Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece.
Department of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
Metabolism. 2023 Jul;144:155552. doi: 10.1016/j.metabol.2023.155552. Epub 2023 Mar 28.
High-Fructose Corn Syrup (HFCS), a sweetener rich in glucose and fructose, is nowadays widely used in beverages and processed foods; its consumption has been correlated to the emergence and progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Nevertheless, the molecular mechanisms by which HFCS impacts hepatic metabolism remain scarce, especially in the context of obesity. Besides, the majority of current studies focuses either on the detrimental role of fructose in hepatic steatosis or compare separately the additive impact of fructose versus glucose in high fat diet-induced NAFLD.
By engaging combined omics approaches, we sought to characterize the role of HFCS in obesity-associated NAFLD and reveal molecular processes, which mediate the exaggeration of steatosis under these conditions.
Herein, C57BL/6 mice were fed a normal-fat-diet (ND), a high-fat-diet (HFD) or a HFD supplemented with HFCS (HFD-HFCS) and upon examination of their metabolic and NAFLD phenotype, proteomic, lipidomic and metabolomic analyses were conducted to identify HFCS-related molecular alterations of the hepatic metabolic landscape in obesity.
Although HFD and HFD-HFCS mice displayed comparable obesity, HFD-HFCS mice showed aggravation of hepatic steatosis, as analysis of the lipid droplet area in liver sections revealed (12,15 % of total section area in HFD vs 22,35 % in HFD-HFCS), increased NAFLD activity score (3,29 in HFD vs 4,86 in HFD-HFCS) and deteriorated hepatic insulin resistance, as compared to the HFD mice. Besides, the hepatic proteome of HFD-HFCS mice was characterized by a marked upregulation of 5 core proteins implicated in de novo lipogenesis (DNL), while an increased phosphatidyl-cholines(PC)/phosphatidyl-ethanolamines(PE) ratio (2.01 in HFD vs 3.04 in HFD-HFCS) was observed in the livers of HFD-HFCS versus HFD mice. Integrated analysis of the omics datasets indicated that Tricarboxylic Acid (TCA) cycle overactivation is likely contributing towards the intensification of steatosis during HFD-HFCS-induced NAFLD.
Our results imply that HFCS significantly contributes to steatosis aggravation during obesity-related NAFLD, likely deriving from DNL upregulation, accompanied by TCA cycle overactivation and deteriorated hepatic insulin resistance.
高果糖玉米糖浆（HFCS）是一种富含葡萄糖和果糖的甜味剂，如今广泛用于饮料和加工食品中；其消费与非酒精性脂肪性肝病（NAFLD）的出现和进展有关。然而，HFCS 影响肝代谢的分子机制仍然很少，尤其是在肥胖的情况下。此外，目前大多数研究要么关注果糖在肝脂肪变性中的有害作用，要么分别比较果糖与高脂肪饮食诱导的 NAFLD 中葡萄糖的附加影响。
通过采用联合组学方法，我们旨在描述 HFCS 在肥胖相关的 NAFLD 中的作用，并揭示介导这些条件下脂肪变性加剧的分子过程。
在此，C57BL/6 小鼠分别喂食正常脂肪饮食（ND）、高脂肪饮食（HFD）或补充 HFCS 的高脂肪饮食（HFD-HFCS），并在检查其代谢和 NAFLD 表型后，进行蛋白质组学、脂质组学和代谢组学分析，以鉴定肥胖时 HFCS 对肝代谢谱的相关分子改变。
尽管 HFD 和 HFD-HFCS 小鼠表现出相似的肥胖，但 HFD-HFCS 小鼠的肝脂肪变性加重，因为对肝切片中脂滴面积的分析表明（HFD 中为 12.15%，HFD-HFCS 中为 22.35%），与 HFD 小鼠相比，NAFLD 活性评分（HFD 中为 3.29，HFD-HFCS 中为 4.86）和肝胰岛素抵抗恶化。此外，HFD-HFCS 小鼠的肝蛋白质组学特征是 5 种参与从头合成脂肪生成（DNL）的核心蛋白明显上调，而 HFD-HFCS 小鼠的肝中磷脂酰胆碱（PC）/磷脂酰乙醇胺（PE）比值增加（HFD 中为 2.01，HFD-HFCS 中为 3.04）。对组学数据集的综合分析表明，三羧酸（TCA）循环过度激活可能有助于在 HFD-HFCS 诱导的 NAFLD 中加剧脂肪变性。
我们的结果表明，HFCS 显著促进肥胖相关的 NAFLD 中脂肪变性的加重，可能源于 DNL 的上调，同时伴有 TCA 循环的过度激活和肝胰岛素抵抗的恶化。
