Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
Laboratory for Studies of Interactions between Nutrition and Genetics, LEING, Institute of Nutrition, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
J Endocrinol. 2020 Oct;247(1):11-24. doi: 10.1530/JOE-20-0139.
Fructose dietary intake affects the composition of the intestinal microbiota and influences the development of hepatic steatosis. Endotoxins produced by gram-negative bacteria alter intestinal permeability and cause bacterial translocation. This study evaluated the effects of gut microbiota modulation by a purified PPAR-alpha agonist (WY14643), a DPP-4 inhibitor (linagliptin), or their association on intestinal barrier integrity, endotoxemia, and hepatic energy metabolism in high-fructose-fed C57BL/6 mice. Fifty mice were divided to receive the control diet (C group) or the high-fructose diet (HFRU) for 12 weeks. Subsequently, the HFRU group was divided to initiate the treatment with PPAR-alpha agonist (3.5 mg/kg/BM) and DPP-4 inhibitor (15 mg/kg/BM). The HFRU group had glucose intolerance, endotoxemia, and dysbiosis (with increased Proteobacteria) without changes in body mass in comparison with the C group. HFRU group showed damaged intestinal ultrastructure, which led to liver inflammation and marked hepatic steatosis in the HFRU group when compared to the C group. PPAR-alpha activation and DPP-4 inhibition countered glucose intolerance, endotoxemia, and dysbiosis, ameliorating the ultrastructure of the intestinal barrier and reducing Tlr4 expression in the liver of treated animals. These beneficial effects suppressed lipogenesis and mitigated hepatic steatosis. In conclusion, the results herein propose a role for PPAR-alpha activation, DPP-4 inhibition, and their association in attenuating hepatic steatosis by gut-liver axis modulation in high-fructose mice model. These observations suggest these treatments as potential targets to treat hepatic steatosis and avoid its progression.
果糖饮食摄入会影响肠道微生物群的组成，并影响肝脂肪变性的发展。革兰氏阴性菌产生的内毒素会改变肠道通透性并导致细菌易位。本研究评估了通过纯化的 PPAR-α激动剂（WY14643）、DPP-4 抑制剂（linagliptin）或它们的联合对肠道微生物群的调节作用，对高脂肪果糖喂养的 C57BL/6 小鼠的肠道屏障完整性、内毒素血症和肝能量代谢的影响。将 50 只小鼠分为对照组（C 组）或高果糖组（HFRU 组），接受对照饮食或高果糖饮食 12 周。随后，HFRU 组分为 PPAR-α激动剂（3.5mg/kg/BM）和 DPP-4 抑制剂（15mg/kg/BM）治疗组。与 C 组相比，HFRU 组葡萄糖耐量受损、内毒素血症和肠道微生物失调（变形菌增加），但体重无变化。HFRU 组显示肠道超微结构受损，导致 HFRU 组肝脏炎症和明显的肝脂肪变性，与 C 组相比。PPAR-α 激活和 DPP-4 抑制可改善葡萄糖耐量、内毒素血症和肠道微生物失调，改善肠道屏障的超微结构，并降低治疗动物肝脏中 Tlr4 的表达。这些有益作用抑制了脂肪生成并减轻了肝脂肪变性。总之，本研究结果表明，在高脂肪果糖小鼠模型中，通过肠道-肝脏轴的调节，PPAR-α 激活、DPP-4 抑制及其联合作用可减轻肝脂肪变性。这些观察结果表明这些治疗方法可能是治疗肝脂肪变性和避免其进展的潜在靶点。
