Key result
A lower TopF transfer/LDL-C ratio was significantly associated with homozygous familial hypercholesterolemia after adjusting for age (OR 0.646), indicating impaired HDL function relative to LDL burden.
Why the study?
It was unknown whether HDL's ability to acquire free cholesterol from triglyceride-rich lipoproteins during lipolysis, as part of the reverse remnant-cholesterol transport pathway, is impaired in patients with familial hypercholesterolemia.
Does HDL capacity to acquire free cholesterol from triglyceride-rich lipoproteins differ in patients with familial hypercholesterolemia compared to healthy controls?
Case-Control (n=54)
Does HDL capacity to acquire free cholesterol from triglyceride-rich lipoproteins differ in patients with familial hypercholesterolemia compared to healthy controls?
In patients with homozygous familial hypercholesterolemia, HDL's capacity to acquire free cholesterol from triglyceride-rich lipoproteins is impaired relative to their severe LDL-C burden, suggesting a potential functional biomarker for residual cardiovascular risk.
May indicate HDL impairment relative to LDL burden in HOFH; hypothesis-generating for TopF transfer/LDL-C as residual-risk biomarker, needs prospective validation.
INTRODUCTION: High-density lipoprotein (HDL) serves as a key protective factor against elevated low-density lipoprotein cholesterol (LDL-C) levels in patients with familial hypercholesterolemia (FH). This study aimed to assess whether HDL's ability to acquire free cholesterol (FC) from triglyceride-rich lipoproteins (TGRLs) during lipolysis, as a part of reverse remnant-cholesterol transport (RRT) pathway, is impaired in FH patients. METHODS: This case-control study included 16 homozygous (HOFH) and 18 heterozygous (HEFH) patients with FH, along with 20 healthy controls. The free cholesterol transfer assay measured the ability of HDL (as apoB-depleted serum) to uptake fluorescently labelled free cholesterol (TopF) from TGRLs during lipoprotein lipase (LPL)-mediated lipolysis. RESULTS: No significant difference was observed among the groups in the overall capacity of HDL to acquire FC from TGRLs during LPL-mediated lipolysis. When normalizing for LDL-C and non-HDL-C levels, significantly lower TopF transfer/LDL-C and TopF transfer/non-HDL-C ratios were observed in HOFH patients in comparison with HEFH and healthy subjects. Lower TopF transfer/LDL-C (OR: 0.605, 95% CI: 0.428-0.857; p < 0.01) and TopF transfer/non-HDL-C (OR: 0.539, 95% CI: 0.339-0.859; p < 0.01) ratios were independently associated with HOFH, while, after adjusting for age only the former association remained significant (OR: 0.646, 95% CI: 0.430-0.971). CONCLUSION: Although HDL's direct capacity to acquire free cholesterol from TGRLs did not differ significantly between the groups, the reduced TopF transfer/LDL-C and TopF transfer non-HDL-C ratios in FH patients is consistent with impaired HDL function. These ratios may serve as a potential biomarker for identifying high-risk FH phenotypes, warranting validation in larger, prospective studies.
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Ganjali et al. (2026) conducted a case-control in Familial hypercholesterolemia (n=54). Homozygous familial hypercholesterolemia vs. Heterozygous familial hypercholesterolemia and healthy controls was evaluated on Association of TopF transfer/LDL-C ratio with homozygous familial hypercholesterolemia (age-adjusted) (OR 0.646, 95% CI 0.430-0.971, p=<0.05). A lower TopF transfer/LDL-C ratio was significantly associated with homozygous familial hypercholesterolemia after adjusting for age (OR 0.646), indicating impaired HDL function relative to LDL burden.
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