Xenobiotic receptors

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Role of intestinal stearoyl-coenzyme A desaturase 1 (SCD1) in metabolic diseases: Obesity and the associated metabolic disorders are globally wide-spread chronic diseases that impair human health and increase economic burden. The accumulation of excessive amounts of body fat drives multiple metabolic abnormalities and diseases, including insulin resistance, diabetes, cardiovascular disease, metabolic dysfunction-associated steatotic liver disease, and cancer. Numerous medications were developed for obesity treatment by exploiting different mechanisms, among which the discovery and development of glucagon-like peptide 1 receptor (GLP-1R) agonist-based drugs that have been considered a transformative breakthrough in the field, and are now recognized promising medications for the treatment of obesity. Despite the widespread use of GLP-1R agonist-based drugs, an increased risk for gastrointestinal side effects is of a major concern for the safety profile of GLP-1R agonists. Thus, developing novel pharmacotherapies with suitable tolerability and safety for the treatment of obesity remains an ongoing challenge. Obesity usually occurs accompanied with systemic oxidative stress, including elevated levels of reactive oxygen species (ROS) and deteriorated capability of antioxidant protection. Oxidative stress is usually an expected result of obesity in humans or long-term chronic high-fat diet (HFD) feeding in mice. Chronic HFD feeding-induced oxidative stress is also thought to causally contribute to weight gain and facilitate the development of insulin resistance since elevated oxidative stress can cause an increase in preadipocyte proliferation, adipocyte differentiation and the size of mature adipocytes, and suppress insulin signaling through phosphorylation of insulin receptor substrate. Pharmacologically, N-acetylcysteine (NAC), an antioxidant listed as an essential drug by the World Health Organization, has shown therapeutic potential in treating obesity-associated complications by decreasing the intracellular antioxidant levels of adipocytes, leading to reduced inflammation and oxidative damage. However, until now, the role of endogenous signaling transduction in modulating obesity-associated oxidative stress is still largely unknown. SCD1 is a key rate-limiting enzyme involved in lipid metabolism, with mouse SCD1 being homologous to human SCD. SCD1 catalyzes the formation of a cis double bond between carbons 9 and 10 of saturated fatty acids, resulting in the formation of the respective delta9 unsaturated monounsaturated fatty acid (MUFA) counterparts, primarily oleic acid (18:1) and palmitoleic acid (16:1), which are two key substrates for important lipids such as phospholipids, triglycerides, cholesteryl esters, and wax esters. Global SCD1 deficient mice (Scd1-null) are resistant to HFD-induced obesity, accompanied by increased energy expenditure, with the phenotype partially recapitulated in skin-specific Scd1-null mice. Liver-specific Scd1-null mice were reported to be protected from high-carbohydrate, but not high-fat, diet-induced adiposity and hepatic steatosis due to reduced production of oleic acid. In addition, intestine-specific Scd1-null mice were demonstrated to be more susceptible to inflammation and tumorigenesis in the intestine due to a deficiency of oleic acid. We found that intestinal SCD1 is highly induced during the progression of obesity 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.