Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
Mol Cell Endocrinol. 2020 Jun 1;509:110804. doi: 10.1016/j.mce.2020.110804. Epub 2020 Apr 4.
To investigate the effects of linagliptin treatment on hepatic energy metabolism and ER stress in high-fat-fed C57BL/6 mice.
Forty male C57BL/6 mice, three months of age, received a control diet (C, 10% of lipids as energy, n = 20) or high-fat diet (HF, 50% of lipids as energy, n = 20) for 10 weeks. The groups were randomly subdivided into four groups to receive linagliptin, for five weeks, at a dose of 30 mg/kg/day added to the diets: C, C-L, HF, and HF-L groups.
The HF group showed higher body mass, total and hepatic cholesterol levels and total and hepatic triacylglycerol levels than the C group, all of which were significantly diminished by linagliptin in the HF-L group. The HF group had higher hepatic steatosis than the C group, whereas linagliptin markedly reduced the hepatic steatosis (less 52%, P < 0.001). The expression of Sirt1 and Pgc1a was more significant in the HF-L group than in the HF group. Linagliptin also elicited enhanced GLP-1 concentrations and a reduction in the expression of the lipogenic genes Fas and Srebp1c. Besides, HF-L showed a reduction in the genes related to endoplasmic reticulum stress Chop, Atf4, and Gadd45 coupled with reduced apoptotic nuclei immunostaining.
Linagliptin caused a marked reduction in hepatic steatosis as a secondary effect of its glucose-lowering property. NAFLD countering involved reduced lipogenesis, increased beta-oxidation, and relief in endoplasmic reticulum stress, leading to reduced apoptosis and better preservation of the hepatic structure. Therefore, linagliptin may be used, preferably in diabetic patients, to avoid the progression of hepatic steatosis.
研究利拉格列汀对高脂喂养 C57BL/6 小鼠肝能量代谢和内质网应激的影响。
40 只 3 月龄雄性 C57BL/6 小鼠给予对照饮食（C 组，能量的 10%来自脂肪，n=20）或高脂饮食（HF 组，能量的 50%来自脂肪，n=20）10 周。两组动物再随机分为四组，分别给予利拉格列汀（30mg/kg/天）治疗 5 周：C 组、C+利拉格列汀（C-L）组、HF 组和 HF+利拉格列汀（HF-L）组。
HF 组的体质量、总胆固醇、肝胆固醇、总三酰甘油和肝三酰甘油水平均高于 C 组，这些指标在 HF-L 组均显著降低。HF 组的肝脂肪变性比 C 组更严重，而利拉格列汀明显减少了肝脂肪变性（减少 52%，P<0.001）。HF-L 组的 Sirt1 和 Pgc1a 表达比 HF 组更显著。利拉格列汀还增加了 GLP-1 浓度，并降低了脂肪生成基因 Fas 和 Srebp1c 的表达。此外，HF-L 组与内质网应激相关的基因 Chop、Atf4 和 Gadd45 的表达减少，同时凋亡细胞核免疫染色减少。
利拉格列汀通过降低血糖的作用，显著减少肝脂肪变性。NAFLD 的逆转涉及减少脂肪生成、增加β氧化和缓解内质网应激，从而减少细胞凋亡和更好地保护肝结构。因此，利拉格列汀可能被用于避免肝脂肪变性的进展，尤其在糖尿病患者中。
