Pancreatic exocrine insufficiency in LXRβ⁻/⁻ mice is associated with a reduction in aquaporin-1 expression
2008
Gabbi, Chiara | Kim, Hyun-Jin | Hultenby, Kjell | Bouton, Didier | Toresson, Gudrun | Warner, Margaret | Gustafsson, Jan-Åke
Liver X receptors (LXRs) α and β are nuclear oxysterol receptors with a key role in cholesterol, triglyceride, and glucose metabolism. In LXRβ⁻/⁻ mice on a normal diet, there is a reduction in size of perigonadal fat pad and, on high-fat diet there is resistance to obesity. In the present study, we investigated the reason for the resistance of LXRβ⁻/⁻ mice to weight gain. In LXRβ⁻/⁻ mice we found pancreatic exocrine insufficiency with reduced serum levels of amylase and lipase, reduced proteolytic activity in feces, chronic inflammatory infiltration, and, in the ductal epithelium, an increased apoptosis without compensatory proliferation. Electron microscopy revealed ductal dilatation with intraductal laminar structures characteristic of cystic fibrosis. To investigate the relationship between LXRβ and pancreatic secretion, we studied the expression of LXRβ and the water channel, aquaporin-1 (AQP1), in the ductal epithelium of the pancreas. In WT mice, ductal epithelial cells expressed LXRβ in the nuclei and AQP1 on the plasma membrane. In LXRβ⁻/⁻ mice neither LXRβ nor AQP1 was detectable. Moreover, in WT mice the LXR agonist (T2320) increased AQP1 gene expression. These data demonstrate that in LXRβ⁻/⁻ mice dietary resistance to weight gain is caused by pancreatic insufficiency and that LXRβ regulates pancreatic exocrine secretion through the control of AQP1 expression. Pancreatic exocrine insufficiency is the main cause of malabsorption syndrome responsible for weight loss in adults and growth failure in children. Several genes are known to be involved in the pathogenesis and susceptibility to pancreatic insufficiency. LXRβ should be included in that list.
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