Hepatic but not intestinal FBP1 is required for fructose metabolism and tolerance

Fructose intolerance in mammals is caused by the defects in fructose absorption and metabolism. Fructose-1,6-bisphosphatase 1 (FBP1) is a key enzyme in gluconeogenesis, and its deficiency results in hypoglycemia as well as intolerance to fructose. However, the mechanism about the fructose intolerance caused by FBP1 deficiency has not been fully elucidated. Here, we demonstrate that hepatic but not intestinal FBP1 is required for fructose metabolism and tolerance. We generated inducible knockout mouse models specifically lacking FBP1 in adult intestine or liver, respectively. Intestine-specific deletion of <em>Fbp1 </em>in adult mice does not compromise fructose tolerance, as evidenced by no significant body weight loss, food intake reduction, or morphological changes of small intestine during 4 weeks of exposure to high-fructose diet. By contrast, liver-specific deletion of <em>Fbp1</em> in adult mice leads to fructose intolerance, as manifested by a substantial weight loss, hepatomegaly, and liver injury after exposure to the high-fructose diet. Notably, the fructose metabolite fructose-1-phosphate is accumulated in FBP1-deficient liver, which indicates a defect of fructolysis and may account for the fructose intolerance. In conclusion, these data have clarified the essential role of hepatic but not intestinal FBP1 in fructose metabolism and tolerance.

哺乳动物果糖不耐受症由果糖吸收与代谢缺陷诱发。果糖-1,6-二磷酸酶1（Fructose-1,6-bisphosphatase 1，FBP1）是糖异生通路中的关键酶，其缺失可引发低血糖及果糖不耐受。但FBP1缺失导致果糖不耐受的具体机制尚未完全阐明。本研究证实，果糖代谢与耐受依赖肝脏而非肠道中的FBP1。我们分别构建了成年小鼠肠道或肝脏特异性缺失FBP1的诱导性基因敲除模型。在为期4周的高果糖饮食干预过程中，成年小鼠肠道特异性敲除<em>Fbp1</em>并未损害果糖耐受能力，具体表现为未出现显著体重下降、进食量减少或小肠形态学改变。与之相反，成年小鼠肝脏特异性敲除<em>Fbp1</em>则会引发果糖不耐受，表现为高果糖饮食干预后出现明显体重下降、肝肿大及肝损伤。值得注意的是，FBP1缺失的肝脏中会蓄积果糖代谢产物1-磷酸果糖，这提示果糖分解代谢存在缺陷，或可解释果糖不耐受的发生。综上，本研究数据明确了肝脏而非肠道中的FBP1在果糖代谢与耐受中的核心作用。