Clear-cell renal cell carcinoma (RCC) is, in most cases, caused by loss of function of the tumor suppressor gene von Hippel–Lindau, resulting in constitutive activation of hypoxia-inducible factor (HIF)-1α and expression of hypoxia-induced genes in normoxic conditions. Clear-cell RCC cells are characterized histologically by accumulation of cholesterol, mainly in its ester form. The origin of the increased cholesterol remains unclear, but it is likely explained by an HIF-1α-driven imbalance between cholesterol uptake and excretion. Here, we showed that expression of the very low-density lipoprotein receptor (VLDL-R) was significantly increased in clear-cell RCC human biopsies compared with normal kidney tissue. Partial knockdown of HIF-1α in clear-cell RCC cells significantly reduced the VLDL-R expression, and knockdown of either HIF-1α or VLDL-R reduced the increased lipid accumulation observed in these cells. We also showed increased uptake of fluorescently labeled lipoproteins in clear-cell RCC cells, which was significantly reduced by knockdown of HIF-1α or VLDL-R. Taken together, our results support the concept that the pathological increase of HIF-1α in clear-cell RCC cells upregulates VLDL-R, which mediates increased uptake and accumulation of lipids. These results explain the morphological characteristics of clear-cell RCC, and open up novel possibilities for detection and treatment of clear-cell RCC.

Perilipin 2 (PLIN2) is the most abundant lipid droplet (LD)-associated protein in nonadipose tissue, and its expression correlates with intracellular lipid accumulation. Here we identified a missense polymorphism, Ser251Pro, that has major effect on protein structure and function, along with an influence on human plasma triglyceride concentration. The evolutionarily conserved Ser251Pro polymorphism was identified with the ClustalW program. Structure modeling using 3D-JigSaw and the Chimera package revealed that the Pro251 allele disrupts a predicted α-helix in PLIN2. Analyses of macrophages from individuals carrying Ser251Pro variants and human embryonic kidney 293 (HEK293) cells stably transfected with either of the alleles demonstrated that the Pro251 variant causes increased lipid accumulation and decreased lipolysis. Analysis of LD size distribution in stably transfected cells showed that the minor Pro251 allele resulted in an increased number of small LDs per cell and increased perilipin 3 protein expression levels as compared with cells carrying the major Ser251 allele. Genotyping of 2113 individuals indicated that the Pro251 variant is associated with decreased plasma triglyceride and very low-density lipoprotein concentrations. Altogether, these data provide the first evidence of a polymorphism in PLIN2 that affects PLIN2 function and may influence the development of metabolic and cardiovascular diseases.

The aim was to clarify the role of vimentin, an intermediate filament protein abundantly expressed in activated macrophages and foam cells, in macrophages during atherogenesis. Global gene expression, lipid uptake, ROS, and inflammation were analyzed in bone-marrow derived macrophages from vimentin-deficient (Vim−/−) and wild-type (Vim+/+) mice. Atherosclerosis was induced in Ldlr−/− mice transplanted with Vim−/− and Vim+/+ bone marrow, and in Vim−/− and Vim+/+ mice injected with a PCSK9 gain-of-function virus. The mice were fed an atherogenic diet for 12–15 weeks. We observed impaired uptake of native LDL but increased uptake of oxLDL in Vim−/− macrophages. FACS analysis revealed increased surface expression of the scavenger receptor CD36 on Vim−/− macrophages. Vim−/− macrophages also displayed increased markers of oxidative stress, activity of the transcription factor NF-κB, secretion of proinflammatory cytokines and GLUT1-mediated glucose uptake. Vim−/− mice displayed decreased atherogenesis despite increased vascular inflammation and increased CD36 expression on macrophages in two mouse models of atherosclerosis. We demonstrate that vimentin has a strong suppressive effect on oxidative stress and that Vim−/− mice display increased vascular inflammation with increased CD36 expression on macrophages despite decreased subendothelial lipid accumulation. Thus, vimentin has a key role in regulating inflammation in macrophages during atherogenesis.

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Myocardial ischemia is associated with intracellular accumulation of lipids and increased depots of myocardial lipids are linked to decreased heart function. Despite investigations in cell culture and animal models, there is little data available on where in the heart the lipids accumulate after myocardial ischemia and which lipid species that accumulate. The aim of this study was to investigate derangements of lipid metabolism that are associated with myocardial ischemia in a porcine model of ischemia and reperfusion. The large pig heart enables the separation of the infarct area with irreversible injury from the area at risk with reversible injury and the unaffected control area. The surviving myocardium bordering the infarct is exposed to mild ischemia and is stressed, but remains viable. We found that cholesteryl esters accumulated in the infarct area as well as in the bordering myocardium. In addition, we found that expression of the low density lipoprotein receptor (LDLr) and the low density lipoprotein receptor-related protein 1 (LRP1) was up-regulated, suggesting that choleteryl ester uptake is mediated via these receptors. Furthermore, we found increased ceramide accumulation, inflammation and endoplasmatic reticulum (ER) stress in the infarcted area of the pig heart. In addition, we found increased levels of inflammation and ER stress in the myocardium bordering the infarct area. Our results indicate that lipid accumulation in the heart is one of the metabolic derangements remaining after ischemia, even in the myocardium bordering the infarct area. Normalizing lipid levels in the myocardium after ischemia would likely improve myocardial function and should therefore be considered as a target for treatment.

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