Apolipoprotein A-IV is regulated by nutritional and metabolic stress: involvement of glucocorticoids, HNF-4 alpha, and PGC-1 alpha.
Apolipoprotein A-IV (apoA-IV) is a 46 kDa glycoprotein that associates with triglyceride-rich and high density lipoproteins. Blood levels of apoA-IV generally correlate with triglyceride levels and are increased in diabetic patients. This study investigated the mechanisms regulating the in vivo expression of apoA-IV in the liver and intestine of mice in response to changes in nutritional status. Fasting markedly increased liver and ileal apoA-IV mRNA and plasma protein concentrations. This induction was associated with increased serum glucocorticoid levels and was abolished by adrenalectomy. Treatment with dexamethasone increased apoA-IV expression in adrenalectomized mice. Marked increases of apoA-IV expression were also observed in two murine models of diabetes. Reporter gene analysis of the murine and human apoA-IV/C-III promoters revealed a conserved cooperative activation by the hepatic nuclear factor-4 alpha (HNF-4 alpha) and the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) but no evidence of a direct regulatory role for the glucocorticoid receptor. Consistent with these in vitro data, induction of apoA-IV in response to fasting was accompanied by increases in HNF-4 alpha and PGC-1 alpha expression and was abolished in liver-specific HNF-4 alpha-deficient mice. Together, these results indicate that the induction of apoA-IV expression in fasting and diabetes likely involves PGC-1 alpha-mediated coactivation of HNF-4 alpha in addition to glucocorticoid-dependent actions.
Hanniman
Elyhisha A
EA
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Lambert
Gilles
G
Inoue
Yusuke
Y
Gonzalez
Frank J
FJ
Sinal
Christopher J
CJ
D000305:Adrenal Cortex Hormones / Q000378:metabolism; D000818:Animals; D001054:Apolipoproteins A / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D005938:Glucocorticoids / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D051557:Hepatocyte Nuclear Factor 4 / Q000096:biosynthesis*; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D051381:Rats; D015534:Trans-Activators / Q000096:biosynthesis*; D014157:Transcription Factors / Q000096:biosynthesis*
D000305:Adrenal Cortex Hormones; D001054:Apolipoproteins A; D005938:Glucocorticoids; D006360:Heat-Shock Proteins; D051557:Hepatocyte Nuclear Factor 4; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C022205:apolipoprotein A-IV