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  2. Berberine reduces hepatic ceramide levels to improve insulin resistance in HFD-fed mice by inhibiting HIF-2α

Berberine reduces hepatic ceramide levels to improve insulin resistance in HFD-fed mice by inhibiting HIF-2α

  • Biomed Pharmacother. 2022 Jun;150:112955. doi: 10.1016/j.biopha.2022.112955.
Qing-Song Xia 1 Fan Wu 1 Wen-Bin Wu 1 Hui Dong 1 Zhao-Yi Huang 2 Lijun Xu 1 Fu-Er Lu 3 Jing Gong 4
Affiliations

Affiliations

  • 1 Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
  • 2 Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
  • 3 Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. Electronic address: felutjh88@163.com.
  • 4 Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. Electronic address: jgongtcm@126.com.
Abstract

Several studies have documented the effects of hypoxia and ceramides on lipid and glucose metabolism, resulting in Insulin resistance. However, the roles of ceramide in hepatic hypoxia and hepatic Insulin resistance remain to be clarified. This study aimed to explore the relationship between hypoxia, ceramide synthesis, and hepatic Insulin resistance in high-fat diet (HFD)-fed mice. Given the interaction of hypoxia-inducible factors 2α(HIF-2α) and berberine determined using molecular docking, this study also assessed the pharmacological effects of berberine on the HIF-2α-ceramide-insulin resistance pathway. In the preliminary phase of the study, gradually aggravated hepatic hypoxia and varying levels of ceramides were observed with the development of type 2 diabetes mellitus (T2DM) due to increasing HIF-2α accumulation. Lipidomic analyses of animal and cell models revealed that berberine reduced hypoxia-induced ceramide production and attenuated ceramide-induced Insulin resistance. This research provides timely and necessary evidence for the role of ceramide in hypoxia and Insulin resistance in the liver. It also contributes to a better understanding of the pharmacological effects of berberine on ameliorating hypoxia and Insulin resistance in T2DM therapy.

Keywords

Berberine; Ceramide; Hepatic insulin resistance; Hypoxia-inducible factor-2α.

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