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Circulatory transport of neutral lipids (fat) in animals relies on members of the large lipid transfer protein (LLTP) superfamily, including mammalian apolipoprotein B (apoB) and insect apolipophorin II/I (apoLp-II/I). Latter proteins, which constitute the structural basis for the assembly of various lipoproteins, acquire lipids through microsomal triglyceride transfer protein (MTP)--another LLTP family member--and bind them by means of amphipathic structures. Comparative research reveals that LLTPs have evolved from the earliest animals and additionally highlights the structural and functional adaptations in these lipid carriers. For instance, in contrast to mammalian apoB, the insect apoB homologue, apoLp-II/I, is post-translationally cleaved by a furin, resulting in their appearance of two non-exchangeable apolipoproteins in the insect low-density lipoprotein (LDL) homologue, high-density lipophorin (HDLp). An important difference between mammalian and insect lipoproteins relates to the mechanism of lipid delivery. Whereas in mammals, endocytic uptake of lipoprotein particles, mediated via members of the LDL receptor (LDLR) family, results in their degradation in lysosomes, the insect HDLp was shown to act as a reusable lipid shuttle which is capable of reloading lipid. Although the recent identification of a lipophorin receptor (LpR), a homologue of LDLR, reveals that endocytic uptake of HDLp may constitute an additional mechanism of lipid delivery, the endocytosed lipoprotein appears to be recycled in a transferrin-like manner. Binding studies indicate that the HDLp-LpR complex, in contrast to the LDL-LDLR complex, is resistant to dissociation at endosomal pH as well as by treatment with EDTA mimicking the drop in Ca(2+) concentration in the endosome. This remarkable stability of the ligand-receptor complex may provide a crucial key to the recycling mechanism. Based on the binding and dissociation capacities of mutant and hybrid receptors, the specific binding interaction of the ligand-binding domain of the receptor with HDLp was characterized. These structural similarities and functional adaptations of the lipid transport systems operative in mammals and insects are discussed from an evolutionary perspective.

Lipid mobilization in long-distance flying insects has revealed a novel concept for lipid transport in the circulatory system during exercise. Similar to energy generation for sustained locomotion in mammals, the work accomplished by non-stop flight activity is powered by oxidation of free fatty acids (FFA) derived from endogenous reserves of triacylglycerol. The transport form of the lipid, however, is diacylglycerol (DAG), which is delivered to the flight muscles associated with lipoproteins. In the insect system, the multifunctional lipoprotein, high-density lipophorin (HDLp) is loaded with DAG while additionally, multiple copies of the exchangeable apolipoprotein, apoLp-III, associate with the expanding particle. As a result, lipid-enriched low-density lipophorin (LDLp) is formed. At the flight muscles, LDLp-carried DAG is hydrolyzed and FFA are imported into the muscle cells for energy generation. The depletion of DAG from LDLp results in the recovery of both HDLp and apoLp-III, HDLp, identified which are reutilized for another cycle of DAG transport. A receptor for as a novel member of the vertebrate low-density lipoprotein (LDL) receptor family, does not seem to be involved in the lipophorin shuttle mechanism operative during flight activity. In addition, endocytosis of HDLp mediated by the insect receptor does not seem to follow the classical mammalian LDL pathway. Many structural elements of the lipid mobilization system in insects are similar to those in mammals. Domain structures of apoLp-I and apoLp-II, the non-exchangeable apolipoprotein components of HDLp, are related to apoB 100. ApoLp-III is a bundle of five amphipathic alpha-helices that binds to a lipid surface very similar to the four-helix bundle of the N-terminal domain of human apoE. Despite these similarities, the functioning of the insect lipoprotein in energy transport during flight activity is intriguingly different, since the TAG-rich mammalian lipoproteins play no role as a carrier of mobilized lipids during exercise and besides, these lipoproteins are not functioning as a reusable shuttle for lipid transport. On the other hand, the deviant behavior of similar molecules in a different biological system may provide a useful alternative model for studying the molecular basis of processes related to human disorders and disease.