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Nutrients 2018, 10(11), 1719; https://doi.org/10.3390/nu10111719

Ursolic Acid Attenuates Hepatic Steatosis, Fibrosis, and Insulin Resistance by Modulating the Circadian Rhythm Pathway in Diet-Induced Obese Mice

1,2,†
,
3,†
and
1,2,*
1
Department of Food Science and Nutrition, Kyungpook National University, 1370 San-Kyuk Dong Puk-Ku, Daegu 41566, Korea
2
Center for Food and Nutritional Genomics Research, Kyungpook National University, 1370 San-Kyuk Dong Puk-Ku, Daegu 41566, Korea
3
Department of Physiology & Obesity-Mediated Disease Research Center, Keimyung University School of Medicine, Daegu 82601, Korea
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 15 October 2018 / Revised: 7 November 2018 / Accepted: 7 November 2018 / Published: 9 November 2018
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Abstract

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 by analyzing transcriptional and metabolic responses, focusing on the role of UR in the modulation of the circadian rhythm pathway in particular. C57BL/6J mice were divided into three groups and fed a normal diet, high-fat diet, or high-fat + 0.05% (w/w) UR diet for 16 weeks. Oligonucleotide microarray profiling revealed that UR is an effective regulator of the liver transcriptome, and 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, adipokine/cytokine dysregulation, and ECM accumulation in the liver, which also contributed to improve hepatic lipotoxicity and fibrosis. Moreover, UR improved pancreatic islet dysfunction, and suppressed hepatic gluconeogenesis, thereby reducing obesity-associated insulin resistance. 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. View Full-Text
Keywords: fibrosis; extracellular matrix; ursolic acid; circadian rhythm; liver-specific fibrosis; extracellular matrix; ursolic acid; circadian rhythm; liver-specific
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Kwon, E.-Y.; Shin, S.-K.; Choi, M.-S. Ursolic Acid Attenuates Hepatic Steatosis, Fibrosis, and Insulin Resistance by Modulating the Circadian Rhythm Pathway in Diet-Induced Obese Mice. Nutrients 2018, 10, 1719.

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