Abstract
BackgroundRecent studies have indicated that low serum testosterone levels are associated with increased risk of developing hepatic steatosis; however, the mechanisms mediating this phenomenon have not been fully elucidated. To gain insight into the role of testosterone in modulating hepatic steatosis, we investigated the effects of testosterone on the development of hepatic steatosis in pigs fed a high-fat and high-cholesterol (HFC) diet and profiled hepatic gene expression by RNA-Seq in HFC-fed intact male pigs (IM), castrated male pigs (CM), and castrated male pigs with testosterone replacement (CMT).ResultsSerum testosterone levels were significantly decreased in CM pigs, and testosterone replacement attenuated castration-induced testosterone deficiency. CM pigs showed increased liver injury accompanied by increased hepatocellular steatosis, inflammation, and elevated serum alanine aminotransferase levels compared with IM pigs. Moreover, serum levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides were markedly increased in CM pigs. Testosterone replacement decreased serum and hepatic lipid levels and improved liver injury in CM pigs. Compared to IM and CMT pigs, CM pigs had lower serum levels of superoxide dismutase but higher levels of malondialdehyde. Gene expression analysis revealed that upregulated genes in the livers of CM pigs were mainly enriched for genes mediating immune and inflammatory responses, oxidative stress, and apoptosis. Surprisingly, the downregulated genes mainly included those that regulate metabolism-related processes, including fatty acid oxidation, steroid biosynthesis, cholesterol and bile acid metabolism, and glucose metabolism. KEGG analysis showed that metabolic pathways, fatty acid degradation, pyruvate metabolism, the tricarboxylic acid cycle, and the nuclear factor-kappaB signaling pathway were the major pathways altered in CM pigs.ConclusionsThis study demonstrated that testosterone deficiency aggravated hypercholesterolemia and hepatic steatosis in pigs fed an HFC diet and that these effects could be reversed by testosterone replacement therapy. Impaired metabolic processes, enhanced immune and inflammatory responses, oxidative stress, and apoptosis may contribute to the increased hepatic steatosis induced by testosterone deficiency and an HFC diet. These results deepened our understanding of the molecular mechanisms of testosterone deficiency-induced hepatic steatosis and provided a foundation for future investigations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1283-0) contains supplementary material, which is available to authorized users.
Highlights
Recent studies have indicated that low serum testosterone levels are associated with increased risk of developing hepatic steatosis; the mechanisms mediating this phenomenon have not been fully elucidated
Body weights and serum testosterone levels Pigs were separated into three groups: intact male pigs fed a high-fat and high-cholesterol (HFC) diet (IM); castrated male pigs fed an High-fat and high-cholesterol (HFC) diet (CM); and castrated male pigs fed an HFC diet and given testosterone replacement therapy (CMT)
We found that testosterone deficiency did not affect serum fasting glucose and insulin levels or homeostatic model assessment of insulin resistance (HOMA-IR) in CM pigs compared to IM pigs
Summary
Recent studies have indicated that low serum testosterone levels are associated with increased risk of developing hepatic steatosis; the mechanisms mediating this phenomenon have not been fully elucidated. Recent studies have shown that men with low serum testosterone levels have a higher risk of developing hepatic steatosis [3,4,5]. Animal studies have demonstrated that the incidence of hepatic steatosis is increased in testosterone-deficient male mice [6,7]. These findings indicate the important role of testosterone in the pathophysiology of NAFLD. The mechanisms underlying the effects of testosterone deficiency on the promotion of diet-induced hepatic steatosis remain unclear
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