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 Fbp1 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 Fbp1 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 after fructose challenge, which indicates a defect of fructolysis probably due to competitive inhibition by fructose-1,6-bisphosphate 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引发。果糖-1,6-二磷酸酶1（Fructose-1,6-bisphosphatase 1, FBP1）是糖异生过程中的关键酶，其缺乏会导致低血糖及果糖不耐受。然而，FBP1缺乏引发果糖不耐受的具体机制尚未完全阐明。本研究证实，参与果糖代谢与果糖耐受的是肝脏来源而非肠道来源的FBP1。我们分别构建了成年小鼠肠道或肝脏特异性缺失FBP1的诱导性基因敲除小鼠模型。在连续4周暴露于高果糖饮食的条件下，成年小鼠肠道特异性敲除Fbp1并不会损害果糖耐受能力，具体表现为未出现显著体重减轻、进食量减少，小肠亦无形态学改变。与之相反，成年小鼠肝脏特异性敲除Fbp1则会引发果糖不耐受，具体表现为暴露于高果糖饮食后出现显著体重下降、肝肿大及肝损伤。值得注意的是，果糖负荷后，FBP1缺陷的肝脏中会积累果糖代谢产物1-磷酸果糖，这提示果糖分解代谢存在缺陷，其原因可能为果糖-1,6-二磷酸的竞争性抑制，而该缺陷或可解释果糖不耐受的发生。综上，本研究明确了肝脏而非肠道FBP1在果糖代谢与果糖耐受中的核心作用。