Project Title: Investigating how HDL mimetics decrease hepatic

inflammation and modulate insulin resistance.

Supervisory Team: Dr Kristine McGrath and Dr Alison Heather

Location: Medical and Molecular Biosciences, Faculty of Science, UTS.

High density lipoproteins (HDL) have anti-inflammatory effects in a number of

cell types including endothelial cells, smooth muscle cells and pancreatic -cells.
We have recently demonstrated that administration of lipid-free apolipoprotein A-
I (apoA-I) protein improved glucose tolerance and insulin sensitivity in a high-fat
diet fed mouse model. These effects were associated with decreased levels of
systemic and hepatic inflammation. We confirmed our in vivo findings using liver
cell models where we demonstrated that reconstituted apoA-I HDL particle
treatment abrogated cytokine-induced activation of IKK/IB-/NF-B the cellular
pathway that drives inflammation.. ApoA-I HDL particles are difficult to
synthesise because they are large, and therefore are not considered suitable for
development as a treatment option for humans. In striking contrast, the much
smaller ApoA-I mimetic peptides show great promise as a therapeutic modality
and have already been used successfully in to treat atherosclerosis, ovarian
cancer, renal disease and arthritis in animal models. We are currently testing in
our laboratory whether apoA-I mimetic peptides will emulate the anti-
inflammatory effects of apoA-I HDL in abrogating hepatic inflammation, thereby
reversing insulin resistance.

The Masters project proposed will ask the question whether apoA-I mimetic
peptides suppress hepatic inflammation in a mouse model of insulin resistance.
Liver tissue will be sectioned and used to investigate by Western blot, ELISAs and
RT-qPCR whether mice that were treated with apoA-I mimetic peptides have
decreased signs of hepatic inflammation than mice that underwent control
treatment.

The aim of the project is to investigate whether apolipoprotein A-I mimetics

suppressed hepatic inflammation in C57BL/6 mice fed a high-fat diet. Western
blot, ELISAs and quantitative real time PCR (qPCR) will be used to examine and
compare the anti-inflammatory effects of the HDL mimetics in the high-fat diet
fed mice to those fed a normal chow diet.