Amer Johnny, Amleh Athar, Salhab Ahmad, Kolodny Yuval, Yochelis Shira, Saffouri Baker, Paltiel Yossi, Safadi Rifaat
Liver Institute, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
Applied Physics Department, Center for Nanoscience and Nanotechnology, Hebrew University Givaat Ram, Jerusalem, Israel.
Front Nutr. 2024 Dec 13;11:1469952. doi: 10.3389/fnut.2024.1469952. eCollection 2024.
Limited data link manufactured sweeteners impact on metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to evaluate the effects of manufactured sugars (L-glucose) compared to natural sugars (D-glucose) on phenotype, molecular and metabolic changes in mice models fed with either regular diet (RD) or high fat diet (HFD).
C57BL/6 mice fed 16-weeks with either RD; 70% carbohydrate or HFD; 60% fat, with or without additional glucose (Glu, at 18% w/v) to drinking tap water at weeks 8-16; of either natural (D-Glu) or manufactured (L-Glu) sugars. Liver inflammation (ALT and AST serum levels, liver H&E histologic stains and cell viability profile by p-AKT), liver fibrosis [quantitated smooth-muscle-actin (αSMA) by western blot and RT-PCR, Masson Trichrome staining (MTC) of liver tissue], liver lipid [steatosis stain by H&E, Adipose Differentiation-Related Protein (ADRP) lipid accumulation, serum and lipid peroxidation Malondialdehyde (MDA) markers by ELISA], glucose hemostasis (serum Glucose and C-peptide with HOMA-IR score calculation) and liver aspects [hepatic glucose transporter 2 (GLUT2), insulin receptor (IR) expressions and GYS2/PYGL ratio] evaluated.
D- and L-Glu supplementations propagate hepatocytes ballooning and steatosis in HFD-fed mice and were associated with αSMA down-expressions by 1.5-fold compared to the untreated group while showed an acceleration in liver fibrosis in the RD-fed mice. Lipid profile (Steatosis, ADRP and MDA) significantly increased in HFD-fed mice, both Glu supplementations (mainly the L-Glu) increased serum MDA while decreased ADRP. HOMA-IR score and IR significantly increased in HFD-fed mice, with further elevation in HOMA-IR score following Glu supplementations (mainly L-Glu). The increase in HOMA-IR negatively correlated with IR and Glut2 expressions. D- and L-Glu supplementations showed significant decrease of Glycogenesis (low GYS2/PYGL ratio) and unchanged p-AKT pattern compared to their RD counterparts.
Our data indicate an increase in rate of de-novo lipogenesis (DNL) in RD-fed mice (High carbohydrate diet) and liver fibrosis following additional sugar supplementations. In contrast, HFD-fed mice (with pre-existing high lipid profile) supplemented with sugar showed less liver fibrosis, because of reduced de-novo fatty acids synthesis and subsequently, the lipid oxidation pathways become dominated and induce the net results of lipid clearance.
关于人工合成甜味剂对代谢功能障碍相关脂肪性肝病（MASLD）影响的数据有限。我们旨在评估与天然糖（D-葡萄糖）相比，人工合成糖（L-葡萄糖）对喂食常规饮食（RD）或高脂饮食（HFD）的小鼠模型的表型、分子和代谢变化的影响。
将C57BL/6小鼠分为四组，分别喂食16周的RD（70%碳水化合物）或HFD（60%脂肪），在第8 - 16周期间，给其中两组小鼠的饮用水中额外添加葡萄糖（Glu，18% w/v），添加的葡萄糖分别为天然的（D-Glu）或人工合成的（L-Glu）。评估肝脏炎症（血清谷丙转氨酶和谷草转氨酶水平、肝脏苏木精-伊红组织染色以及通过磷酸化AKT检测细胞活力）、肝纤维化（通过蛋白质免疫印迹法和逆转录-聚合酶链反应定量平滑肌肌动蛋白（αSMA）、肝脏组织的Masson三色染色（MTC））、肝脏脂质（通过苏木精-伊红染色检测脂肪变性、脂肪分化相关蛋白（ADRP）脂质积累、通过酶联免疫吸附测定法检测血清和脂质过氧化丙二醛（MDA）标志物）、葡萄糖稳态（血清葡萄糖和C肽并计算胰岛素抵抗指数（HOMA-IR））以及肝脏方面（肝葡萄糖转运蛋白2（GLUT2）、胰岛素受体（IR）表达以及糖原合酶2/糖原磷酸化酶（GYS2/PYGL）比值）。
在喂食HFD的小鼠中，补充D-葡萄糖和L-葡萄糖会导致肝细胞气球样变和脂肪变性，与未处理组相比，αSMA表达下调1.5倍，而在喂食RD的小鼠中，补充葡萄糖会加速肝纤维化。喂食HFD的小鼠脂质谱（脂肪变性、ADRP和MDA）显著增加，两种葡萄糖补充剂（主要是L-葡萄糖）均使血清MDA增加而ADRP减少。喂食HFD的小鼠HOMA-IR评分和IR显著增加，补充葡萄糖（主要是L-葡萄糖）后HOMA-IR评分进一步升高。HOMA-IR的增加与IR和Glut2表达呈负相关。与喂食RD的对应组相比，补充D-葡萄糖和L-葡萄糖均使糖原生成显著减少（GYS2/PYGL比值低）且磷酸化AKT模式无变化。
我们的数据表明，喂食RD的小鼠（高碳水化合物饮食）在额外补充糖后从头脂肪生成（DNL）速率增加且出现肝纤维化。相比之下，喂食HFD的小鼠（已有高脂血症）补充糖后肝纤维化较少，这是因为从头脂肪酸合成减少，随后脂质氧化途径占主导并导致脂质清除的净结果。
