1. Academic Validation
  2. Identification of novel SCD1 inhibitor alleviates nonalcoholic fatty liver disease: critical role of liver-adipose axis

Identification of novel SCD1 inhibitor alleviates nonalcoholic fatty liver disease: critical role of liver-adipose axis

  • Cell Commun Signal. 2023 Sep 30;21(1):268. doi: 10.1186/s12964-023-01297-9.
Wei Wang 1 Yulin Kong 1 Xia Wang 2 Zhe Wang 1 Chunlei Tang 2 Jinyou Li 3 Qin Yang 1 Yong Q Chen 1 Shenglong Zhu 4
Affiliations

Affiliations

  • 1 Jiangnan University Medical Center, Wuxi School of Medicine, Jiangnan University, Wuxi, China.
  • 2 School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China.
  • 3 Affiliated Hospital of Jiangnan University, Wuxi, China.
  • 4 Jiangnan University Medical Center, Wuxi School of Medicine, Jiangnan University, Wuxi, China. shenglongzhu@jiangnan.edu.cn.
Abstract

Due to the complexity and incomplete understanding of the crosstalk between liver and adipose tissue, especially the processes of hepatic lipogenesis and adipogenic differentiation, there are currently no effective drugs for the treatment of nonalcoholic fatty liver disease (NAFLD). Stearoyl-coenzyme A desaturase 1 (SCD1), which is abundantly expressed in liver and adipose tissue, may mediate the cross-talk between liver and adipose tissue. Thus, it is essential to develop specific SCD1 inhibitors that target the liver-adipose axis. Herein, we identified a novel SCD1 inhibitor, E6446, through a high-throughput virtual screen. E6646 significantly inhibited adipogenic differentiation and hepatic lipogenesis via SCD1-ATF3 signaling. The SPR results showed that E6446 had a strong interaction ability with SCD1 (KD:4.61 μM). Additionally, E6646 significantly decreased hepatic steatosis, hepatic lipid droplet accumulation and Insulin resistance in high-fat diet (HFD)-fed mice. Taken together, our findings not only suggest that E6446 can serve as a new, safe and highly effective anti-NAFLD agent for future clinical use but also provide a molecular basis for the future development of SCD1 inhibitors that inhibit both adipogenic differentiation and hepatic lipogenesis. Video Abstract.

Keywords

ATF3; E6446; Liver-adipose axis; Non-alcoholic fatty liver disease.

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