title: Circadian regulation of intestinal lipid absorption by apolipoprotein AIV involves forkhead transcription factors A2 and O1 and microsomal triglyceride transfer protein.
abstract: We have shown previously that Clock, microsomal triglyceride transfer protein (MTP), and nocturnin are involved in the circadian regulation of intestinal lipid absorption. Here, we clarified the role of apolipoprotein AIV (apoAIV) in the diurnal regulation of plasma lipids and intestinal lipid absorption in mice. Plasma triglyceride in apoAIV(-/-) mice showed diurnal variations similar to apoAIV(+/+) mice; however, the increases in plasma triglyceride at night were significantly lower in these mice. ApoAIV(-/-) mice absorbed fewer lipids at night and showed blunted response to daytime feeding. To explain reasons for these lower responses, we measured MTP expression; intestinal MTP was low at night, and its induction after food entrainment was less in apoAIV(-/-) mice. Conversely, apoAIV overexpression increased MTP mRNA in hepatoma cells, indicating transcriptional regulation. Mechanistic studies revealed that sequences between -204/-775 bp in the MTP promoter respond to apoAIV and that apoAIV enhances expression of FoxA2 and FoxO1 transcription factors and their binding to the identified cis elements in the MTP promoter at night. Knockdown of FoxA2 and FoxO1 abolished apoAIV-mediated MTP induction. Similarly, knockdown of apoAIV in differentiated Caco-2 cells reduced MTP, FoxA2, and FoxO1 mRNA levels, cellular MTP activity, and media apoB. Moreover, FoxA2 and FoxO1 expression showed diurnal variations, and their expression was significantly lower in apoAIV(-/-) mice. These data indicate that apoAIV modulates diurnal changes in lipid absorption by regulating forkhead transcription factors and MTP and that inhibition of apoAIV expression might reduce plasma lipids.
authors.affiliation: Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York 11203, USA. xiaoyue.pan@downstate.edu
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Pan
authors.forename: Mohamed Khalid
authors.initials: MK
authors.lastname: Munshi
authors.forename: Jahangir
authors.initials: J
authors.lastname: Iqbal
authors.forename: Joyce
authors.initials: J
authors.lastname: Queiroz
authors.forename: Alaa Ahmed
authors.initials: AA
authors.lastname: Sirwi
authors.forename: Shrenik
authors.initials: S
authors.lastname: Shah
authors.forename: Abdullah
authors.initials: A
authors.lastname: Younus
authors.forename: M Mahmood
authors.initials: MM
authors.lastname: Hussain
mesh_terms: D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002940:Circadian Rhythm; D004435:Eating; D020895:Enterocytes / Q000378:metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption; D008055:Lipids / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001054:Apolipoproteins A; D002352:Carrier Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C496503:Foxa2 protein, mouse; C467200:Foxo1 protein, mouse; D008055:Lipids; C022205:apolipoprotein A-IV; C106092:microsomal triglyceride transfer protein; D051542:Hepatocyte Nuclear Factor 3-beta
keywords: Apolipoproteins; Intestine; Lipid Absorption; Transcription Factors; Triglyceride