栀子提取物GJ-4通过激活PPARα信号通路减轻代谢综合征诱导的病理损伤

【OBJECTIVE】To investigate whether GJ-4, a crocin-enriched extract derived from Gardenia jasminoides J. Ellis, mitigates high-fat diet (HFD)/streptozotocin (STZ)-induced metabolic syndrome (MS) and explore the underlying mechanisms.

【METHODS】Male C57BL/6J mice were assigned to control and model groups. Mice in the model group were fed with a 60% HFD for 19 weeks and STZ (50 mg/kg) was intraperitoneally injected for 3 consecutive days at the 12th week. Then, the model mice were further divided into 3 groups based on their fasting blood glucose (FBG) levels at the 14th week: MS, GJ-4, and rosiglitazone groups. GJ-4 (50 mg/kg) and rosiglitazone (10 mg/kg) were orally administered to mice from 14th to 19th weeks. The effects of GJ-4 on glucose metabolism were assessed via oral glucose tolerance test and measurement of FBG and serum insulin. Lipid metabolism was evaluated by measuring serum levels of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol (LDL-C), as well as hepatic TG and TC, and by oil red O staining of liver sections. Organ damage was assessed by measuring the serum levels of biomarkers and conducting hematoxylin and eosin staining. Superoxide dismutase (SOD) activity, and malondialdehyde (MDA) and glutathione (GSH) levels were analyzed to evaluate oxidative stress. Inflammatory cytokine levels were detected via quantitative real-time PCR (qPCR). Proteomics analysis was utilized to investigate the molecular mechanisms, followed by Western blot analysis for validation of differentially expressed proteins and the related signaling pathways.

【RESULTS】GJ-4 treatment reduced the FBG, improved glucose tolerance, and increased the fasting serum insulin (P<0.05 or P<0.01). GJ-4 intervention reduced TG, TC and LDL-C levels in serum, as well as TG and TC contents in liver (P<0.05 or P<0.01). In addition, GJ-4 significantly reduced serum levels of alanine aminotransferase, aspartate aminotransferase, and blood urea nitrogen, and alleviated pathological damage in liver, kidney and pancreas tissue (P<0.05 or P<0.01). GJ-4 increased serum GSH content and SOD activity, and decreased hepatic MDA level, while enhancing hepatic SOD activity (P<0.01). qPCR results revealed that GJ-4 significantly reduced hepatic mRNA expression of tumor necrosis factor-α, interleukin (IL)-6 and IL-1β (P<0.05). Western blot results showed that GJ-4 treatment inhibited the expression of malic enzyme 1 (ME1), peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α), and cAMP-response element binding protein (CREB), and promoted the expression of acetyl coenzyme A acyltransferase 1 (ACAA1) and peroxisome proliferator-activated receptor α (PPARα, P<0.05 or P<0.01) in the liver of MS mice.

【CONCLUSIONS】GJ-4 ameliorated glycolipid metabolic disorder, hepatic-renal injury, oxidative stress and inflammation in MS mice. Mechanistically, GJ-4 activated PPARα signaling to inhibit CREB/PGC-1α-driven gluconeogenesis and ME1-dependent lipogenesis, while stimulating ACAA1-mediated fatty acid β-oxidation.