Tramontano, D. | Search bioRxiv

bioRxiv2025

ANGPTL3 binds to PCSK9 to coordinately regulate intracellular lipid homeostasis.

ANGPTL3 and PCSK9 are core proteins involved in lipid metabolism. Literature evidence highlights a potential mutual regulation between them: patients harboring loss-of-function variants in ANGPTL3 show reduced levels of circulating PCSK9. After predicting their interaction using an in-silico model, we verified the direct interaction between ANGPTL3 and PCSK9 through co-immunoprecipitation. The ANGPTL3-PCSK9 complex persisted under fasting conditions and dissociated under feeding conditions. Treatment with human LDLs was sufficient to simulate the feeding response. Then, we observed that the overexpression of PCSK9 enhances the uptake of LDLs that are not further metabolized, while the overexpression of ANGPTL3 enhances LDL turnover. The overexpression of both proteins restored LDL uptake and degradation, which became comparable to those of control cells. In conclusion, our findings indicate the existence of an ANGPTL3-PCSK9 complex, which coordinately contributes to the regulation of intracellular lipid homeostasis, aiming to prevent cellular metabolic overload. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/631413v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1339998org.highwire.dtl.DTLVardef@a8d715org.highwire.dtl.DTLVardef@c0a92aorg.highwire.dtl.DTLVardef@a22ed7_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO Mechanistic model of ANGPTL3-PCSK9 complex function in the regulation of lipoprotein metabolism Increased uptake of extracellular nutrients determines the separation of the ANGPTL3-PCSK9 complex. The two free proteins have different functions (1). Increased levels of PCSK9 determine an increased intracellular entrapment of circulating LDLs (2) that are not catabolized unless there is a presence of high intracellular levels of ANGPTL3. Increased ANGPTL3 levels also favor ApoB lipidation and secretion (3), whereas an increase in intracellular PCSK9 increases intracellular ApoB degradation. The increase in intracellular PCSK9 also determines a block in lipogenesis and favors beta-oxidation, thus decreasing the intracellular lipid content (4). C_FIG

cell biology↗

bioRxiv2018

Positive selection in Europeans and East-Asians at the ABCA12 gene

Natural selection acts on genetic variants by increasing the frequency of alleles responsible for a cellular function that is favorable in a certain environment. In a previous genome-wide scan for positive selection in contemporary humans, we identified a signal of positive selection in European and Asians at the genetic variant rs10180970. The variant is located in the second intron of the ABCA12 gene, which is implicated in the lipid barrier formation and down-regulated by UVB radiation. We studied the signal of selection in the genomic region surrounding rs10180970 in a larger dataset that includes DNA sequences from ancient samples. We also investigated the functional consequences of gene expression of the alleles of rs10180970 and another genetic variant in its proximity in healthy volunteers exposed to similar UV radiation.\n\nWe confirmed the selection signal and refine its location that extends over 35 kb and includes the first intron, the first two exons and the transcription starting site of ABCA12. We found no obvious effect of rs10180970 alleles on ABCA12 gene expression. We reconstructed the trajectory of the T allele over the last 80,000 years to discover that it was specific to H. sapiens and frequent among non-Africans already 45,000 years ago.

genomics↗