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PMID:18806227

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Citation

Gabbi, C, Kim, HJ, Hultenby, K, Bouton, D, Toresson, G, Warner, M and Gustafsson, JA (2008) Pancreatic exocrine insufficiency in LXRbeta-/- mice is associated with a reduction in aquaporin-1 expression. Proc. Natl. Acad. Sci. U.S.A. 105:15052-7

Abstract

Liver X receptors (LXRs) alpha and beta are nuclear oxysterol receptors with a key role in cholesterol, triglyceride, and glucose metabolism. In LXRbeta(-/-) 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 LXRbeta(-/-) mice to weight gain. In LXRbeta(-/-) 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 LXRbeta and pancreatic secretion, we studied the expression of LXRbeta and the water channel, aquaporin-1 (AQP1), in the ductal epithelium of the pancreas. In WT mice, ductal epithelial cells expressed LXRbeta in the nuclei and AQP1 on the plasma membrane. In LXRbeta(-/-) mice neither LXRbeta nor AQP1 was detectable. Moreover, in WT mice the LXR agonist (T2320) increased AQP1 gene expression. These data demonstrate that in LXRbeta(-/-) mice dietary resistance to weight gain is caused by pancreatic insufficiency and that LXRbeta 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. LXRbeta should be included in that list.

Links

PubMed PMC2567491 Online version:10.1073/pnas.0808097105

Keywords

Adipose Tissue/metabolism; Animals; Aquaporin 1/biosynthesis; Aquaporin 1/genetics; Body Weight/genetics; DNA-Binding Proteins/agonists; DNA-Binding Proteins/genetics; Exocrine Pancreatic Insufficiency/genetics; Exocrine Pancreatic Insufficiency/metabolism; Exocrine Pancreatic Insufficiency/pathology; Female; Gene Expression Regulation/drug effects; Male; Mice; Mice, Knockout; Orphan Nuclear Receptors; Pancreas, Exocrine/metabolism; Pancreas, Exocrine/secretion; Pancreas, Exocrine/ultrastructure; Pancreatic Ducts/metabolism; Pancreatic Ducts/secretion; Pancreatic Ducts/ultrastructure; RNA, Messenger/biosynthesis; Receptors, Cytoplasmic and Nuclear/agonists; Receptors, Cytoplasmic and Nuclear/genetics; Weight Gain/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:NR1H2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NR1H2

involved_in

GO:0010884: positive regulation of lipid storage

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NR1H2

involved_in

GO:0055088: lipid homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NR1H2

involved_in

GO:0045861: negative regulation of proteolysis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NR1H2

involved_in

GO:0090340: positive regulation of secretion of lysosomal enzymes

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NR1H2

involved_in

GO:0090187: positive regulation of pancreatic juice secretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NR1H3

involved_in

GO:0090188: negative regulation of pancreatic juice secretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NR1H3

involved_in

GO:0055088: lipid homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NR1H3

involved_in

GO:0045861: negative regulation of proteolysis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NR1H3

involved_in

GO:0090341: negative regulation of secretion of lysosomal enzymes

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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