Impact of the loss of caveolin-1 on lung mass and cholesterol metabolism in mice with and without the lysosomal cholesterol transporter, Niemann–Pick type C1

Abstract

Caveolin-1 (Cav-1) is a major structural protein in caveolae in the plasma membranes of many cell types, particularly endothelial cells and adipocytes. Loss of Cav-1 function has been implicated in multiple diseases affecting the cardiopulmonary and central nervous systems, as well as in specific aspects of sterol and lipid metabolism in the liver and intestine. Lungs contain an exceptionally high level of Cav-1. Parameters of cholesterol metabolism in the lung were measured, initially in Cav-1-deficient mice (Cav-1−/−), and subsequently in Cav-1−/− mice that also lacked the lysosomal cholesterol transporter Niemann-Pick C1 (Npc1) was also absent (Cav-1−/−:Npc1−/−). In 50-day-old Cav-1−/− mice fed a low- or high-cholesterol chow diet, the total cholesterol concentration (mg/g) in the lungs was marginally lower than in the Cav-1+/+ controls, but due to an expansion in their lung mass exceeding 30%, whole-lung cholesterol content (mg/organ) was moderately elevated. Lung mass (g) in the Cav-1−/−:Npc1−/− mice (0.356 ± 0.022) markedly exceeded that in their Cav-1+/+:Npc1+/+ controls (0.137 ± 0.009), as well as in their Cav-1−/−:Npc1+/+ (0.191 ± 0.013) and Cav-1+/+:Npc1−/− (0.213 ± 0.022) littermates. The corresponding lung total cholesterol content (mg/organ) in mice of these genotypes was 6.74 ± 0.17, 0.71 ± 0.05, 0.96 ± 0.05 and 3.12 ± 0.43, respectively, with the extra cholesterol in the Cav-1−/−:Npc1−/− and Cav-1+/+:Npc1−/− mice being nearly all unesterified (UC). The exacerbation of the Npc1 lung phenotype and increase in the UC level in the Cav-1−/−:Npc1−/− mice imply a regulatory role of Cav-1 in pulmonary cholesterol metabolism when lysosomal sterol transport is disrupted.

Extensive macrophage accumulation in young and old Niemann–Pick C1 model mice involves the alternative, M2, activation pathway and inhibition of macrophage apoptosis

“…These values were not corrected by HPBCD therapy which has also been found by others [12]. Severity of lung disease was enhanced by concomitant absence of caveolin [13] which is normally increased in Npc1 −/− mouse livers [14] and even heterozygous NPC1 fibroblasts [15]. …”

Differently increased volumes of multiple brain areas in Npc1 mutant mice following various drug treatments

“…Additionally, the reduced density of oligodendrocytes in white matter structures of Npc1 −/− mice ( Weintraub et al, 1987 ; Takikita et al, 2004 ; Yan et al, 2011 , 2014 ; Yu and Lieberman, 2013 ; Bernardo et al, 2021 ; Kunkel et al, 2023 ) should contribute to reduced fresh volume. In Npc1 −/− mice, from early postnatal development onwards, defects of differentiation of post-mitotic pre-myelinating oligodendrocytes into mature myelinating oligodendrocytes have been described by various groups ( Weintraub et al, 1987 ; Takikita et al, 2004 ; Miller and Auchus, 2011 ; Yan et al, 2011 , 2014 ; Hedrich, 2012 ; Yu and Lieberman, 2013 ; Mundy et al, 2014 ; Bernardo et al, 2021 ; Kunkel et al, 2023 ). As also seen in the present study, the amount of hypomyelination varied between different parts of the brain ( Payne and Hales, 2004 ; Miller, 2013 ; Cole et al, 2019 ).…”

Caveolin-1 Expression Ameliorates Nephrotic Damage in a Rabbit Model of Cholesterol-Induced Hypercholesterolemia

“…Several studies have revealed that CAV-1 protein overexpression markedly reduced total cholesterol and free cholesterol (FC) content as well as their accumulation in lipid-loading cells [ 6 – 8 ]. In CAV-1-deficient mice, moderately elevated whole-lung cholesterol content, impaired liver regeneration, cardiovascular disorders, and FC accumulation in mitochondrial membranes resulted in mitochondrial diseases [ 9 – 11 ]. However, Frank et al .…”