Abstract
Marine mammals, which are essential to the health and stability of marine ecosystems, have developed very different physiological adaptations than those of terrestrial mammals because of burdens placed on them by the marine environment. These challenges create substantial metabolic demands, which are met primarily by lipids, an energy rich fuel source. Lipid transport, facilitated by lipoprotein particles, plays an essential role in satisfying these extensive metabolic demands. In humans, High-density lipoprotein (HDL), particularly HDL-cholesterol (HDL-C), is known for its cardioprotective role because of its correlation with reduced risk of cardiovascular disease (CVD). However, HDL can also interact with triglyceride (TG)-rich very low-density lipoproteins (VLDL) via the cholesterol ester transfer protein (CETP) resulting in the formation of unstable TG-rich HDL. TG-rich HDL is elevated in hypertriglyceridemic individuals, which may increase the risk of CVD. In marine mammals, however, TG-rich HDL is not elevated, despite similar or higher levels of TG in their diet compared to humans. Instead, total cholesterol, HDL and HDL-cholesterol are chronically high than in humans. There are several possible reasons for this, including low expression of proteins involved in lipid exchange between lipoproteins. The properties of marine mammal lipoproteins themselves, which may contribute to serum lipoprotein distribution, have never been examined. The goal of this thesis research was to use computational tools to examine the sequences and structures of the major HDL protein Apolipoprotein A-I (apoA-I) of several marine mammals including sea otters and compare them to the human protein to identify similarities and differences that may impact lipoprotein metabolism and homeostasis. Sea otters were particularly chosen because among marine mammals, this species lacks many of the physiological adaptations in other marine mammals such as blubber, they have very high energy requirements, and they have chronically elevated HDL and HDL-C.
Homology models of sea otter and pinniped (California sea lion, Hawaiian monk seal and Weddell seal) Apo A-I are highly similar to human Apo A-I lipid-free and lipid-bound structures, containing many of the same structural features such as proline kinks, which contribute to the protein’s overall flexibility, and a mobile central hinge segment that aids in the conversion between lipid-free and lipid-bound states. Two other conserved features include an N-terminal domain, which stabilizes both lipid-free and lipid-bound Apo A-I, and the formation of a stable LL5/5 salt bridge alignment in HDL particles. This suggests that the role of Apo A-I in marine mammals, despite their different physiological adaptations compared to humans, is likely the same in HDL formation and stability and that lipoprotein structure and stability does not contribute to the different HDL serum profiles found in marine mammals.