**Acknowledgements**

*Management of Dyslipidemia*

to conclude in 2022 (NCT03473223), assessing the potential benefits of CSL112 in reducing adverse cardiovascular events in subjects with acute coronary syndrome. ApoA1 mimetic peptides have also been explored in the treatment of the adverse effects of atherosclerosis. These have the advantage to be structurally simpler than the native full-length protein, although retaining the same biological functions, and have the potential to be administered orally instead of *via* injection. One of these ApoA1 mimetic peptides is Rev-D4F, which reduced atherosclerotic lesion area and macrophage content at the lesion site in Apoe−/− mice, while also decreasing LDL oxidation [88]. Another ApoA1 mimetic, RG54, showed increased glucose tolerance, was able to stimulate cholesterol efflux from macrophages, and prevented the formation of atherosclerotic plaques in Apoe−/− mice [89]. Finally, 2F\*, a photoactivatable ApoA1 mimetic peptide, was able to increase cholesterol efflux in stably transfected baby hamster kidney cells [90]. Although very promising, these peptides have been explored only from a pre-clinical point of view and their efficacy in

Another apolipoprotein that has been suggested as a good candidate for HDL therapy is ApoE. ApoE is well known for its atheroprotective properties including the ability to induce RCT from peripheral cells to the liver [91] and to stimulate cholesterol efflux from macrophages thus, in turn, preventing the formation of foam cells in the development to atherosclerosis [92, 93]. Various studies have shown ApoE to have an increased ability to protect against atherosclerosis compared to ApoA1 [94]. The Ac-hE18A-NH2 ApoE mimetic has been shown to have a superior ability than the 4F ApoA1 mimetic to reduce atherosclerotic lesions in Apoe−/− mice [95]. The Ac-hE18A-NH2 mimetic has also demonstrated more effective antiinflammatory properties than the 4F mimetic [96]. Most studies that have been carried out with the use of ApoE peptide mimetics are only in the pre-clinical trial stage and have not yet been tested in clinical studies for therapeutic use [94].

The variability of the outcomes of the pre-clinical and clinical studies described

In this chapter we discussed the composition, function and structure of the two most studied lipoprotein types: LDL and HDL. In particular, we presented an updated model for determining the ultrastructure of LDL based on SAXS data that potentially enables determination of LDL phenotype from the total fraction measurement while highlighting structural differences in the small dense LDL subfraction between individuals with normal and high plasma serum triglyceride levels. Such differences, unknown until recently, may explain the different atherogenic potential of small dense LDL subfractions between different individuals and help unravel the controversies related to their atherogenic potential. Moreover, the capacity of lipoprotein fractions and subfractions to transfer lipids and cholesterol

above points towards the need for a deeper understanding of the functionality (RCT and fat exchange, for example) and the structure of the HDL particles before considering them as a potential therapeutic for CVD. For example, a very recent study shows that the type of lipids used in the rHDL formulation has a significant effect on their ability to mediate cholesterol efflux [97], with saturated lipids having the greatest potential for cholesterol efflux. This mimics the results for fat exchange on simplistic models presented in **Figure 3** and discussed in Section 4.1 in which saturated fats are more easily taken up by lipoproteins than unsaturated ones or those in the presence of cholesterol. Thus, not only the type of apolipoprotein but also the type of lipids used in the formulation have a fundamental role in the

functionality of the rHDL and need to be further explored.

humans and lack of side effects have still to be proved.

**30**

**6. Conclusions**

The authors thank the Swedish Research Council for funding.
