Apolipoprotein-AI mimetic peptides D-4F and L-5F decrease hepatic inflammation and increase insulin sensitivity in C57BL/6 mice

BACKGROUND: Apolipoprotein-AI (apo-AI) is the major apolipoprotein found in high density lipoprotein particles (HDLs). We previously demonstrated that apo-AI injected directly into high-fat diet fed mice improved insulin sensitivity associated with decreased hepatic inflammation. While our data provides compelling proof of concept, apoA-I mimetic peptides are more clinically feasible. The aim of this study was to test whether apo-AI mimetic peptide (D-4F and L-5F) treatment will emulate the effects of full-length apo-AI to improve insulin sensitivity. METHODS: Male C57BL/6 mice were fed a high-fat diet for 16 weeks before receiving D4F mimetic peptide administered via drinking water or L5F mimetic peptide administered by intraperitoneal injection bi-weekly for a total of five weeks. Glucose tolerance and insulin tolerance tests were conducted to assess the effects of the peptides on insulin resistance. Effects of the peptides on inflammation, gluconeogenic enzymes and lipid synthesis were assessed by real-time PCR of key markers involved in the respective pathways. RESULTS: Treatment with apo-AI mimetic peptides D-4F and L-5F showed: (i) improved blood glucose clearance (D-4F 1.40-fold AUC decrease compared to HFD, P<0.05; L-4F 1.17-fold AUC decrease compared to HFD, ns) in the glucose tolerance test; (ii) improved insulin tolerance (D-4F 1.63-fold AUC decrease compared to HFD, P<0.05; L-5F 1.39-fold AUC compared to HFD, P<0.05) in the insulin tolerance test. The metabolic test results were associated with (i) decreased hepatic inflammation of SAA1, IL-1β IFN-γ and TNFα (2.61–5.97-fold decrease compared to HFD, P<0.05) for both mimetics; (ii) suppression of hepatic mRNA expression of gluconeogenesis-associated genes (PEPCK and G6Pase; 1.66–3.01-fold decrease compared to HFD, P<0.001) for both mimetics; (iii) lipogenic-associated genes, (SREBP1c and ChREBP; 2.15–3.31-fold decrease compared to HFD, P<0.001) for both mimetics and; (iv) reduced hepatic macrophage infiltration (F4/80 and CD68; 1.77–2.15-fold compared to HFD, P<0.001) for both mimetics. CONCLUSION: Apo-AI mimetic peptides treatment led to improved glucose homeostasis. This effect is associated with reduced expression of inflammatory markers in the liver and reduced infiltration of macrophages, suggesting an overall suppression of hepatic inflammation. We also showed altered expression of genes associated with gluconeogenesis and lipid synthesis, suggesting that glucose and lipid synthesis is suppressed. These findings suggest that apoA-I mimetic peptides could be a new therapeutic option to reduce hepatic inflammation that contributes to the development of overnutrition-induced insulin resistance.