Enrichment of Short-Chain Ceramides and Free Fatty Acids in the Skin Epidermis, Liver, and Kidneys of db/db Mice, a Type 2 Diabetes Mellitus Model

Abstract

Patients with diabetes mellitus (DM) often suffer from diverse skin disorders, which might be attributable to skin barrier dysfunction. To explore the role of lipid alterations in the epidermis in DM skin disorders, we quantitated 49 lipids (34 ceramides, 14 free fatty acids (FFAs), and cholesterol) in the skin epidermis, liver, and kidneys of db/db mice, a Type 2 DM model, using UPLC-MS/MS. The expression of genes involved in lipid synthesis was also evaluated. With the full establishment of hyperglycemia at the age of 20 weeks, remarkable lipid enrichment was noted in the skin of the db/db mice, especially at the epidermis and subcutaneous fat bed. Prominent increases in the ceramides and FFAs (>3 fold) with short or medium chains (<C26) occurred in the skin epidermis (16NS, 18NS, 24NS, 16NDS, 18NDS, 20NDS, 22NDS, 24NDS, C16:1FA, C18:2FA, and C18:1FA) and the liver (16NS, 18NS, 20NS, 24:1NS, 18NDS, 20NDS, 22NDS, C16:1FA, C18:2FA, C18:1FA), whereas those with very long chains were not affected. In the kidney, only slight increases (<3 fold) were observed for 16NS, 18NS, 20NS, 26NDS, C26FA, and C22:1FA. Consistently, LXRα/β and PPARγ, nuclear receptors promoting lipid synthesis, lipid synthesis enzymes such as elongases 1, 4, and 6, and fatty acid synthase and stearoyl-CoA desaturase were highly expressed in the skin and livers of the db/db mice. Collectively, our study demonstrates an extensive alteration in the skin and systemic lipid profiles of db/db mice, which could contribute to the development of skin disorders in DM.

Rab25 Deficiency Perturbs Epidermal Differentiation and Skin Barrier Function in Mice

“…1D). Increased TEWL, with accompanying low skin hydration, can be observed in dry skin diseases, like diabetes mellitus (Park et al ., 2011; Kim et al ., 2019) or atopic dermatitis (Joo et al ., 2015), reflecting that Rab25 KO mice might have xerotic skin…”

A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury

“…Ceramide contents and activity of enzymes involved in ceramide generation are altered in various types of oxidative stress-mediated kidney diseases ( Table 2 ) [ 13 , 22 , 26 , 27 , 31 , 35 , 43 , 44 , 47 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ]. Ceramide levels were increased in the kidney tissue of toxic nephropathy [ 31 , 62 , 63 , 64 ...…”

“…This indicates a pathogenic role of ceramide in the development of DN. Short- and medium-chain ceramides were elevated in the kidney of diabetic mice [ 97 ]. Despite increased plasma levels of long-chain ceramides, long-chain and very-long-chain ceramides were decreased in the kidney tissue due to the reduced activity of DES and nSMase in diabetic mice [ 98 ].…”

“…Ceramide can induce apoptosis and/or necrosis in various types of kidney cells including ECs associated with oxidative stress-mediated kidney diseases ( Table 2 ) [ 13 , 22 , 26 , 27 , 31 , 35 , 43 , 62 , 63 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 97 , 98 , 99 , 100 , 101 , 102 , 103 ]. In support of this, exposure of MCs, GECs [ 104 ] and RTCs [ 77 ] to ROS [ 104 ] increased ceramide production, leading to apoptosis/necrosis, while antioxidants prevented ROS-induced ceramide production and apoptosis in ECs [ 70 ].…”

Alterations in epidermal function in type 2 diabetes: Implications for the management of this disease

“…[26][27][28] A high concentration of glucose (30 mM) also downregulates connexin 43 expression, resulting in reductions in zonula occludens-1 and occluding levels in rat retinal endothelial and in human airway epithelial cell cultures, and is accompanied by increased airway epithelial permeability. 29,30 Furthermore, mouse models of type 2 diabetes exhibit increased short and medium chain fatty acid contents, 31 in addition to reductions in overall epidermal lipid synthesis. 14 Because either excessive fatty acids or decreased epidermal lipid content can compromise epidermal permeability barrier function, 32,33 increased epidermal fatty acids can result in delayed permeability barrier recovery in patients with type 2 diabetes.…”