Soy protein isoflavones differentially regulate liver X receptor isoforms to modulate lipid metabolism and cholesterol transport in the liver and intestine in mice

• Published in: Diabetologia Vol. 55; no. 9; pp. 2469 - 2478
• Main Authors: González-Granillo, M., Steffensen, K. R., Granados, O., Torres, N., Korach-André, M., Ortíz, V., Aguilar-Salinas, C., Jakobsson, T., Díaz-Villaseñor, A., Loza-Valdes, A., Hernandez-Pando, R., Gustafsson, J.-Å., Tovar, A. R.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-09-2012; Springer; Springer Nature B.V
• Subjects: Animals; Bile; Bile Acids and Salts - metabolism; Biological and medical sciences; Biological Transport; Cholesterol; Diabetes. Impaired glucose tolerance; Diet; Diet, High-Fat; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Gene Expression Regulation; Hepatocytes - drug effects; Hepatocytes - metabolism; Human Physiology; Insulin Resistance; Internal Medicine; Intestines - metabolism; Isoflavones - metabolism; Kinases; Lipid Metabolism - drug effects; Lipids; Liver; Liver - metabolism; Liver X Receptors; Male; Medical sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mice, Transgenic; Nutrition research; Orphan Nuclear Receptors - drug effects; Orphan Nuclear Receptors - metabolism; Phosphorylation; Protein Isoforms - metabolism; Proteins; Soybean Proteins - pharmacology; Mexico; Soy protein; Intestine; Liver; LXRα; AMPK; Insulin resistance; Mice; Cholesterol; Isoflavones; LXRβ; Endocrinopathy; Molecular form; Biological transport; Lipids; Biological receptor; Digestive system; Diabetes mellitus; Rodentia; Gut; Metabolic diseases; Metabolism; Protein; Target tissue resistance; Vertebrata; Mammalia; Mouse; Animal
• ISSN: 0012-186X; 1432-0428; 1432-0428
• DOI: 10.1007/s00125-012-2599-9

Aims/hypothesis
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/interpretation
Our results suggest that SP isoflavones stimulate the phosphorylation of LXRα or LXRβ, resulting in different biological effects for each LXR isoform.