Intestinal stearoyl-coenzyme A desaturase-inhibition improves obesity-associated metabolic disorders

  • Acta Pharm Sin B. 2025 Feb;15(2):892-908. doi: 10.1016/j.apsb.2024.11.022.
Yangliu Xia  1 ,  Yang Zhang  2 ,  Zhipeng Zhang  3 ,  Nana Yan  1  4 ,  Vorthon Sawaswong  1 ,  Lulu Sun  5 ,  Wanwan Guo  5 ,  Ping Wang  1 ,  Kristopher W Krausz  1 ,  Oksana Gavrilova  6 ,  James M Ntambi  7 ,  Haiping Hao  4 ,  Tingting Yan  1  4 ,  Frank J Gonzalez  1
Affiliations
  • 1. Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 2. Section on Human Iron Metabolism, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
  • 3. Department of General Surgery, Cancer Center, Third Hospital, Peking University, Beijing 100191, China.
  • 4. State Key Laboratory of Natural Medicines, Laboratory of Metabolic Regulation and Drug Target Discovery, China Pharmaceutical University, Nanjing 210009, China.
  • 5. State Key Laboratory of Female Fertility Promotion, Department of Endocrinology and Metabolism, Third Hospital, Peking University, Beijing 100191, China.
  • 6. Mouse Metabolism Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  • 7. Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
PMID: 40177566 DOI: 10.1016/j.apsb.2024.11.022
Abstract

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.

Keywords
High-fat diet; Intestinal epithelium; MT1; Metabolic disorders; Obesity; Oxidative stress; SCD1; Steatosis.
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