Delayed Hepatic Adaptation to Weaning in ACBP−/− Mice Is Caused by Disruption of the Epidermal Barrier

• Published in: Cell reports (Cambridge) 2013-12, Vol.5 (5), p.1403-1412
• Main Authors: Neess, Ditte, Bek, Signe, Bloksgaard, Maria, Marcher, Ann-Britt, Færgeman, Nils J., Mandrup, Susanne
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological; Adipose Tissue, White - metabolism; Animals; Body Water - metabolism; Diazepam Binding Inhibitor - genetics; Diazepam Binding Inhibitor - metabolism; Epidermis - metabolism; Hepatocytes - metabolism; Keratinocytes - metabolism; Lipolysis; Mice; Mice, Inbred C57BL; Mice, Knockout; Sterol Regulatory Element Binding Proteins - genetics; Sterol Regulatory Element Binding Proteins - metabolism; Weaning
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.11.010

We previously reported that mice deficient in acyl-CoA-binding protein (ACBP) display a delayed metabolic adaptation to weaning. This includes a delayed activation of the hepatic lipogenic gene program, which may result from hepatic accumulation of triacylglycerol and/or cholesteryl esters in the late suckling period. To further investigate the basis for this phenotype, we generated mice deficient in ACBP in hepatocytes (Alb-ACBP−/−) and keratinocytes (K14-ACBP−/−). Surprisingly, the delayed adaptation to weaning, including hepatic lipid accumulation, is caused by ACBP deficiency in the skin rather than in the liver. Similarly to ACBP−/− mice, K14-ACBP−/− mice exhibit an increased transepidermal water loss, and we show that the hepatic phenotype is caused specifically by the epidermal barrier defect, which leads to increased lipolysis in white adipose tissue. Our data demonstrate that an imperfect epidermal barrier leads to profound suppression of the hepatic SREBP gene program and lipid accumulation in the liver. [Display omitted] •Keratinocyte-specific ACBP depletion in mice compromises epidermal barrier function•Compromised epidermal barrier function suppresses hepatic SREBP gene programs•Hepatic SREBP gene program suppression correlates with hepatic lipid accumulation Mandrup and colleagues report a link between epidermal barrier function and hepatic gene regulation and metabolism. Impaired epidermal barrier function through skin-specific ACBP disruption leads to suppression of the hepatic lipogenic gene program during weaning. This phenotype can be rescued by applying an artificial skin barrier. The data support a model in which increased lipolysis in white adipose tissue results in hepatic accumulation of lipids and suppression of hepatic SREBP activity.