👤 Nabil G Seidah

Familial hypobetalipoproteinemia is a rare autosomal codominant disorder, often caused by a defect in apolipoprotein B (apoB) production required for lipoprotein formation and secretion. Characterization of the lipid profiles of 3 family members exhibiting very low circulating cholesterol levels. Plasma samples from the control sibling and the affected patients were analyzed. Fast protein liquid chromatography and high-performance liquid chromatography were used to characterize the lipid profiles, size, and distribution of lipoprotein particles. Exome sequencing of family members revealed a single-nucleotide deletion in APOB in the 3 affected individuals. The effect of the single-nucleotide deletion on the secretion of apoB was analyzed in Immortalized Human Hepatocyte (IHH) cells. Plasma lipid profiles revealed that the affected individuals have low levels of total cholesterol and low-density lipoprotein cholesterol, with no difference in lipoprotein particle size. DNA sequencing of APOB revealed a single heterozygote deletion of an adenosine in exon 3 at the nucleotide position 1268 in all affected members. This deletion introduces a reading frame shift at glutamine 380, resulting in a stop codon at position 397. The C-terminally truncated apoB, called apoB9, is a variant spanning ∼9% of the full-length protein. Upon expression of apoB9 in IHH cells, the protein did not exit the endoplasmic reticulum/cis-Golgi and, hence, was not secreted into the media. Molecular modeling revealed that apoB9 lacks the βA- and βB-sheets that are required for lipid particle formation, which can explain the absence of apoB9 secretion. Our data suggested that the affected family members have ∼50% to 60% lower apoB levels and are likely protected against the development of atherosclerosis and cardiovascular diseases. Show less

Prostate cancer (PCa) cells are known to heavily depend on lipids to support their growth. We hypothesized that hyperlipidemic factors, for which inhibitors are already available and used to treat cardiovascular disease, would be dysregulated in metastatic PCa (mPCa). The goal of this case-control study, including 35 men per group, was to compare the levels of PCSK9, ANGPTL3, Apo CIII, leptin, and the lipid profile in patients with mPCa versus localized Gleason 8/9 PCa (lPCa) and patients at risk of developing PCa (controls). Protein levels were assessed using ELISAs, while lipids were measured using the Roche Cobas analytical platform. The following circulating analytes were higher in mPCa: triglycerides (in mmol/L; controls 1.7 ± 1.2, lPCa 1.5 ± 0.7, mPCa 2.3 ± 1.2, In this cohort of men, whole-body lipid metabolic rewiring is a feature restricted to the metastatic phase of prostate cancer, suggesting it may play a significant role in the progression toward more aggressive cancer forms. Given the availability of drugs targeting ANGPTL3 and Apo CIII, the therapeutic potential of these drugs should be evaluated in metastatic PCa. Show less

The locus of the human proprotein convertase subtilisin-kexin type-7 (PC7) gene (PCSK7) is on chromosome 11q23.3 close to the gene cluster APOA5/APOA4/APOC3/APOA1, a region implicated in the regulation of lipoprotein metabolism. A GWAS reported the association of PCSK7 SNPs with plasma triglyceride (TG), and exome sequencing of African Americans revealed the association of a low-frequency coding variant of PC7 (R504H; SNP rs142953140) with a ~ 30% TG reduction. Another PCSK7 SNP rs508487 is in linkage disequilibrium with a promoter variant of the liver-derived apolipoprotein A-V (apoA-V), an indirect activator of the lipoprotein lipase (LpL), and is associated with elevated TG levels. We thus hypothesized that PC7 regulates the levels/activity of apoA-V. Studies in the human hepatic cell line HuH7 revealed that wild-type (WT) PC7 and its endoplasmic reticulum (ER)-retained forms bind to and enhance the degradation of human apoA-V in acidic lysosomes in a nonenzymatic fashion. PC7-induced degradation of apoA-V is inhibited by bafilomycin A1 and the alkalinizing agents: chloroquine and NH Show less