New role for ceramide in hypoxia and insulin resistance

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.