Internal Medicine Research Unit, Pfizer Worldwide Research, Development, and Medical, Cambridge, MA 02139 USA.
Early Clinical Development, Pfizer Worldwide Research, Development, and Medical, Groton, CT 06340 USA.
Mol Metab. 2021 Jun;48:101196. doi: 10.1016/j.molmet.2021.101196. Epub 2021 Mar 3.
Recent studies suggest that excess dietary fructose contributes to metabolic dysfunction by promoting insulin resistance, de novo lipogenesis (DNL), and hepatic steatosis, thereby increasing the risk of obesity, type 2 diabetes (T2D), non-alcoholic steatohepatitis (NASH), and related comorbidities. Whether this metabolic dysfunction is driven by the excess dietary calories contained in fructose or whether fructose catabolism itself is uniquely pathogenic remains controversial. We sought to test whether a small molecule inhibitor of the primary fructose metabolizing enzyme ketohexokinase (KHK) can ameliorate the metabolic effects of fructose.
The KHK inhibitor PF-06835919 was used to block fructose metabolism in primary hepatocytes and Sprague Dawley rats fed either a high-fructose diet (30% fructose kcal/g) or a diet reflecting the average macronutrient dietary content of an American diet (AD) (7.5% fructose kcal/g). The effects of fructose consumption and KHK inhibition on hepatic steatosis, insulin resistance, and hyperlipidemia were evaluated, along with the activation of DNL and the enzymes that regulate lipid synthesis. A metabolomic analysis was performed to confirm KHK inhibition and understand metabolite changes in response to fructose metabolism in vitro and in vivo. Additionally, the effects of administering a single ascending dose of PF-06835919 on fructose metabolism markers in healthy human study participants were assessed in a randomized placebo-controlled phase 1 study.
Inhibition of KHK in rats prevented hyperinsulinemia and hypertriglyceridemia from fructose feeding. Supraphysiologic levels of dietary fructose were not necessary to cause metabolic dysfunction as rats fed the American diet developed hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis, which were all reversed by KHK inhibition. Reversal of the metabolic effects of fructose coincided with reductions in DNL and inactivation of the lipogenic transcription factor carbohydrate response element-binding protein (ChREBP). We report that administering single oral doses of PF-06835919 was safe and well tolerated in healthy study participants and dose-dependently increased plasma fructose indicative of KHK inhibition.
Fructose consumption in rats promoted features of metabolic dysfunction seen in metabolic diseases such as T2D and NASH, including insulin resistance, hypertriglyceridemia, and hepatic steatosis, which were reversed by KHK inhibition.
最近的研究表明，过量的膳食果糖通过促进胰岛素抵抗、从头合成脂肪（DNL）和肝脂肪变性，从而增加肥胖、2 型糖尿病（T2D）、非酒精性脂肪性肝炎（NASH）和相关合并症的风险，导致代谢功能障碍。这种代谢功能障碍是由果糖中所含的过量膳食卡路里驱动的，还是果糖分解代谢本身具有独特的致病性，这仍然存在争议。我们试图测试一种小分子酮己糖激酶（KHK）的抑制剂是否可以改善果糖的代谢作用。
使用 KHK 抑制剂 PF-06835919 阻断原代肝细胞和给予高果糖饮食（30%果糖卡路里/克）或反映美国饮食中平均宏量营养素饮食含量的饮食（7.5%果糖卡路里/克）的 Sprague Dawley 大鼠中的果糖代谢。评估果糖消耗和 KHK 抑制对肝脂肪变性、胰岛素抵抗和高脂血症的影响，以及 DNL 的激活和调节脂质合成的酶。进行代谢组学分析以确认 KHK 抑制，并了解体外和体内果糖代谢时的代谢物变化。此外，在一项随机安慰剂对照的 1 期研究中，评估了单次递增剂量的 PF-06835919 对健康人类研究参与者中果糖代谢标志物的影响。
在大鼠中抑制 KHK 可防止果糖喂养引起的高胰岛素血症和高甘油三酯血症。高果糖饮食的生理水平不是引起代谢功能障碍所必需的，因为给予美国饮食的大鼠发生高胰岛素血症、高甘油三酯血症和肝脂肪变性，而这些都可以通过 KHK 抑制逆转。果糖代谢作用的逆转与 DNL 的减少和脂肪生成转录因子碳水化合物反应元件结合蛋白（ChREBP）的失活一致。我们报告，在健康研究参与者中，单次口服给予 PF-06835919 是安全且耐受良好的，并剂量依赖性地增加了血浆果糖，表明 KHK 抑制。
在大鼠中消耗果糖可促进 2 型糖尿病和 NASH 等代谢疾病中观察到的代谢功能障碍特征，包括胰岛素抵抗、高甘油三酯血症和肝脂肪变性，这些都可以通过 KHK 抑制逆转。
