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

Autoři: Kristine C. McGrath aff001;  Xiaohong Li aff002;  Stephen M. Twigg aff003;  Alison K. Heather aff004
Působiště autorů: School of Life Sciences, University of Technology Sydney, Broadway, NSW, Australia aff001;  Health Management Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China aff002;  Sydney Medical School (Central) and Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, NSW, Australia aff003;  Department of Physiology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand aff004;  Heart Otago, University of Otago, Dunedin, New Zealand aff005
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0226931



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.


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.


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.


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.

Klíčová slova:

Diet – Fats – Glucose tolerance tests – Inflammation – Insulin – Lipids – Mouse models – Insulin resistance


1. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005;11: 183–190. doi: 10.1038/nm1166 15685173

2. McGrath KC, Li XH, Whitworth PT, Kasz R, Tan JT, McLennan S V, et al. High density lipoproteins improve insulin sensitivity in high-fat diet-fed mice by suppressing hepatic inflammation. J Lipid Res. 2014;55: 421–30. doi: 10.1194/jlr.M043281 24347528

3. Getz GS, Reardon CA. Apolipoprotein A-I and A-I mimetic peptides: a role in atherosclerosis. J Inflamm Res. 2011;4: 83–92. doi: 10.2147/JIR.S12983 22096372

4. Navab M, Shechter I, Anantharamaiah GM, Reddy ST, Van Lenten BJ, Fogelman AM. Structure and Function of HDL Mimetics. Arterioscler Thromb Vasc Biol. 2010;30: 164–168. doi: 10.1161/ATVBAHA.109.187518 19608977

5. Anantharamaiah GM, Mishra VK, Garber DW, Datta G, Handattu SP, Palgunachari MN, et al. Structural requirements for antioxidative and anti-inflammatory properties of apolipoprotein A-I mimetic peptides. J Lipid Res. 2007;48: 1915–23. doi: 10.1194/jlr.R700010-JLR200 17570869

6. Navab M, Reddy ST, Meriwether D, Fogelman SI, Fogelman AM. ApoA-I Mimetic Peptides: A Review of the Present Status. Apolipoprotein Mimetics in the Management of Human Disease. Cham: Springer International Publishing; 2015. pp. 15–27. doi: 10.1007/978-3-319-17350-4_2

7. Getz GS, Wool GD, Reardon CA. Biological properties of apolipoprotein a-I mimetic peptides. Curr Atheroscler Rep. 2010;12: 96–104. doi: 10.1007/s11883-010-0097-4 20425244

8. Navab M, Anantharamaiah GM, Reddy ST, Hama S, Hough G, Grijalva VR, et al. Oral D-4F causes formation of pre-beta high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice. Circulation. 2004;109: 3215–20. doi: 10.1161/01.CIR.0000134275.90823.87 15197147

9. Williams KJ. What does HDL do? A new mechanism to slow atherogenesis—but a new problem in type 2 diabetes mellitus. Atherosclerosis. 2012;225: 36–8. doi: 10.1016/j.atherosclerosis.2012.06.023 22770128

10. Reardon CA. Apolipoprotein E mimetic is more effective than apolipoprotein A-I mimetic in reducing lesion formation in older female apo E null mice: a commentary. Atherosclerosis. 2012;225: 39–40. doi: 10.1016/j.atherosclerosis.2012.09.020 23040866

11. Garber DW, Datta G, Chaddha M, Palgunachari MN, Hama SY, Navab M, et al. A new synthetic class A amphipathic peptide analogue protects mice from diet-induced atherosclerosis. J Lipid Res. 2001;42: 545–552. 11290826

12. Vaziri ND, Moradi H, Pahl M V, Fogelman AM, Navab M. In vitro stimulation of HDL anti-inflammatory activity and inhibition of LDL pro-inflammatory activity in the plasma of patients with end-stage renal disease by an apoA-1 mimetic peptide. Kidney Int. 2009;76: 437–44. doi: 10.1038/ki.2009.177 19471321

13. Lo L, McLennan S V, Williams PF, Bonner J, Chowdhury S, McCaughan GW, et al. Diabetes is a progression factor for hepatic fibrosis in a high fat fed mouse obesity model of non-alcoholic steatohepatitis. J Hepatol. 2011;55: 435–44. doi: 10.1016/j.jhep.2010.10.039 21184785

14. Su F, Kozak KR, Imaizumi S, Gao F, Amneus MW, Grijalva V, et al. Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor development in a mouse model of ovarian cancer. Proc Natl Acad Sci. 2010; doi: 10.1073/pnas.1009010107 21041624

15. McGrath KC, Li XH, Whitworth PT, Kasz R, Tan JT, McLennan SV, et al. High density lipoproteins improve insulin sensitivity in high-fat diet-fed mice by suppressing hepatic inflammation. J Lipid Res. 2014;55. doi: 10.1194/jlr.M043281 24347528

16. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, et al. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med. 2005;11: 191–198. doi: 10.1038/nm1185 15685170

17. Peterson SJ, Drummond G, Kim DH, Li M, Kruger AL, Ikehara S, et al. L-4F treatment reduces adiposity, increases adiponectin levels, and improves insulin sensitivity in obese mice. J Lipid Res. 2008;49: 1658–69. doi: 10.1194/jlr.M800046-JLR200 18426778

18. Navab M, Reddy ST, Van Lenten BJ, Buga GM, Hough G, Wagner AC, et al. High-density lipoprotein and 4F peptide reduce systemic inflammation by modulating intestinal oxidized lipid metabolism: Novel hypotheses and review of literature. Arterioscler Thromb Vasc Biol. 2012;32: 2553–2560. doi: 10.1161/ATVBAHA.112.300282 23077141

19. Navab M, Reddy ST, Anantharamaiah GM, Imaizumi S, Hough G, Hama S, et al. Intestine may be a major site of action for the apoA-I mimetic peptide 4F whether administered subcutaneously or orally. J Lipid Res. 2011;52: 1200–1210. doi: 10.1194/jlr.M013144 21444758

20. Averill MM, Kim EJ, Goodspeed L, Wang S, Subramanian S, Den Hartigh LJ, et al. The apolipoprotein-AI mimetic peptide L4F at a modest dose does not attenuate weight gain, inflammation, or atherosclerosis in LDLR-null mice. PLoS One. 2014;9: e109252. doi: 10.1371/journal.pone.0109252 25286043

21. Navab M, Hough G, Buga GM, Su F, Wagner AC, Meriwether D, et al. Transgenic 6F tomatoes act on the small intestine to prevent systemic inflammation and dyslipidemia caused by Western diet and intestinally derived lysophosphatidic acid. J Lipid Res. 2013;54: 3403–18. doi: 10.1194/jlr.M042051 24085744

22. Navab M, Anantharamaiah GM, Hama S, Garber DW, Chaddha M, Hough G, et al. Oral administration of an Apo A-I mimetic Peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation. 2002;105: 290–2. Available: http://www.ncbi.nlm.nih.gov/pubmed/11804981 doi: 10.1161/hc0302.103711 11804981

23. Navab M, Reddy ST, Anantharamaiah GM, Hough G, Buga GM, Danciger J, et al. D-4F-mediated reduction in metabolites of arachidonic and linoleic acids in the small intestine is associated with decreased inflammation in low-density lipoprotein receptor-null mice. J Lipid Res. 2012;53: 437–45. doi: 10.1194/jlr.M023523 22167743

24. Gowri MS, Van der Westhuyzen DR, Bridges SR, Anderson JW. Decreased protection by HDL from poorly controlled type 2 diabetic subjects against LDL oxidation may Be due to the abnormal composition of HDL. Arterioscler Thromb Vasc Biol. 1999;19: 2226–33. doi: 10.1161/01.atv.19.9.2226 10479666

25. Drew BG, Duffy SJ, Formosa MF, Natoli AK, Henstridge DC, Penfold SA, et al. High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus. Circulation. 2009;119: 2103–11. doi: 10.1161/CIRCULATIONAHA.108.843219 19349317

26. Siebel AL, Natoli AK, Yap FYT, Carey AL, Reddy-Luthmoodoo M, Sviridov D, et al. Effects of high-density lipoprotein elevation with cholesteryl ester transfer protein inhibition on insulin secretion. Circ Res. 2013;113: 167–75. doi: 10.1161/CIRCRESAHA.113.300689 23676183

27. Fryirs MA, Barter PJ, Appavoo M, Tuch BE, Tabet F, Heather AK, et al. Effects of high-density lipoproteins on pancreatic beta-cell insulin secretion. Arterioscler Thromb Vasc Biol. 2010;30: 1642–1648. doi: 10.1161/ATVBAHA.110.207373 20466975

28. Dalla-Riva J, Stenkula KG, Petrlova J, Lagerstedt JO. Discoidal HDL and apoA-I-derived peptides improve glucose uptake in skeletal muscle. J Lipid Res. 2013;54: 1275–82. doi: 10.1194/jlr.M032904 23471027

29. McGrath KC, Li XH, Puranik R, Liong EC, Tan JT, Dy VM, et al. Role of 3beta-hydroxysteroid-delta 24 reductase in mediating antiinflammatory effects of high-density lipoproteins in endothelial cells. Arter Thromb Vasc Biol. 2009;29: 877–882.

30. Zhang Q, Zhang Y, Feng H, Guo R, Jin L, Wan R, et al. High density lipoprotein (HDL) promotes glucose uptake in adipocytes and glycogen synthesis in muscle cells. PLoS One. 2011;6: 4–11. doi: 10.1371/journal.pone.0023556 21886796

Článek vyšel v časopise


2020 Číslo 1
Nejčtenější tento týden