Discovery of N -Aryl- N '-[4-(aryloxy)cyclohexyl]squaramide-Based Inhibitors of LXR/SREBP-1c Signaling Pathway Ameliorating Steatotic Liver Disease: Navigating the Role of SIRT6 Activation.
Long Huu NguyenYe Eun ChoSoyeong KimYeonsoo KimJinsook KwakJung-Soo SuhJinyoung LeeKyuwon SonMinseong KimEun Seo JangNaghyun SongBuChul ChoiJiah KimYealin TakTaeyeon HwangJeyun JoEun-Woo LeeSang-Bum KimSanghyun KimOh-Bin KwonSangok KimSeoung Rak LeeHaeseung LeeTae-Jin KimSeonghwan HwangHwayoung YunPublished in: Journal of medicinal chemistry (2024)
Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily attributed to the abnormal upregulation of hepatic lipogenesis, which is especially caused by the overactivation of the liver X receptor/sterol regulatory element-binding protein-1c (LXR/SREBP-1c) pathway in hepatocytes. In this study, we report the rational design and synthesis of a novel series of squaramides via bioisosteric replacement, which was evaluated for its inhibitory activity on the LXR/SREBP-1c pathway using dual cell-based assays. Compound 31 was found to significantly downregulate LXR, SREBP-1c, and their target genes associated with lipogenesis. Further investigation revealed that compound 31 may indirectly inhibit the LXR/SREBP-1c pathway by activating the upstream regulator sirtuin 6 (SIRT6). Encouragingly, compound 31 substantially attenuated lipid accumulation in HepG2 cells and in the liver of high-fat-diet-fed mice. These findings suggest that compound 31 holds promise as a candidate for the development of treatments for MASLD and other lipid metabolism-related diseases.
Keyphrases
- high fat diet
- signaling pathway
- binding protein
- high fat diet induced
- insulin resistance
- oxidative stress
- single cell
- adipose tissue
- high throughput
- transcription factor
- small molecule
- ischemia reperfusion injury
- cell proliferation
- pi k akt
- cell therapy
- epithelial mesenchymal transition
- induced apoptosis
- stem cells
- liver injury
- drug induced
- mesenchymal stem cells
- endoplasmic reticulum stress
- long non coding rna