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World J Gastroenterol. May 14, 2020; 26(18): 2177-2186
Published online May 14, 2020. doi: 10.3748/wjg.v26.i18.2177
New role for ceramide in hypoxia and insulin resistance
Qing-Song Xia, Fu-Er Lu, Fan Wu, Zhao-Yi Huang, Hui Dong, Li-Jun Xu, Jing Gong
Qing-Song Xia, Fu-Er Lu, Fan Wu, Zhao-Yi Huang, Hui Dong, Li-Jun Xu, Jing Gong, Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Author contributions: Xia QS and Wu F performed the literature search and drafted the manuscript; Huang ZY designed the figures; Dong H and Xu LJ summarized the literature; Gong J and Lu FE supervised and approved the final version of the manuscript.
Supported by the National Natural Science Foundation of China, No. 81904158; TCM Modernization Research of National Key Research and Development Program, No. 2018YFC1704202.
Conflict-of-interest statement: There is no conflict of interest associated with any of the senior author or other coauthors who contributed their efforts in this manuscript.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Jing Gong, MD, Doctor, Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Road, Wuhan 430030, Hubei Province, China. jgongtcm@126.com
Received: December 30, 2019
Peer-review started: December 30, 2019
First decision: March 27, 2020
Revised: April 8, 2020
Accepted: April 24, 2020
Article in press: April 24, 2020
Published online: May 14, 2020
Processing time: 136 Days and 2.4 Hours
Abstract

Ceramides are significant metabolic products of sphingolipids in lipid metabolism and are associated with insulin resistance and hepatic steatosis. In chronic inflammatory pathological conditions, hypoxia occurs, the metabolism of ceramide changes, and insulin resistance arises. Hypoxia-inducible factors (HIFs) are a family of transcription factors activated by hypoxia. In hypoxic adipocytes, HIF-1α upregulates pla2g16 (a novel HIF-1α target gene) gene expression to activate the NLRP3 inflammasome pathway and stimulate insulin resistance, and adipocyte-specific Hif1a knockout can ameliorate homocysteine-induced insulin resistance in mice. The study on the HIF-2α—NEU3—ceramide pathway also reveals the role of ceramide in hypoxia and insulin resistance in obese mice. Under obesity-induced intestinal hypoxia, HIF-2α increases the production of ceramide by promoting the expression of the gene Neu3 encoding sialidase 3, which is a key enzyme in ceramide synthesis, resulting in insulin resistance in high-fat diet-induced obese mice. Moreover, genetic and pathophysiologic inhibition of the HIF-2α—NEU3—ceramide pathway can alleviate insulin resistance, suggesting that these could be potential drug targets for the treatment of metabolic diseases. Herein, the effects of hypoxia and ceramide, especially in the intestine, on metabolic diseases are summarized.

Keywords: Ceramide; Intestinal hypoxia; Insulin resistance; Diabetes mellitus; Hypoxia-inducible factors; Obesity

Core tip: Hypoxia is an essential risk factor that promotes insulin resistance in a variety of tissues, such as adipocytes, intestines, and the liver. In hypoxic adipocytes, hypoxia-inducible factor-1α upregulates pla2g16 gene expression to activate the NLRP3 inflammasome pathway, leading to insulin resistance. In obese animals or people, increased ceramide further results in insulin resistance under hypoxia. In intestinal epithelial cells, hypoxia-inducible factor-2α is activated and accumulates under hypoxia in high-fat diet-fed mice, which upregulates the target gene Neu3, accelerating the process of insulin resistance.