Hypercholesterolemia in young adult APOE−/− mice alters epidermal lipid composition and impairs barrier function

Long-term exposure to hypercholesterolemia induces the development of skin xanthoma's characterized by the accumulation of lipid-laden foam cells in humans and in mice. Early skin changes in response to hypercholesterolemia are however unknown. In this study, we investigated the skin lipid composition and associated barrier function in young adult low-density lipoprotein receptor knockout (LDLR−/−) and apolipoprotein E knockout (APOE−/−) mice, two commonly used hypercholesterolemic mouse models characterized by the accumulation of apolipoprotein B containing lipoproteins. No effects were observed on cholesterol content in the epidermis in LDLR−/− mice nor in the more extremely hypercholesterolemic APOE−/− mice. Interestingly, the free fatty acids in the APOE−/− epidermis shifted towards shorter and unsaturated chains. Genes involved in the synthesis of cholesterol and fatty acids were downregulated in APOE−/− skin suggesting a compensation for the higher influx of plasma lipids, most probably as cholesteryl esters. Importantly, in vivo transepidermal water loss and permeability studies with murine lipid model membranes revealed that the lipid composition of the APOE−/− skin resulted in a reduced skin barrier function. In conclusion, severe hypercholesterolemia associated with increased apolipoprotein B containing lipoproteins affects the epidermal lipid composition and its protective barrier.Biopharmaceutic

Hyperalphalipoproteinemic scavenger receptor BI knockout mice exhibit a disrupted epidermal lipid barrier

Scavenger receptor class B type I (SR-BI) mediates the selective uptake of cholesteryl esters (CE) from high-density lipoproteins (HDL). An impaired SR-BI function leads to hyperalphalipoproteinemia with elevated levels of cholesterol transported in the HDL fraction. Accumulation of cholesterol in apolipoprotein B (apoB)-containing lipoproteins has been shown to alter skin lipid composition and barrier function in mice. To investigate whether these hypercholesterolemic effects on the skin also occur in hyperalphalipoproteinemia, we compared skins of wild-type and SR-BI knockout (SR-BI−/−) mice. SR-BI deficiency did not affect the epidermal cholesterol content and induced only minor changes in the ceramide subclasses. The epidermal free fatty acid (FFA) pool was, however, enriched in short and unsaturated chains. Plasma CE levels strongly correlated with epidermal FFA C18:1 content. The increase in epidermal FFA coincided with downregulation of cholesterol and FFA synthesis genes, suggesting a compensatory response to increased flux of plasma cholesterol and FFAs into the skin. Importantly, the SR-BI−/− epidermal lipid barrier showed increased permeability to ethyl-paraminobenzoic acid, indicating an impairment of the barrier function. In conclusion, increased HDL-cholesterol levels in SR-BI−/− mice can alter the epidermal lipid composition and lipid barrier function similarly as observed in hypercholesterolemia due to elevated levels of apoB-containing lipoproteins.BiopharmaceuticsDrug Delivery Technolog

The structure of the Yang-Mills spectrum for arbitrary simple gauge algebras

The mass spectrum of pure Yang-Mills theory in 3+1 dimensions is discussed for an arbitrary simple gauge algebra within a quasigluon picture. The general structure of the low-lying gluelump and two-quasigluon glueball spectrum is shown to be common to all algebras, while the lightest $C=-$ three-quasigluon glueballs only exist when the gauge algebra is A$_{r\geq 2}$, that is in particular $\mathfrak{su}(N\geq3)$. Higher-lying $C=-$ glueballs are shown to exist only for the A$_{r\geq2}$, D$_{{\rm odd}-r\geq 4}$ and E$_6$ gauge algebras. The shape of the static energy between adjoint sources is also discussed assuming the Casimir scaling hypothesis and a funnel form; it appears to be gauge-algebra dependent when at least three sources are considered. As a main result, the present framework's predictions are shown to be consistent with available lattice data in the particular case of an $\mathfrak{su}(N)$ gauge algebra within 't Hooft's large-$N$ limit.Comment: 21 pages, 4 figures; remarks added, typos corrected in v2. v3 to appear in EPJ