Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRβ-deficient mice
S. Alberti, … , S. Pettersson, J.-Å. Gustafsson
S. Alberti, … , S. Pettersson, J.-Å. Gustafsson
Published March 1, 2001
Citation Information: J Clin Invest. 2001;107(5):565-573. https://doi.org/10.1172/JCI9794.
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Article

Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRβ-deficient mice

Abstract

The nuclear oxysterol-receptor paralogues LXRα and LXRβ share a high degree of amino acid identity and bind endogenous oxysterol ligands with similar affinities. While LXRα has been established as an important regulator of cholesterol catabolism in cholesterol-fed mice, little is known about the function of LXRβ in vivo. We have generated mouse lines with targeted disruptions of each of these LXR receptors and have compared their responses to dietary cholesterol. Serum and hepatic cholesterol levels and lipoprotein profiles of cholesterol-fed animals revealed no significant differences between LXRβ–/– and wild-type mice. Steady-state mRNA levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl diphosphate synthase, and squalene synthase were increased in LXRβ–/– mice compared with LXRβ+/+ mice, when fed standard chow. The mRNA levels for cholesterol 7α-hydroxylase, oxysterol 7α-hydroxylase, sterol 12α-hydroxylase, and sterol 27-hydroxylase, respectively, were comparable in these strains, both on standard and 2% cholesterol chow. Our results indicate that LXRβ–/– mice — in contrast to LXRα–/– mice — maintain their resistance to dietary cholesterol, despite subtle effects on the expression of genes coding for enzymes involved in lipid metabolism. Thus, our data indicate that LXRβ has no complete overlapping function compared with LXRα in the liver.

Authors

S. Alberti, G. Schuster, P. Parini, D. Feltkamp, U. Diczfalusy, M. Rudling, B. Angelin, I. Björkhem, S. Pettersson, J.-Å. Gustafsson

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Figure 4

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Serum lipoprotein profiles after separation by FPLC in LXRβ–/– (top) and...
Serum lipoprotein profiles after separation by FPLC in LXRβ–/– (top) and LXRα–/– (bottom) mice. Animals were fed standard rodent diet (left) or challenged with 2% cholesterol (right) for 28 days. Ten microliters of pooled serum from each group was directly separated on a FPLC Superose 6B column. Cholesterol content was determined using the commercially available kit MPR 21442350 (Roche Molecular Biochemicals, Indianapolis, Indiana, USA) that was mixed online with the separated lipoproteins at a flow rate of 40 + 40 μl/min. The mixture was passed over a 37°C reaction coil and adsorbance was monitored every 20 seconds at 500 nm. The adsorbance profiles from two independent analyses are shown in the upper and lower panels.