Ursolic acid attenuates hepatic steatosis, fibrosis, and insulin resistance by modulating the circadian rhythm pathway in diet-induced obese mice

ABSTRACT: Background/Objectives: The aim of the current study was to elucidate the effects of long-term supplementation with dietary ursolic acid (UR) on obesity and associated comorbidities, such as hepatic fibrosis, by analyzing transcriptional and metabolic responses, focusing on the role of UR in the modulation of the circadian rhythm pathway in particular. Subjects/Methods: C57BL/6J mice were divided into three groups and fed a normal diet, high-fat diet (HFD), or high-fat + 0.05% (w/w) UR diet for 16 weeks. Results: Oligonucleotide microarray profiling revealed that the liver transcriptome was more significantly altered by UR supplementation than that of the skeletal muscle and epididymal white adipose tissue, suggesting that UR is an effective regulator of the liver transcriptome. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway mapper analyses showed that canonical pathways associated with the “circadian rhythm” and “extracellular matrix (ECM)-receptor interactions” were effectively regulated by UR in the liver. UR altered the expression of various clock and clock-controlled genes (CCGs), which may be linked to the improvement of hepatic steatosis and fibrosis via lipid metabolism control and detoxification enhancement. UR reduced excessive reactive oxygen species production via an increase in plasma paraoxonase activity, adipokine/cytokine dysregulation, and ECM accumulation in the liver, which also contributed to improve hepatic lipotoxicity and fibrosis. In addition, UR treatment improved and normalized pancreatic islet dysfunction, and suppressed hepatic gluconeogenesis, thereby reducing obesity-associated insulin resistance in HFD-fed mice. Conclusions: Therapeutic approaches targeting hepatic circadian clock and CCGs using UR may ameliorate the deleterious effects of diet-induced obesity and associated complications such as hepatic fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE120243 | GEO | 2018/09/21

REPOSITORIES: GEO