Wang Ying, Yan Weihui, Lu Ying, Du Jun, Tian Xinbei, Wu Bo, Peng Shicheng, Gu Beilin, Cai Wei, Xiao Yongtao
Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Institute for Pediatric Research, Shanghai, China.
JHEP Rep. 2023 Apr 1;5(6):100700. doi: 10.1016/j.jhepr.2023.100700. eCollection 2023 Jun.
BACKGROUND & AIMS: Regenerating gene family member 4 (REG4) is a novel marker for enteroendocrine cells and is selectively expressed in specialised enteroendocrine cells of the small intestine. However, the exact roles of REG4 are largely unknown. In this study we investigate the effects of REG4 on the development of dietary fat-dependent liver steatosis and the mechanisms involved.
Mice with intestinal-specific deficiency ( ) and -floxed alleles ( ) were generated to investigate the effects of Reg4 on diet-induced obesity and liver steatosis. Serum levels of REG4 were also measured in children with obesity using ELISA.
mice fed a high-fat diet demonstrated significantly increased intestinal fat absorption and were prone to obesity and hepatic steatosis. Importantly, mice exhibit enhanced activation of adenosine monophosphate-activated protein kinase (AMPK) signalling and increased protein abundance of the intestinal fat transporters, as well as enzymes involved in triglyceride synthesis and packaging at the proximal small intestine. Moreover, REG4 administration reduced fat absorption, and decreased the expression of intestinal fat absorption-related proteins in cultured intestinal cells possibly via the CaMKK2-AMPK pathway. Serum REG4 levels were markedly lower in children with obesity with advanced liver steatosis ( <0.05). Serum REG4 levels were inversely correlated with levels of liver enzymes, homeostasis model assessment of insulin resistance, low-density lipoprotein cholesterol, and triglycerides.
Our findings directly link deficiency with increased fat absorption and obesity-related liver steatosis, and suggest that REG4 may provide a potential target for prevention and treatment of liver steatosis in children.
Hepatic steatosis is a key histological feature of non-alcoholic fatty liver disease, which is the leading chronic liver disease in children leading to the development of metabolic diseases; however, little is known about mechanisms induced by dietary fat. Intestinal REG4 acts as a novel enteroendocrine hormone reducing high-fat-diet-induced liver steatosis with decreasing intestinal fat absorption. REG4 may be a novel target for treatment of paediatric liver steatosis from the perspective of crosstalk between intestine and liver.
再生基因家族成员4（REG4）是肠内分泌细胞的一种新型标志物，在小肠特化的肠内分泌细胞中选择性表达。然而，REG4的确切作用在很大程度上尚不清楚。在本研究中，我们探究REG4对饮食性脂肪依赖型肝脂肪变性发展的影响及其相关机制。
构建肠道特异性Reg4基因缺陷（Reg4-/-）和Reg4基因floxed等位基因（Reg4fl/fl）小鼠，以研究Reg4对饮食诱导的肥胖和肝脂肪变性的影响。还采用酶联免疫吸附测定法（ELISA）检测肥胖儿童血清REG4水平。
喂食高脂饮食的Reg4-/-小鼠肠道脂肪吸收显著增加，且易患肥胖症和肝脂肪变性。重要的是，Reg4-/-小鼠在近端小肠表现出增强的腺苷单磷酸激活的蛋白激酶（AMPK）信号通路激活，以及肠脂肪转运蛋白、参与甘油三酯合成和包装的酶的蛋白丰度增加。此外，给予REG4可减少脂肪吸收，并可能通过钙调蛋白激酶2-AMPK途径降低培养的肠细胞中肠脂肪吸收相关蛋白的表达。肥胖且有晚期肝脂肪变性的儿童血清REG4水平显著降低（P<0.05）。血清REG4水平与肝酶水平、胰岛素抵抗稳态模型评估、低密度脂蛋白胆固醇和甘油三酯水平呈负相关。
我们的研究结果直接将Reg4缺陷与脂肪吸收增加及肥胖相关的肝脂肪变性联系起来，并表明REG4可能为儿童肝脂肪变性的预防和治疗提供一个潜在靶点。
肝脂肪变性是非酒精性脂肪性肝病的关键组织学特征，非酒精性脂肪性肝病是导致代谢性疾病发生的儿童主要慢性肝病；然而，关于饮食脂肪诱导的机制知之甚少。肠道REG4作为一种新型肠内分泌激素，通过减少肠道脂肪吸收减轻高脂饮食诱导的肝脂肪变性。从肠肝相互作用的角度来看，REG4可能是治疗儿童肝脂肪变性的一个新靶点。
