1.Intestinal stearoyl-coenzyme A desaturase-inhibition improves obesity-associated metabolic disorders.
Yangliu XIA ; Yang ZHANG ; Zhipeng ZHANG ; Nana YAN ; Vorthon SAWASWONG ; Lulu SUN ; Wanwan GUO ; Ping WANG ; Kristopher W KRAUSZ ; Oksana GAVRILOVA ; James M NTAMBI ; Haiping HAO ; Tingting YAN ; Frank J GONZALEZ
Acta Pharmaceutica Sinica B 2025;15(2):892-908
Stearoyl-coenzyme A desaturase 1 (SCD1) catalyzes the rate-limiting step of de novo lipogenesis and modulates lipid homeostasis. Although numerous SCD1 inhibitors were tested for treating metabolic disorders both in preclinical and clinic studies, the tissue-specific roles of SCD1 in modulating obesity-associated metabolic disorders and determining the pharmacological effect of chemical SCD1 inhibition remain unclear. Here a novel role for intestinal SCD1 in obesity-associated metabolic disorders was uncovered. Intestinal SCD1 was found to be induced during obesity progression both in humans and mice. Intestine-specific, but not liver-specific, SCD1 deficiency reduced obesity and hepatic steatosis. A939572, an SCD1-specific inhibitor, ameliorated obesity and hepatic steatosis dependent on intestinal, but not hepatic, SCD1. Mechanistically, intestinal SCD1 deficiency impeded obesity-induced oxidative stress through its novel function of inducing metallothionein 1 in intestinal epithelial cells. These results suggest that intestinal SCD1 could be a viable target that underlies the pharmacological effect of chemical SCD1 inhibition in the treatment of obesity-associated metabolic disorders.
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