Zhao Juan, Liu Xuelong, Yue Jingyu, Zhang Shouquan, Li Li, Wei Hengxi
State Key Laboratory of Swine and Poultry Breeding Industry, National Engineering Research Center for Breeding Swine Industry, Guangdong Provincial Key Lab of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangdong, China.
Front Vet Sci. 2024 Jul 31;11:1429639. doi: 10.3389/fvets.2024.1429639. eCollection 2024.
Fibroblast growth factor 21 (FGF21) is a peptide hormone that is primarily expressed and secreted by the liver. The hormone is crucial for regulation of glucose homeostasis, lipid metabolism, and energy balance. Compared with natural FGF21, FGF21 analogs have become drug candidates for the treatment of cardiovascular and metabolic diseases owing to their long half-life and greater stability . Apolipoprotein E (-knockout ( ) mice exhibit progressive disruptions in lipid metabolism and develop further atherosclerosis pathological features owing to deletion. Therefore, this study used an mouse model to investigate the effects of a long-acting FGF21 analog (PF-05231023) on lipid metabolism and related parameters. Eighteen female mice were fed a Western diet equivalent for 12 weeks, and then randomly assigned to intraperitoneally receive either physiological saline (the control group) or 10 mg/kg PF-05231023 (the treatment group) three times a week for seven consecutive weeks. Body composition, glucose tolerance, blood and liver cholesterol, triglyceride levels, liver vacuolization levels, peri-ovarian white adipocyte hypertrophy, aortic atherosclerotic plaque formation, and the expression of genes related to lipid metabolism in adipose tissue were subsequently assessed before and after treatment. The aortic atherosclerotic plaque area was reduced in mice in the PF-05231023 treatment group compared with that in the saline group. Although the effect of PF-05231023 on the plasma biochemical indexes of mice was small, it significantly reduced lipid levels and lipid droplet accumulation in the liver, and reduced adipocyte hypertrophy in white adipose tissue. Transcriptome analysis of adipose tissue showed that PF-05231023 treatment downregulated the expression of lipid synthesis-related genes and inhibited the sterol regulatory element binding transcription factor 1 gene, thereby improving lipid deposition. PF-05231023 effectively improved the lipid metabolism of mice, demonstrating an anti-atherosclerotic effect and providing a scientific basis and experimental foundation for the clinical treatment of cardiovascular diseases by using long-acting FGF21 analogs.
成纤维细胞生长因子21（FGF21）是一种主要由肝脏表达和分泌的肽类激素。该激素对于调节葡萄糖稳态、脂质代谢和能量平衡至关重要。与天然FGF21相比，FGF21类似物因其较长的半衰期和更高的稳定性，已成为治疗心血管和代谢疾病的候选药物。载脂蛋白E基因敲除（ApoE-/-）小鼠由于基因缺失，脂质代谢出现进行性紊乱，并出现进一步的动脉粥样硬化病理特征。因此，本研究使用ApoE-/-小鼠模型来研究长效FGF21类似物（PF-05231023）对脂质代谢及相关参数的影响。18只雌性ApoE-/-小鼠接受12周的西式饮食，然后随机分为两组，连续7周每周3次腹腔注射生理盐水（对照组）或10 mg/kg PF-05231023（治疗组）。随后在治疗前后评估身体组成、葡萄糖耐量、血液和肝脏胆固醇、甘油三酯水平、肝脏空泡化水平、卵巢周围白色脂肪细胞肥大、主动脉粥样硬化斑块形成以及脂肪组织中脂质代谢相关基因的表达。与生理盐水组相比，PF-05231023治疗组小鼠的主动脉粥样硬化斑块面积减小。虽然PF-05231023对小鼠血浆生化指标的影响较小，但它显著降低了肝脏中的脂质水平和脂滴积累，并减少了白色脂肪组织中的脂肪细胞肥大。脂肪组织的转录组分析表明，PF-05231023治疗下调了脂质合成相关基因的表达，并抑制了固醇调节元件结合转录因子1基因，从而改善了脂质沉积。PF-05231023有效改善了ApoE-/-小鼠的脂质代谢，显示出抗动脉粥样硬化作用，为使用长效FGF21类似物临床治疗心血管疾病提供了科学依据和实验基础。
