Liver lipid metabolism is altered by increased circulating estrogen to androgen ratio in male mouse.

Estrogens are suggested to lower the risk of developing metabolic syndrome in both sexes. In this study, we investigated how the increased circulating estrogen-to-androgen ratio (E/A) alters liver lipid metabolism in males. The cytochrome P450 aromatase (P450arom) is an enzyme converting androgens to estrogens. Male mice overexpressing human aromatase enzyme (AROM+ mice), and thus have high circulating E/A, were used as a model in this study. Proteomics and gene expression analyses indicated an increase in the peroxisomal β-oxidation in the liver of AROM+ mice as compared with their wild type littermates. Correspondingly, metabolomic analysis revealed a decrease in the amount of phosphatidylcholines with long-chain fatty acids in the plasma. With interest we noted that the expression of Cyp4a12a enzyme, which specifically metabolizes arachidonic acid (AA) to 20-hydroxy AA, was dramatically decreased in the AROM+ liver. As a consequence, increased amounts of phospholipids having AA as a fatty acid tail were detected in the plasma of the AROM+ mice. Overall, these observations demonstrate that high circulating E/A in males is linked to indicators of higher peroxisomal β-oxidation and lower AA metabolism in the liver. Furthermore, the plasma phospholipid profile reflects the changes in the liver lipid metabolism. BIOLOGICAL SIGNIFICANCE: The role of sex steroid hormones in the development of metabolic diseases is a topical issue. Lipid metabolism in both sexes supposedly benefits from estrogens, and low circulating estrogen to androgen ratio has been shown to lead to liver steatosis in males. However, there are no comprehensive studies showing the effects of sex steroid hormones on the expression of genes regulating liver lipid metabolism on both mRNA and protein levels. In this study a combination of quantitative MS-based proteome measurements and mRNA microarray both consistently indicated a set of genes that are deregulated in the liver of male mice having high circulating E/A. Interestingly, the results of targeted profiling of phospholipids in the plasma by LC-MS/MS were in line with the mRNA and protein measurements carried out in the liver, suggesting that plasma phospholipid profile could be used as an indicator of altered liver lipid metabolism