Intestinal stearoyl-coenzyme A desaturase-inhibition improves obesity-associated metabolic disorders.
10.1016/j.apsb.2024.11.022
- Author:
Yangliu XIA
1
;
Yang ZHANG
2
;
Zhipeng ZHANG
3
;
Nana YAN
1
;
Vorthon SAWASWONG
1
;
Lulu SUN
4
;
Wanwan GUO
4
;
Ping WANG
1
;
Kristopher W KRAUSZ
1
;
Oksana GAVRILOVA
5
;
James M NTAMBI
6
;
Haiping HAO
7
;
Tingting YAN
1
;
Frank J GONZALEZ
1
Author Information
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 Female Fertility Promotion, Department of Endocrinology and Metabolism, Third Hospital, Peking University, Beijing 100191, China.
5. Mouse Metabolism Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
6. Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
7. State Key Laboratory of Natural Medicines, Laboratory of Metabolic Regulation and Drug Target Discovery, China Pharmaceutical University, Nanjing 210009, China.
- Publication Type:Journal Article
- Keywords:
High-fat diet;
Intestinal epithelium;
MT1;
Metabolic disorders;
Obesity;
Oxidative stress;
SCD1;
Steatosis
- From:
Acta Pharmaceutica Sinica B
2025;15(2):892-908
- CountryChina
- Language:English
-
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.
