Archives

  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • Coelenterazine mTOR signaling pathway has been described to

    2019-07-11

    mTOR signaling pathway has been described to play an important role in lipid biosynthesis [[21], [22], [23], [24]]. This notion has emerged from observations of clinical trials involving rapamycin or rapalog administration. Side effects of these drugs have been reported such as hyperlipidemia and hypercholesterolemia and activation of gluconeogenesis in liver, a major organ for lipid biosynthesis [[25], [26], [27]]. Furthermore, rodents treated with rapamycin and rapalogs develop NAFLD associated with elevated free fatty Coelenterazine levels [28]. Although numerous studies have illustrated the positive effects of RYGB on NAFLD [10,29,30], to the best of our knowledge, the underlying mechanism is unknown. Over the past years, several studies revealed that mTOR plays a crucial role in promoting lipid biosynthesis and that such connection could be linked to diseases including obesity and NAFLD [[31], [32], [33]]. Furthermore, hepatic AKT2 is essential for lipid biosynthesis [34]. We thus hypothesized that mTOR-AKT2 pathway is associated with the improvement effect of RYGB on NAFLD. Here, we present evidence that RYGB ameliorates hepatic steatosis induced by high-fat diet through mTOR-AKT2-Insig2 signaling pathway in mice. In the present study, underlying mechanism of RYGB ameliorating hepatic steatosis caused by high-fat diet was explored to provide a novel insight of medical intervention strategies for NAFLD therapy.
    Materials and methods
    Results
    Discussion Roux-en-Y Gastric Bypass (RYGB) is proven to be a safe and effective treatment of obesity and related co-morbidities including NAFLD [4,9]. RYGB is likely to have potential benefits in ameliorating the factors such as insulin resistance, lipid profile, inflammation, weight loss, and adipokines that contribute in a marked way to the pathogenesis of NAFLD [7]. RYGB protects the liver against HFD-induced fatty liver disease by attenuating ER stress and excess apoptosis [41]. According to Andriy's study, change of serum bile composition is responsible for the suppression of lipogenesis in mice after VSG surgery [42]. Here we show that RYGB resolves steatosis induced by high-fat diet via alteration of hepatic mTOR-AKT2-Insig2 signaling pathway. The inhibition of hepatic AKT2 substantially elicits an improvement in Insig2a and repression of lipogenic genes after RYGB. De novo lipogenesis plays a substantial role in the pathogenesis of NAFLD, accounting for 26% hepatic triglycerides in human subjects [43]. The notion that mTOR promotes lipogenesis and may contribute to NAFLD came from a series of observations showing the positive effects of mTOR on SREBP1c expression and activity that lead to de novo lipid synthesis [17,18,21,24]. In vitro study showed that mTOR signaling pathway promotes de novo lipid synthesis. In isolated rat hepatocytes, insulin-mediated stimulation of SREBP1c processing requires mTOR, which is also required for insulin-mediated SREBP1c mRNA induction [20]. Rapamycin decreased expression of genes encoding acetyl-coenzyme A carboxylase I and mitochondrial glycerol phosphate acyltransferase in isolated hepatocytes [24]. However, mTOR hyperactivity per se does not induce steatosis, but instead, protects against high-fat diet-induced steatosis in mice. Mice with a liver-specific deletion of tuberous sclerosis complex 1 (TSC1) show increased mTOR activity, but have defective SREBP1c activation and lipogenesis due to an attenuation of AKT signaling [44]. Elevated FGF21 expression is considered to explain the improvement of lipid metabolism in liver-specific TSC1 knockout mice [45]. Moreover, plasma FGF21 is significantly increased in post-RYGB subjects [46,47]. Our studies demonstrate for the first time that mTOR signaling in liver is necessary in the process of RYGB reversing high-fat diet and rapamycin-induced steatosis. Hepatic mTOR signaling activity is elevated significantly after RYGB in rodents. Both RYGB and over-expression of S6K1, representing hyperactivation of mTOR signaling, protect the liver against HFD-induced fatty liver disease. Consistently, Ad-S6K1 decreased OA-induced lipid deposition in vitro study. Transcription factors SREBP1C and PPARĪ³, and key enzymes encoded by genes such as ACC and FAS were reduced in response to RYGB or Ad-S6K1.