Intestinal monocarboxylate transporter 1 mediates lactate transport in the gut and regulates metabolic homeostasis of mouse in a sex-dimorphic pattern

一元羧酸盐转运体 内科学 内分泌学 生物 平衡 葡萄糖稳态 小肠 葡萄糖转运蛋白 乳酸脱氢酶 体内 运输机 胰岛素抵抗 胰岛素 生物化学 医学 基因 生物技术
作者
Shuo Wang,Lingling Zhang,Jingyu Zhao,Meijuan Bai,Yijun Lin,Qianqian Chu,Jue Gong,Ju Qiu,Yan Chen
标识
DOI:10.1093/lifemeta/load041
摘要

Abstract The monocarboxylate transporter 1 (MCT1), encoded by gene Slc16a1, is a proton-coupled transporter for lactate and other monocarboxylates. MCT1-mediated lactate transport was recently found to regulate various biological functions. However, how MCT1 and lactate in the intestine modulate the physiology and pathophysiology of the body is unclear. In this study, we generated a mouse model with specific deletion of Slc16a1 in the intestinal epithelium (Slc16a1IKO mice) and investigated the functions of MCT1 in the gut. When fed a high-fat diet, Slc16a1IKO male mice had improvement in glucose tolerance and insulin sensitivity, while Slc16a1IKO female mice only had increased adiposity. Deficiency of intestinal MCT1 in male mice was associated with downregulation of pro-inflammatory pathways, together with decreased circulating levels of inflammatory cytokines including tumor necrosis factor alpha (TNFα) and C–C motif chemokine ligand 2 (CCL2). Lactate had a stimulatory effect on pro-inflammatory macrophages in vitro. The number of intestinal macrophages was reduced in Slc16a1IKO male mice in vivo. Intestinal deletion of Slc16a1 in male mice reduced interstitial lactate level in the intestine. In addition, treatment of male mice with estrogen lowered interstitial lactate level in the intestine and abolished the difference in glucose homeostasis between Slc16a1IKO and wild-type mice. Deficiency of intestinal MCT1 also blocked the transport of lactate and short-chain fatty acids from the intestine to the portal vein. The effect of Slc16a1 deletion on glucose homeostasis in male mice was partly mediated by alterations in gut microbiota. In conclusion, our work reveals that intestinal MCT1 regulates glucose homeostasis in a sex-dependent manner.
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