Abstract
Apolipoprotein C1 (apoC1), the smallest of all apolipoproteins, participates in lipid transport and metabolism. In humans, APOC1 gene is in linkage disequilibrium with APOE gene on chromosome 19, a proximity that spurred its investigation. Apolipoprotein C1 associates with triglyceride-rich lipoproteins and HDL and exchanges between lipoprotein classes. These interactions occur via amphipathic helix motifs, as demonstrated by biophysical studies on the wild-type polypeptide and representative mutants. Apolipoprotein C1 acts on lipoprotein receptors by inhibiting binding mediated by apolipoprotein E, and modulating the activities of several enzymes. Thus, apoC1 downregulates lipoprotein lipase, hepatic lipase, phospholipase A2, cholesterylester transfer protein, and activates lecithin-cholesterol acyl transferase. By controlling the plasma levels of lipids, apoC1 relates directly to cardiovascular physiology, but its activity extends beyond, to inflammation and immunity, sepsis, diabetes, cancer, viral infectivity, and—not last—to cognition. Such correlations were established based on studies using transgenic mice, associated in the recent years with GWAS, transcriptomic and proteomic analyses. The presence of a duplicate gene, pseudogene APOC1P, stimulated evolutionary studies and more recently, the regulatory properties of the corresponding non-coding RNA are steadily emerging. Nonetheless, this prototypical apolipoprotein is still underexplored and deserves further research for understanding its physiology and exploiting its therapeutic potential.
Highlights
Apolipoproteins are the physiological agents for the transport along the body of aqueous fluids of the hydrophobic lipids
Compelling evidence for an apoE-independent Alzheimer’s disease (AD) risk provided by Apolipoprotein C1 (apoC1) haplotypes was provided by a recent GWAS study performed on the mainland Chinese GWS cohort; these findings supported by chromatin interaction data indicated a physical interaction between the APOE and apolipoproteinC1 gene (APOC1) loci in human brain in both the fetal and adult state [172]
A recent GWAS analysis performed on large numbers of individuals indicated the heterogeneous polygenetic predisposition to AD in the APOE region, as there are no less than 30 polymorphisms from genes BCAM, NECTIN2, TOMM40, APOE, and APOC1 in region 19q13.3 [174], as well as associations with other pathologies such as infections, cancer, diabetes [175,176], and epigenetic changes of the regulatory elements within the apolipoprotein cluster [177]
Summary
Apolipoproteins are the physiological agents for the transport along the body of aqueous fluids of the hydrophobic lipids. Besides the structural role in the formation of lipoproteins, the apolipoproteins actively participate in the metabolic processing of both endogenous and exogenous lipids, serving as ligands for cell membrane receptors and modulating the activity of relevant enzymes, transporters, and lipid transfer proteins, as reviewed in [2,3]. Apolipoproteins encoded by the genes in the E/C1/C4/C2 cluster are important for controlling plasma lipid levels, with subsequent implications in cardiovascular physiology and pathology. Much less was investigated in its neighbor, the apolipoproteinC1 gene (APOC1), and its corresponding polypeptide (apoC1); yet a significant part of that research was prompted by the physical proximity of the two genes in the genome This association have led in various situations to confounding results, and apoC1 continues to remain a relatively elusive issue to our current comprehension. We overview the main aspects regarding apoC1 structure and activity with a focus on more recent findings, as well as we underscore some of the less clarified aspects
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