Collagen XVIII is an evolutionary conserved ubiquitously expressed basement membrane proteoglycan produced in three isoforms via two promoters (P). Here, we assess the function of the N-terminal, domain of unknown function/frizzled-like sequences unique to medium/long collagen XVIII by creating P-specific null mice. P2-null mice, which only produce short collagen XVIII, developed reduced bulk-adiposity, hepatic steatosis, and hypertriglyceridemia. These abnormalities did not develop in P1-null mice, which produce medium/long collagen XVIII. White adipose tissue samples from P2-null mice contain larger reserves of a cell population enriched in early adipocyte progenitors; however, their embryonic fibroblasts had ∼50% lower adipocyte differentiation potential. Differentiating 3T3-L1 fibroblasts into mature adipocytes produced striking increases in P2 gene-products and dramatic falls in P1-transcribed mRNA, whereas Wnt3a-induced dedifferentiation of mature adipocytes produced reciprocal changes in P1 and P2 transcript levels. P2-derived gene-products containing frizzledlike sequences bound the potent adipogenic inhibitor, Wnt10b, in vitro. Previously, we have shown that these same sequences bind Wnt3a, inhibiting Wnt3a-mediated signaling. P2-transcript levels in visceral fat were positively correlated with serum free fatty acid levels, suggesting that collagen α1 (XVIII) expression contributes to regulation of adipose tissue metabolism in visceral obesity. Medium/long collagen XVIII is deposited in the Space of Disse, and interaction between hepatic apolipoprotein E and this proteoglycan is lost in P2-null mice. These results describe a previously unidentified extracellular matrix-directed mechanism contributing to the control of the multistep adipogenic program that determines the number of precursors committing to adipocyte differentiation, the maintenance of the differentiated state, and the physiological consequences of its impairment on ectopic fat deposition.

Background/Aim: Inflammatory markers have been observed in proliferative diabetic retinopathy (PDR). We assessed vitreous concentrations of adhesion molecules and cytokines in PDR and non-diabetic controls and plasma concentrations to differentiate local inflammation from the breakdown of the blood-retina barrier. Methods: 38 patients with PDR and 16 controls with macular hole or epiretinal membrane underwent vitrectomy. Vitreous and plasma soluble adhesion molecules [sE-selectin, intercellular adhesion molecule (sICAM)-1 and -3, platelet-endothelial cell adhesion molecule (sPECAM)-1, sP-selectin, vascular cell adhesion molecule (sVCAM)-1] and cytokines [interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 (p70), tumour necrosis factor-α and -β, γ-interferon] were detected by the multiplex assay. Results: Levels of IL-6 and IL-8 were 26-fold (p = 0.001) and 6-fold higher (p = 0.001) in vitreous than in plasma in PDR. Vitreous IL-10 (p = 0.004), sPECAM-1, sE-selectin, sICAM-1 and sVCAM-1 were higher in PDR than controls (p = 0.001 for all). Adhesion molecule concentrations in vitreous in PDR were less than 10% of those in plasma. IL-10 was lower in vitreous than plasma (3.0 vs. 12.8 pg/ml, p = 0.007), and the vitreous IL-10/IL-8 ratio was significantly lower in PDR than in controls (0.10 vs. 0.55 pg/ml, p = 0.003). Conclusion: The elevated IL-6 and IL-8 levels in vitreous, but not in plasma, are evidence favouring local over systemic inflammation in PDR. Furthermore, there was imbalance between inflammatory and anti-inflammatory cytokines in the vitreous.

BACKGROUND HDL-mediated cholesterol efflux capacity (HDL-CEC) is a functional attribute that may have a protective role in atherogenesis. However, the estimation of HDL-CEC is based on in vitro cell assays that are laborious and hamper large-scale phenotyping. METHODS Here, we present a cost-effective high-throughput nuclear magnetic resonance (NMR) spectroscopy method to estimate HDL-CEC directly from serum. We applied the new method in a population-based study of 7603 individuals including 574 who developed incident coronary heart disease (CHD) during 15 years of follow-up, making this the largest quantitative study for HDL-CEC. RESULTS As estimated by NMR-spectroscopy, a 1-SD higher HDL-CEC was associated with a lower risk of incident CHD (hazards ratio, 0.86; 95%CI, 0.79–0.93, adjusted for traditional risk factors and HDL-C). These findings are consistent with published associations based on in vitro cell assays. CONCLUSIONS These corroborative large-scale findings provide further support for a potential protective role of HDL-CEC in CHD and substantiate this new method and its future applications.

High-density lipoprotein mediated cholesterol efflux capacity (HDL-CEC) is a functional attribute that may have a protective role in atherogenesis. However, the estimation of HDL-CEC is based on in vitro cell assays that are laborious and hamper large-scale phenotyping. Here, we present a cost-effective high-throughput nuclear magnetic resonance (NMR) spectroscopy method to estimate HDL-CEC directly from serum. We applied the new method in a population-based study of 7,603 individuals including 574 who developed incident coronary heart disease (CHD) during 15 years of follow-up, making this the largest quantitative study for HDL-CEC. As estimated by NMR-spectroscopy, a 1-SD higher HDL-CEC was associated with a lower risk of incident CHD (hazards ratio 0.86; 95%CI 0.79-0.93, adjusted for traditional risk factors and HDL-C). These findings are consistent with published associations based on in vitro cell assays. These corroborative large-scale findings provide further support for a potential protective role of HDL-CEC in CHD, and substantiate this new method and its future applications.

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Data-driven subgrouping algorithm was trained by multivariate lipoprotein data.• Four coherent subgroups were identified in two large-scale population-based cohorts.• Subgroups had characteristic lipoprotein profiles and risk for CHD.• Apolipoprotein B quartiles stratified CHD risk better than multivariate subgroups.• Caution on multivariate data-driven subgrouping in risk assessment is warranted.

ObjectiveThe potential of high-density lipoproteins (HDL) to facilitate cholesterol removal from arterial foam cells is a key function of HDL. We studied whether cholesterol efflux to serum and HDL subfractions is impaired in subjects with early coronary heart disease (CHD) or metabolic syndrome (MetS) in families where a low HDL-cholesterol level (HDL-C) predisposes to early CHD.MethodsHDL subfractions were isolated from plasma by sequential ultracentrifugation. THP-1 macrophages loaded with acetyl-LDL were used in the assay of cholesterol efflux to total HDL, HDL2, HDL3 or serum.ResultsWhile cholesterol efflux to serum, total HDL and HDL3 was unchanged, the efflux to HDL2 was 14% lower in subjects with MetS than in subjects without MetS (p<0.001). The efflux to HDL2 was associated with components of MetS such as plasma HDL-C (r = 0.76 in men and r = 0.56 in women, p<0.001 for both). The efflux to HDL2 was reduced in men with early CHD (p<0.01) only in conjunction with their low HDL-C. The phospholipid content of HDL2 particles was a major correlate with the efflux to HDL2 (r = 0.70, p<0.001). A low ratio of HDL2 to total HDL was associated with MetS (p<0.001).ConclusionOur results indicate that impaired efflux to HDL2 is a functional feature of the low HDL-C state and MetS in families where these risk factors predispose to early CHD. The efflux to HDL2 related to the phospholipid content of HDL2 particles but the phospholipid content did not account for the impaired efflux in cardiometabolic disease, where a combination of low level and poor quality of HDL2 was observed.

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