• 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • AKT the major isoform of AKT


    AKT2, the major isoform of AKT expressed in livers mediating lipogenesis by the stimulation of de novo lipogenesis. Recent reports have found that AKT2 is required for hepatic lipid accumulation in models of insulin resistance [34]. Rapamycin selectively activates the AKT2 isoform in vascular smooth muscle Rottlerin [48]. In the present study, we show that hepatic AKT2 expression is decreased dramatically in RYGB-operated mice. Inhibition of mTOR signaling by rapamycin markedly increased but infusion of Ad-S6K1 decreased AKT2 in liver. Rapamycin also stimulated AKT2 in primary mouse hepatocytes. Therefore, hepatic mTOR contributes to the modulation of lipogenic genes and de novo lipogenesis. In sum, RYGB ameliorates hepatic steatosis induced by high-fat diet and rapamycin through mTOR-AKT2 signaling pathway. mTOR nucleates at least two distinct multi-protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Hagiwara et al. report that mTORC2-AKT signaling promotes hepatic de novo lipogenesis [49]. It is worth of noting that mTORC2-AKT signaling pathway may involve the effects of RYGB surgery on NAFLD. Further studies on mTORC2-AKT signaling pathways will address this potential. According to Jessica's study, AKT2 is responsible for Insig2a suppression, leading to up-regulating of SREBP1c and lipogenesis in liver [44]. In present study, RYGB promoted Insig2a expression, while inhibited SREBP1c. In contrast with RYGB, rapamycin decreased Insig2a expression. Tail-vein injection of Ad-S6K1 significantly enhanced Insig2a, thus inhibited SREBP1c. Increased hepatic phosphorylation of AKT is associated with the amelioration of steatosis in diabetic mice [50]. As expected, both RYGB and Ad-S6K1 treated livers exhibited elevated phosphorylation of AKT at Ser473. Hepatic pAKT473 was inhibited by rapamycin, which was blocked by RYGB operation. Akt-mediated phosphorylation and inhibition of GSK3 stimulates glycogen synthesis and promotes SREBP stability thus enhances lipid production [51]. The mRNA levels of GSK3β showed a substantial decrease after RYGB in subjects and rats [52,53]. Our study found RYGB significantly promoted the phosphorylation of AKT at Ser473 and GSK3β, while the expression of SREBP1c is down-regulated in RYGB-operated mice. It suggests that AKT2-Insig2 signaling but not AKT-GSK3β-SREBP contributes to the improvement of hepatic steatosis after Roux-en-Y Gastric Bypass in mice. Rapamycin is commonly used as an immunosuppressant following renal transplant, and more recently, its analogs have gained FDA approval for use in human tumors such as renal cell carcinoma and subependymal giant cell astrocytoma [54]. Posttransplantation diabetes is very common [55], it is conceivable that in this clinical setting, rapamycin adversely affects a preexisting metabolic syndrome and is toxic to endogenous or transplanted pancreatic islets [56]. Reports of rapamycin-induced numerous features of the metabolic syndrome including hyperlipidemia, hypercholesterolemia, and insulin resistance in humans and in mice [[57], [58], [59]] are consistent with our observations. Chronic rapamycin treatment increased hepatic lipid deposition and plasma triglyceride level measured by oil-red staining and enzymatic assay kits in mice fed HFD. Considerable studies have showed that RYGB is associated with marked improvement in NAFLD induced by high-fat diet, our current study showed that RYGB also contributes to the improvement of rapamycin-induced steatosis. Stimulation of hepatic mTOR activity may therefore provide a potential therapeutic strategy for deteriorated lipid metabolism associated with rapamycin treatment after transplantation. The mechanism by which stimulation of mTOR generate an decrease in lipogenesis involves a multitude of factors that includes AKT2, Insig2a, SREBP1c and PPARγ that interplay with each other to regulate the lipogenic gene program. In summary, our studies demonstrate that RYGB alters mTOR-AKT2-Insig2 signaling activity in liver and mTOR signaling is necessary to the amelioration of NAFLD by down-regulating de novo lipid synthesis (Fig. 9). Furthermore, high-fat diet-induced and rapamycin-induced steatosis could be reversed by RYGB in mice. Hepatic mTOR signaling may represent a novel mechanism responsible for the metabolic benefit of RYGB on NAFLD, thus providing a potential target for the therapy of NAFLD by “pharmaceutical gastric bypass”.