sirolimus and Lipid-Metabolism-Disorders

The incident of lipid metabolism disorders has obviously increased under the undue pursuit of efficiency, which had seriously threatened to the health development of poultry industry. As an important cholesterol-derived intermediate, though dehydroepiandrosterone (DHEA) has the fat-reduction effect in animals and humans, but the underlying mechanism still poorly understood. Herein, the present study aimed to investigate the regulatory effects and its molecular mechanism of DHEA on disturbance of lipid metabolism induced by oleic acid (OA) in primary chicken hepatocytes. The hepatocytes were treated with 0, 0.1, 1, 10 μM DHEA for 4 h, and then supplemented with 0 or 0.5 mM OA stimulation for another 24 h. Our findings demonstrated that DHEA treatment effectively reduced TG content and alleviated lipid droplet deposition in OA-induced hepatocytes. DHEA inhibited the lipogenesis related factors (ACC, FAS, SREBP-1c, and ACLY) mRNA level and increased the lipolysis key factors (CPT-1 and PPARα) mRNA levels. In addition, DHEA obviously elevated the protein levels of CPT-1A, p-ACC, and ECHS1; whereas decreased the protein levels of FAS and SREBP-1 in hepatocytes stimulated by OA. Furthermore, DHEA promoted the phosphorylation of AMP-activated protein kinase (AMPK) and inhibited the phosphorylation of mammalian target of rapamycin (mTOR). Mechanistically, the hepatocytes were pre-treated with AMPK inhibitor compound C or AMPK activator AICAR before addition of DHEA treatment, and the results certified that DHEA activated cAMP/AMPK pathway and which subsequently led the inhibition of mTOR signal, which finally reduced the fat excessive accumulation in OA-stimulated hepatocytes. Collectively, our study unveiled that DHEA protects against the lipid metabolism disorders triggered by OA stimulation through activation of AMPK-mTOR signaling pathway, which prompts the value of DHEA as a potential nutritional supplement in regulating the lipid metabolism and its related disease in poultry.

Topics: AMP-Activated Protein Kinases; Animals; Chickens; Dehydroepiandrosterone; Hepatocytes; Lipid Metabolism; Lipid Metabolism Disorders; Mammals; Oleic Acid; RNA, Messenger; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Rapamycin is a crucial immunosuppressive regimen for patients that have undergone liver transplantation (LT). However, one of the major side effects of rapamycin include metabolic disorders such as dyslipidemia, and the mechanism remains unknown. This study aims to explore the biomolecules that are responsible for rapamycin-induced dyslipidemia and the control strategies that can reverse the lipid metabolism disorder. In this study, data collected from LT patients, cell and mouse models treated with rapamycin were analyzed. Results showed an increase of triglycerides (TGs) induced by rapamycin. MicroRNAs (miRNAs) play important roles in many vital biological processes including TG metabolism. hsa-miR-372-3p was filtered using RNA sequencing and identified as a key regulator in rapamycin-induced TGs accumulation. Using bioinformatics and experimental analyses, target genes of hsa-miR-372-3p were predicted. These genes were alkylglycerone phosphate synthase (AGPS) and apolipoprotein C4 (APOC4), which are reported to be involved in TG metabolism. LncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) was also identified as an upstream regulatory factor of hsa-miR-372-3p. From the results of this study, NEAT1/hsa-miR-372-3p/AGPS/APOC4 axis plays a vital role in rapamycin-disruption of lipid homeostasis. Therefore, targeting this axis is a potential therapeutic target combating rapamycin-induced dyslipidemia after LT.

Topics: Animals; Humans; Lipid Metabolism Disorders; Lipids; Mice; MicroRNAs; Sirolimus