ABSTRACT
Mutations in the lipid transport protein ABCA12 cause the life-threatening skin condition harlequin ichthyosis (HI), which is characterized by the loss of skin barrier function, inflammation, and dehydration. Inflammatory responses in HI increase disease severity by impairing keratinocyte differentiation, suggesting amelioration of this phenotype as a possible therapy for the condition. Existing treatments for HI are based around the use of retinoids, but their value in treating patients during the neonatal period has been questioned relative to other improved management regimens, and their long-term use is associated with side effects. We have developed a conditional mouse model to demonstrate that topical application of the aminosalicylic acid derivatives 5ASA or 4ASA considerably improves HI keratinocyte differentiation without the undesirable side effects of the retinoid acitretin and salicylic acid (aspirin). Analysis of changes in gene expression shows that 4ASA in particular elicits compensatory upregulation of a large family of barrier function-related genes, many of which are associated with other ichthyoses, identifying this compound as a lead candidate for developing topical treatments for HI.
Subject(s)
Aminosalicylic Acid/pharmacology , Cell Differentiation/drug effects , Ichthyosis, Lamellar/drug therapy , Keratinocytes/drug effects , ATP-Binding Cassette Transporters/metabolism , Acitretin/pharmacology , Animals , Disease Models, Animal , Epidermis/drug effects , Epidermis/metabolism , Gene Expression/drug effects , Ichthyosis, Lamellar/metabolism , Keratinocytes/metabolism , Mice , Mice, Knockout , Mutation/drug effects , Phenotype , Salicylic Acid/pharmacology , Skin/drug effects , Skin/metabolism , Up-Regulation/drug effectsABSTRACT
Dysregulation of lipid homeostasis is intimately associated with defects in insulin secretion, a key feature of type 2 diabetes. Here, we explore the role of the putative lipid transporter ABCA12 in regulating insulin secretion from ß-cells. Mice with ß-cell-specific deletion of Abca12 display impaired glucose-stimulated insulin secretion and eventual islet inflammation and ß-cell death. ABCA12's action in the pancreas is independent of changes in the abundance of two other cholesterol transporters, ABCA1 and ABCG1, or of changes in cellular cholesterol or ceramide content. Instead, loss of ABCA12 results in defects in the genesis and fusion of insulin secretory granules and increases in the abundance of lipid rafts at the cell membrane. These changes are associated with dysregulation of the small GTPase CDC42 and with decreased actin polymerisation. Our findings establish a new, pleiotropic role for ABCA12 in regulating pancreatic lipid homeostasis and insulin secretion.
Subject(s)
Diabetes Mellitus, Type 2 , Insulin-Secreting Cells , ATP Binding Cassette Transporter 1/genetics , ATP Binding Cassette Transporter 1/metabolism , ATP-Binding Cassette Transporters/metabolism , Animals , Diabetes Mellitus, Type 2/metabolism , Glucose/metabolism , Insulin/metabolism , Insulin Secretion , Insulin-Secreting Cells/metabolism , MiceABSTRACT
Harlequin ichthyosis (HI) is a severe skin disease which leads to neonatal death in â¼50% of cases. It is the result of mutations in ABCA12, a protein that transports lipids required to establish the protective skin barrier needed after birth. To better understand the life-threatening newborn HI phenotype, we analysed the developing epidermis for consequences of lipid dysregulation in mouse models. We observed a pro-inflammatory signature which was characterized by chemokine upregulation in embryonic skin which is distinct from that seen in other types of ichthyosis. Inflammation also persisted in grafted HI skin. To examine the contribution of inflammation to disease development, we overexpressed interleukin-37b to globally suppress fetal inflammation, observing considerable improvements in keratinocyte differentiation. These studies highlight inflammation as an unexpected contributor to HI disease development in utero, and suggest that inhibiting inflammation may reduce disease severity.
