Threshold Effects of Circulating Angiopoietin-like 3 Levels on Plasma Lipoproteins

Context: Angiopoietin-like 3 (ANGPTL3) deficiency in plasma due to loss-of-function (LOF) gene mutations causes familial combined hypobetalipoproteinemia (FHBL) type 2 in homozygotes. However, the lipid phenotype in heterozygotes is much milder and does not appear to relate directly to ANGPTL3 levels. Furthermore, the low LDL phenotype in carriers of ANGPTL3 mutations is unexplained. Objective: To determine whether a reduction below a critical threshold in plasma ANGPTL3 levels is a determinant of lipoprotein metabolism in FHBL2, and to study the whether PCSK9 is involved in determining low LDL levels in this condition. Design: We studied subjects from 19 families with ANGPTL3 mutations, and subjects with FHBL type 1 due to truncated apolipoprotein B (apoB) species. Results: Total cholesterol, HDL-c, triglycerides, and HDL and LDL particle concentration correlated with plasma ANGPTL3 levels, but only when this was below 25% of normal (<60 ng/ml); (ii) VLDL particle concentration strongly correlated with plasma ANGPTL3 when this was below 58% of normal; (iii) both FHBL1 and FHBL2 subjects showed low levels of mature and LDL-bound PCSK9, and higher levels of its furin-cleaved form; and (iv) LDL-bound PCSK9 is protected from cleavage by furin, and binds to the LDL receptor more strongly compared to apoB-free PCSK9. Conclusion: Our studies suggest that the hypolipidemic effects of ANGPTL3 mutations in FHBL2 are dependent on threshold plasma ANGPTL3 levels, with differential effects on various lipoprotein particles. The increased inactivation of PCSK9 by furin in FHBL1 and FHBL2 is likely to cause increased LDL clearance and suggests novel therapeutic avenues

Plasma Lipidomic Patterns in Patients with Symptomatic Coronary Microvascular Dysfunction.

Coronary microvascular dysfunction (MVD) is a syndrome of abnormal regulation of vascular tone, particularly during increased metabolic demand. While there are several risk factors for MVD, some of which are similar to those for coronary artery disease (CAD), the cause of MVD is not understood. We hypothesized that MVD in symptomatic non-elderly subjects would be characterized by specific lipidomic profiles. Subjects (n = 20) aged 35-60 years and referred for computed tomography coronary angiography (CTA) for chest pain but who lacked obstructive CAD (\u3e50% stenosis), underwent quantitative regadenoson stress-rest myocardial contrast echocardiography (MCE) perfusion imaging for MVD assessment. The presence of MVD defined by kinetic analysis of MCE data was correlated with lipidomic profiles in plasma measured by liquid chromatography and high-resolution mass spectrometry. Nine of twenty subjects had evidence of MVD, defined by reduced hyperemic perfusion versus other subjects (beta-value 1.62 ± 0.44 vs. 2.63 ± 0.99 s-1, p = 0.009). Neither the presence of high-risk but non-obstructive CAD on CTA, nor CAD risk factors were different for those with versus without MVD. Lipidomic analysis revealed that patients with MVD had lower concentrations of long-carbon chain triacylglycerols and diacylglycerols, and higher concentrations of short-chain triacylglycerols. The diacylglycerol containing stearic and linoleic acid classified all participants correctly. We conclude that specific lipidomic plasma profiles occur in MVD involving saturated long-chain fatty acid-containing acylglycerols that are distinctly different from those in non-obstructive CAD. These patterns could be used to better characterize the pathobiology and potential treatments for this condition