Hyuk Lee; Hyejin Moon; Jisue Lee; Heaji Lee; Yunsook Lim; Myoung Gyu Park; Hakwon Kim; Sun Yeou Kim

doi:10.3389/fphar.2022.943879

Identification of a potent NAFLD drug candidate for controlling T2DM-mediated inflammation and secondary damage in vitro and in vivo

Front Pharmacol. 2022 Aug 19:13:943879. doi: 10.3389/fphar.2022.943879. eCollection 2022.

Authors

Md Samsuzzaman¹, Jae Hyuk Lee¹, Hyejin Moon², Jisue Lee², Heaji Lee³, Yunsook Lim³, Myoung Gyu Park⁴, Hakwon Kim², Sun Yeou Kim^{1

5}

Affiliations

¹ College of Pharmacy, Gachon University, Incheon, South Korea.
² Department of Applied Chemistry and Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Seoul, Gyeonggi, South Korea.
³ Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea.
⁴ MetaCen Therapeutics Company, Suwon, Gyeonggi, South Korea.
⁵ Gachon Institute of Pharmaceutical Science, Gachon University, Incheon, South Korea.

Abstract

Accumulation of glucose/sugar results in the formation of reactive di-carbonyl compounds such as MGO and GO that interact with several amino acids and proteins to form toxic advanced glycation end products (AGEs). Induction of AGEs breakdown can control symptoms and severity in T2DM and other related complications like NAFLD where AGEs are the key players. Therefore, an AGE cross-link breaker has been suggested for preventing the onset/progression of NAFLD. In this study, we reported novel synthetic naphthalene-2-acyl thiazolium derivatives (KHAGs). Among synthesized KHAG derivatives, we observed that a novel KHAG-04, a 1,4-dimethoxynaphthalen-2-acyl thiazolium salt which is an analog of alagebrium, dramatically cleaves MGO/GO-AGE cross-links, and it also inhibited inflammation by lowering the level of nitric oxide production and IL-1β and TNF-α secretion in LPS and/or MGO-AGE-activated macrophage. Moreover, it also reduced FFA and MGO-AGE-induced lipogenesis in Hep-G2 cells. In mice, KHAG-04 significantly reduced the level of glyoxal in the liver, which was induced by DMC. Furthermore, KHAG-04 treatment significantly reduced blood glucose levels, lipid accumulation, and inflammation in the NAFLD/T2DM animal model. Novel KHAG-04-mediated induction of AGEs breakdown could be the possible reason for its anti-inflammatory, antihyperglycemic, and anti-lipidemic effects in cells and NAFLD in the T2DM animal model, respectively. Further research might explore the pharmacological efficacy and usefulness and consider the ability of this compound in the treatment strategy against various models of NAFLD in T2DM where MGO/GO-AGEs play a key role in the pathogenesis.

Keywords: KHAG-04; NASH; glucotoxicity; inflammation; lipogenesis.