Improved metabolic control by depletion of Liver X Receptors in mice.

Liver X Receptors (LXRs) coordinate the regulation of lipid and carbohydrate metabolism and insulin signaling. LXR-ligands lower plasma glucose in hyperglycemic rodents and have consequently been proposed as anti-diabetic agents. We investigated the metabolic effects induced by high carbohydrate diet in LXRalpha(-/-)beta(-/-) mice. Irrespective of diets, LXRalpha(-/-)beta(-/-) mice had reduced fatty acid, insulin, and C-peptide plasma levels than wild-type controls, suggesting a lower insulin production. High carbohydrate diet decreased the plasma glucose levels and the homeostasis model assessment (HOMA)-index in LXRalpha(-/-)beta(-/-) mice and increased hepatic triglyceride content and mRNA levels of lipogenic genes in wild-type and LXRalpha(-/-)beta(-/-) mice, proportionally. In wild-type mice high carbohydrate diet was associated with induced expression of LXR (1.5-fold), despite unchanged SREBP-1c expression. LXRalpha(-/-)beta(-/-) mice responded to this diet by induction of SREBP-1c. Our study suggests that in LXRalpha(-/-)beta(-/-) mice, glucose utilization seems to be privileged possibly due to reduced circulating free fatty acid levels.

Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol transport in euthyroid mice.

Thyroid hormones [predominantly 3,5,3'-triiodo-L-thyronine (T3)] regulate cholesterol and lipoprotein metabolism, but cardiac effects restrict their use as hypolipidemic drugs. T3 binds to thyroid hormone receptors (TRs) alpha and beta. TRbeta is the predominant isoform in liver, whereas T3 effects on heart rate are mediated mostly by TRalpha. Drugs that target TRbeta or exhibit tissue-selective uptake may improve plasma lipid levels while sparing the heart. Here, we asked how the TRbeta- and liver uptake-selective agonist GC-1 influences cholesterol and triglyceride metabolism in euthyroid mice. GC-1 treatment reduced serum cholesterol levels by 25% and serum triglycerides by 75% in chow-fed mice and also attenuated diet-induced hypercholesterolemia. GC-1 reduced plasma high-density lipoprotein cholesterol levels; increased expression of the hepatic high-density lipoprotein receptor, SR-BI; stimulated activity of cholesterol 7alpha-hydroxylase; and increased fecal excretion of bile acids. Collectively, these results suggest that GC-1 stimulates important steps in reverse cholesterol transport. Use of TRbeta and uptake selective agonists such as GC-1 should be further explored as a strategy to improve lipid metabolism in dyslipoproteinemia.

LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver.

Metabolic transformation by the superfamily of cytochromes P450 (CYPs) plays an important role in the detoxification of xenobiotics such as drugs, environmental pollutants, and food additives. Endogenous substrates of CYPs include fatty acids, sterols, steroids, and bile acids. Induction of CYPs via transcriptional activation by substrates and other xenobiotics is an important adaptive mechanism that increases the organism's defense capability against toxicity. Numerous in vivo and in vitro data have highlighted the concept that the molecular mechanism of hepatic drug induction is linked to endogenous regulatory pathways. In particular, in vitro data suggest that oxysterols via the liver X receptor (LXR) inhibit phenobarbital (PB)-mediated induction of CYPs. To study the link between LXR, cholesterol homeostasis, and drug induction in vivo, we designed experiments in wild-type, LXRalpha-, LXRbeta-, and LXRalpha/beta-deficient mice. Our data expose differential regulatory patterns for Cyp2b10 and Cyp3a11 dependent on the expression of LXR isoforms and on challenge of cholesterol homeostasis by excess dietary cholesterol. Our results suggest that, in the mouse, liver cholesterol status significantly alters the pattern of expression of Cyp3a11, whereas the absence of LXR leads to an increase in PB-mediated activation of Cyp2b10.

The liver X receptor-{beta} is essential for maintaining cholesterol homeostasis in the testis.

The liver X receptor (LXR)alpha and -beta has been found to play a central role in maintaining cellular cholesterol homeostasis. In this study we comprehensively investigated the effect of deleting LXRalpha and -beta on testicular morphology and function. In the absence of LXRbeta, excessive cholesterol accumulated in the Sertoli cells from 2.5 months, resulting in severe cellular disruption and dysregulation of spermatogenesis by 10 months of age. This correlated with gene expression analyses that clearly indicated that LXRbeta was the dominant transcript in the testis Although the LXRalpha(-/-) testis was normal, the LXRalpha(-/-)beta(-/-) testis presented with a more severe phenotype than the LXRbeta(-/-) mice, and males were infertile by 4 months of age, indicating LXRalpha may partially rescue the testicular phenotype. Although Leydig cells did not accumulate excessive cholesterol, declining serum and intratesticular androgen levels with age suggested that these cells were in fact less functional. Treatment of a Sertoli cell line with the LXR agonist T0901317 led to increased expression of known LXR target genes like ATP binding cassette-G1 and sterol regulatory binding protein-1c; similar results were observed in wild-type testis after in vivo administration, suggesting the LXR is functioning in the same way as in other tissues. Ordinarily increased levels of cholesterol activate intracellular sensors to decrease these levels; however, the increasing amount of cholesterol in the Sertoli cells indicates improper control of cholesterol metabolism when LXRbeta is absent. Although the precise molecular mechanism at this time remains unclear, our study highlights the crucial role for LXRbeta in retaining cholesterol homeostasis in Sertoli cells.