RESUMO
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a central role in cholesterol homeostasis in humans as a major regulator of LDLR levels. PCSK9 is an intriguing protease in that it does not act by proteolysis but by preventing LDLR recirculation from endosomes to the plasma membrane. This, and the inexistence of any other proteolytic substrate but itself could suggest that PCSK9 is an exquisite example of evolutionary fine-tuning. However, the gene has been lost in several mammalian species, and null alleles are present (albeit at low frequencies) in some human populations without apparently deleterious health effects, raising the possibility that the PCSK9 may have become dispensable in the mammalian lineage. To address this issue, we systematically recovered, assembled, corrected, annotated and analysed publicly available PCSK9 sequences for 420 eutherian species to determine the distribution, frequencies, mechanisms and timing of PCSK9 pseudogenization events, as well as the evolutionary pressures underlying the preservation or loss of the gene. We found a dramatic difference in the patterns of PCSK9 retention and loss between Euarchontoglires-where there is strong pressure for gene preservation-and Laurasiatheria, where multiple independent events have led to PCSK9 loss in most species. These results suggest that there is a fundamental difference in the regulation of cholesterol metabolism between Euarchontoglires and Laurasiatheria, which in turn has important implications for the use of Laurasiatheria species (e.g. pigs) as animal models of human cholesterol-related diseases.
Assuntos
Colesterol/genética , Evolução Molecular , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Animais , Colesterol/metabolismo , Eutérios/genética , Variação Genética/genética , Humanos , Filogenia , Pseudogenes/genética , Suínos/genéticaRESUMO
The investigation of familial hypercholesterolemia (FH) and its relationship to atherosclerosis has led to enormous scientific and medical progress, including the identification of genetic defects underlying FH, the elucidation of molecular mechanisms crucial for cellular cholesterol homeostasis and the development of current pharmaceutical tools for FH treatment (which are directed at increasing LDL uptake). These successes also led to the establishment of a model centered on cellular rather than whole organism processes, and a view of FH as resulting from a deficiency in LDL uptake. On the other hand, whole organism fluxes of cholesterol (like those of other nutrients) are centered on the liver, LDL (ultimately derived from the liver) is the main cholesterol transporter in plasma, and there is evidence of evolutionary pressure favoring mechanisms to maintain LDL plasma concentrations. Furthermore, the alterations in cellular metabolism observed in FH are consistent with a coordinated response by the liver to increase the levels of plasma LDL, suggesting that a signaling defect (rather than an uptake deficiency) is the fundamental problem underlying hypercholesterolemia - an hypothesis that explains the occurrence of hypercholesterolemia in CESD, despite normal LDL binding and uptake. I therefore propose that the liver contains a mechanism to assess and regulate plasma levels of LDL (an "LDL-ostat"), and that hypercholesterolemia is caused by defects in it. This model has implications for future research directions, and suggests alternative therapeutic approaches, particularly centered on efforts to restore LDL measurement/signaling (rather than its uptake), some of which are in stark contrast to those currently in use.
Assuntos
Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Colesterol/metabolismo , Humanos , Hipercolesterolemia/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Receptores de LDL/metabolismoRESUMO
Pararge aegeria is a palearctic butterfly used as a model organism in ecology, behavior, evolution and development, with significant geographically-correlated morphological variation and two close relatives in Macaronesia. In this study, I have determined the complete mitogenome sequence of P. aegeria. The genome is 15,240 bp long, and has the typical gene organization of other lepidopteran mitogenomes. Salient features include the IMQ order of tRNA genes, a sizable (52 bp) spacer between trnQ and nad2, a CGA start codon in cox1 and the ATAGA(T)19 motif in the control region. Interestingly, this region also contains four copies of the imperfect palindrome TAAATATWTATAWATATTTA.