New HDL biosynthesis defect identified
MedWire News: Study results indicate that phospholipid and cholesterol efflux may be two distinct processes in cellular high-density lipoprotein (HDL) biosynthesis.
The research team also found that a defect in phospholipid efflux resulting in low levels of large HDL particles could be corrected by treatment with physiological oxysterols.
“Severe HDL cholesterol deficiency is attributed to mutations in several genes and may contribute to the genetic basis of coronary artery disease,” say Shirya Rashid (McMaster University, Hamilton, Ontario, Canada) and fellow researchers.
They attempted to identify the cellular basis of a new HDL-deficiency phenotype by screening 54 French Canadian individuals with severe HDL deficiency who did not have mutations in genes already associated with low levels of HDL such as ABCA1, LCAT, APOA-I, and SMPD1.
Rashid and co-workers identified two patients with impaired phospholipid efflux, but normal cholesterol efflux. Despite these patients having no known mutations in the coding region of ABCA1, this defect was found to be caused by defective ABCA1 protein regulation and primarily affected the larger α-HDL subpopulations.
Populations of fibroblast cells were cultured from the affected individuals and the authors found that the phospholipid efflux defect could be corrected with the use of oxysterols, or liver-specific receptor (LXR) agonists, “a current therapeutic target of interest, that may, with further studies, be used to raise HDL levels in patients with severe HDL deficiencies,” according to the study authors.
Rashid et al conclude in the European Heart Journal: “A key finding is that treatment with physiological oxysterols (LXR agonists) can reverse both the impaired ABCA1 protein expression and phospholipid efflux defect, markedly increasing both large and small HDL species.”
They add: “Consistent with other investigators, we have demonstrated the strong potential of LXR agonists in enhancing reverse cholesterol transport and raising HDL levels to decrease cardiovascular disease risk in humans, even when HDL deficiency is severe.”
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By Helen Albert