title: Soy protein isoflavones differentially regulate liver X receptor isoforms to modulate lipid metabolism and cholesterol transport in the liver and intestine in mice.
abstract: OBJECTIVE
  Liver X receptor (LXR)α regulates the genes involved in cholesterol, fatty acid and glucose metabolism. Soy protein (SP) consumption reduces the hepatic accumulation of cholesterol and triacylglycerol, and improves insulin sensitivity. However, it is not known whether these effects are mediated via LXRα. We therefore investigated whether the consumption of SP regulates metabolic changes in cholesterol metabolism and insulin sensitivity via LXRα.
  
  
  METHODS
  Wild-type (WT) and Lxrα(-/-) (Lxrα, also known as Nr1h3) mice were fed an SP diet with or without cholesterol for 28 days. The expression of LXRα target genes was measured in liver and intestine, as were hepatic lipid content and faecal bile acid concentration. Oral glucose and insulin tolerance tests were also performed. Hepatocytes were used to study the effect of isoflavones on LXR activity.
  
  
  RESULTS
  The livers of WT and Lxrα(-/-) mice fed an SP high-cholesterol diet showed less steatosis than those fed casein. The SP diet increased the expression of the ATP-binding cassette (ABC) sub-family genes Abca1, Abcg5 and Abcg8 in the liver and intestine, as well as increasing total faecal bile acid excretion and insulin sensitivity in WT mice compared with mice fed a casein diet. However, these effects of SP were not observed in Lxrα(-/-) mice. The SP isoflavone, genistein, repressed the activation of LXRα target genes by T0901317, whereas it stimulated the activation of LXRβ target genes. The AMP-activated protein kinase inhibitor, compound C, had the opposite effects to those of genistein.
  
  
  CONCLUSIONS
  Our results suggest that SP isoflavones stimulate the phosphorylation of LXRα or LXRβ, resulting in different biological effects for each LXR isoform.
authors: Departamento Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición, Vasco de Quiroga No 15, Tlalpan, México DF 14000, México.
authors: M
authors: M
authors: González-Granillo
authors: K R
authors: KR
authors: Steffensen
authors: O
authors: O
authors: Granados
authors: N
authors: N
authors: Torres
authors: M
authors: M
authors: Korach-André
authors: V
authors: V
authors: Ortíz
authors: C
authors: C
authors: Aguilar-Salinas
authors: T
authors: T
authors: Jakobsson
authors: A
authors: A
authors: Díaz-Villaseñor
authors: A
authors: A
authors: Loza-Valdes
authors: R
authors: R
authors: Hernandez-Pando
authors: J-Å
authors: JÅ
authors: Gustafsson
authors: A R
authors: AR
authors: Tovar
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport; D059305:Diet, High-Fat; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D007333:Insulin Resistance; D007413:Intestinal Mucosa / Q000378:metabolism*; D007529:Isoflavones / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000187:drug effects / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D030262:Soybean Proteins / Q000494:pharmacology*
chemical_list: D001647:Bile Acids and Salts; D007529:Isoflavones; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms; D030262:Soybean Proteins