2. Academic Validation
  3. Intestinal stearoyl-coenzyme A desaturase-inhibition improves obesity-associated metabolic disorders

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

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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