Hong John G, Carbajal Yvette, Trotman Joshaya, Glass Mariel, Sclar Victoria, Alter Isaac L, Zhang Peng, Wang Liheng, Chen Li, Petitjean Matthieu, Friedman Scott L, DeRossi Charles, Chu Jaime
bioRxiv. 2024 Jan 17:2024.01.17.576067. doi: 10.1101/2024.01.17.576067.
Metabolic dysfunction-associated steatohepatitis (MASH) can progress to cirrhosis and liver cancer. There are no approved medical therapies to prevent or reverse disease progression. Fructose and its metabolism in the liver play integral roles in MASH pathogenesis and progression. Here we focus on mannose, a simple sugar, which dampens hepatic stellate cell activation and mitigates alcoholic liver disease and . In the well-validated FAT-MASH murine model, oral mannose supplementation improved both liver steatosis and fibrosis at low and high doses, whether administered either at the onset of the model ("Prevention") or at week 6 of the 12-week MASH regimen ("Reversal"). The anti-fibrotic effects of mannose supplementation were validated in a second model of carbon tetrachloride-induced liver fibrosis. human and mouse primary hepatocytes revealed that the anti-steatotic effects of mannose are dependent on the presence of fructose, which attenuates expression of ketohexokinase (KHK), the main enzyme in fructolysis. KHK is decreased with mannose supplementation and and overexpression of KHK abrogated the anti-steatotic effects of mannose. Our study identifies mannose as a simple, novel therapeutic candidate for MASH that mitigates metabolic dysregulation and exerts anti-fibrotic effects.
代谢功能障碍相关脂肪性肝炎（MASH）可进展为肝硬化和肝癌。目前尚无获批的药物疗法来预防或逆转疾病进展。果糖及其在肝脏中的代谢在MASH的发病机制和进展中起着不可或缺的作用。在此，我们聚焦于甘露糖，一种单糖，它可抑制肝星状细胞活化并减轻酒精性肝病。在经过充分验证的FAT-MASH小鼠模型中，无论在模型开始时（“预防”）还是在12周MASH方案的第6周（“逆转”）给予口服甘露糖补充剂，低剂量和高剂量均能改善肝脏脂肪变性和纤维化。甘露糖补充剂的抗纤维化作用在四氯化碳诱导的肝纤维化的第二个模型中得到验证。对人和小鼠原代肝细胞的研究表明，甘露糖的抗脂肪变性作用取决于果糖的存在，果糖会减弱果糖分解的主要酶酮己糖激酶（KHK）的表达。补充甘露糖时KHK会降低，而KHK的过表达会消除甘露糖的抗脂肪变性作用。我们的研究确定甘露糖是一种简单的新型MASH治疗候选药物，可减轻代谢失调并发挥抗纤维化作用。
