Histological evaluation reveals widely altered lipid deposition, local and systemic inflammation in normocholesterolemic mice lacking high-density lipoprotein

It is commonly believed that an unbalanced diet, rich in lipids, is crucial to develop atherosclerosis and to promote an abnormal lipid deposition in various organs and tissues. High-density lipoprotein (HDL) and its major protein component, apolipoprotein A-I, plays a unique role in regulating cell cholesterol homeostasis and in modulating immune cell activation. In the present study, we investigated the impact of genetic manipulation of HDL/apoA-I levels on lipid deposition in skin, lymphoid organs and heart vessels in mice fed a normal laboratory diet (NLD). ApoE deficient (EKO) mice, apoE/apoA-I double deficient (DKO) mice, DKO mice overexpressing human apoA-I (DKO/hA-I) and C57Bl/6 control mice (WT) were fed NLD diet until 30 weeks of age. Plasma lipids were quantified, atherosclerosis development at the aortic sinus and in coronary arteries was measured, skin ultrastructure was evaluated by electron microscopy. Blood and lymphoid organs were characterized with histological and immunocytofluorimetric analyses. DKO were characterized by almost complete HDL deficiency and by plasma total cholesterol levels comparable to control mice. Only DKO mice showed a disarranged subpapillary dermis filled with cholesterol clefts and foam cells were interspersed in the reticular dermis. Neutral lipid deposition was increased in the thickened dermis of DKO mice, compared with the other genotypes. In addition, features of severe inflammation were detected in the skin-draining lymph nodes of DKO mice: i) accumulation of foamy macrophages surrounded by lymphoid cells; ii) presence of cholesterol crystals and granulomatous reactions in the inner cortex and medulla; iii) dilation of subcapsular, cortico-medullary and medullary sinuses. Moreover, the deposition of neutral lipids in lymph node parenchyma was low and comparable in WT, EKO and DKO/hA-I mice, whereas in DKO mice it was dramatically elevated. An increased presence of CD4+ T effector memory (TEM) cells was detected in blood, spleen and in the skin-draining lymph nodes of DKO mice. A worsening of atherosclerosis at the aortic sinus and coronary arteries was also observed in DKO vs EKO mice. Human apoA-I overexpression in the DKO background was able to rescue the skin phenotype and to halt atherosclerosis development. In conclusion, HDL deficiency, in the absence of hyperlipidemia, is associated with severe alterations of skin morphology, aortic and coronary atherosclerosis, local and systemic inflammation.