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Research Article

CFTR KNOCKDOWN STIMULATES LIPID SYNTHESIS AND TRANSPORT IN INTESTINAL CACO-2/15 CELLS

¹Université de Montréal ²Université de Montreal ³Research Centre hospitalier de l'Université de Montréal (CHUM) - Hôtel-Dieu ⁴CHU Sainte-Justine

Submitted 1 June 2009 ; revision received 9 September 2009 ; accepted in final form 17 September 2009

ABSTRACT

Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel highly expressed in epithelial cells of the gastrointestinal tract. Mutations in the CFTR gene cause cystic fibrosis (CF), a disease characterized by pancreatic insufficiency, fat malabsorption and steatorrhea. Despite the administration of pancreatic enzymes to normalize malabsorption, CF patients still experienced lipid fecal loss, nutritional deficiencies and abnormalities in serum lipid profile suggesting the presence of intrinsic defects in the intestinal handling of nutrients. The objective of the present study was to assess the impact of CFTR gene knockdown on intracellular lipid metabolism of the intestinal Caco-2/15 cell line. Partial CFTR gene inactivation led to cellular lipid accretion of phospholipids, triglycerides and cholesteryl esters. Likewise, secretion of these lipid fractions was significantly increased following CFTR gene manipulation. As expected from these findings, the output of TG-rich lipoproteins showed the same increasing pattern. Investigation of the mechanisms underlying these changes revealed that CFTR knockdown resulted in raised levels of apolipoproteins in cells and media and microsomal transfer protein (MTP) activity, two important factors for the efficient assembly and secretion of lipoproteins. Similarly, scrutiny of the enzymatic MGAT and DGAT, which exhibit dynamic function in triacylglycerol resynthesis and chylomicron formation in enterocytes, revealed a significant augmentation in their activity. Conversely, cholesterol uptake mediated by Niemann-Pick C1 like 1, Scavenger Receptor Class B Type I and ATP-binding cassette G8 remains unaffected by genetic modification of CFTR. Collectively, these results highlight the role played by CFTR in intestinal handling of lipids and may suggest that factors other than defective CFTR are responsible for the abnormal intracellular events leading to fat malabsorption in CF patients.

Intestinal fat absorption; lipids; lipoproteins; apolipoproteins