The S6K-independent pathway involves the mTORC1 substrate phosphatidic acid phosphatase

lipin-1, a negative regulator of SREBP-1 activity [ 77•]. In response to nutrients and growth factors, mTORC1 directly phosphorylates lipin-1. This prevents translocation of lipin-1 into the nucleus, thereby allowing SREBP transcriptional activity. Although it is well established that mTORC1 is required to activate SREBP-1 and lipid synthesis in cultured cells, GDC-0199 clinical trial the role of mTORC1 in lipogenesis in vivo is less clear. Liver-specific mTORC1 deficient (raptor knockout) mice display decreased hepatic triglyceride content and a reduction in plasma cholesterol levels only when fed a high fat diet [ 77•]. Thus, mTORC1 signaling appears to be necessary for hepatic triglyceride accumulation in vivo only under pathological conditions. Patients with type 2 diabetes exhibit ‘selective hepatic insulin resistance’. This is a state in which insulin fails to inhibit hepatic

glucose production yet paradoxically maintains lipogenesis, resulting in hyperglycemia and hyperlipidemia [78]. However, humans with mutations in the insulin receptor gene or liver-specific AZD1208 molecular weight insulin receptor knockout mice exhibit hyperglycemia and hypolipidemia — a state referred to as ‘total hepatic insulin resistance’ in which insulin is unable to suppress hepatic glucose production or to stimulate lipogenesis [56, 79 and 80]. It was suggested that selective hepatic insulin resistance might be due to nutrient activated

mTORC1 even in the absence of upstream, insulin-stimulated Akt activity [76 and 81]. However, three independent studies have shown that liver-specific tsc1 knockout mice (LTsc1KO), in which mTORC1 L-gulonolactone oxidase is ectopically activated, are protected against age-induced and diet-induced hepatic steatosis [ 69••, 70•• and 82••]. Yecies et al. [ 70••] demonstrated that protection against hepatic lipid accumulation in LTsc1KO mice is due to attenuation of Akt signaling, as restoration of Akt2 (the main hepatic isoform of Akt) signaling restores lipogenesis. This suggests that Akt and mTORC1 are independently necessary for lipogenesis. Decreased Akt signaling in LTsc1KO mice is due to the well-known mTORC1-mediated negative feedback loop [ 70••]. Yecies et al. [ 70••] propose that Akt is required to prevent expression of Insig2a encoding an SREBP inhibitor. mTORC1 is required for a separate step in the activation of SREBP, as described further above. Thus, both Akt and mTORC1 are required for lipogenesis, and the molecular basis of selective hepatic insulin resistance remains to be determined. However, complicating matters, Kenerson et al. [ 69••] reported that mTORC1 is not necessary for hepatic lipid accumulation, since rapamycin treatment fails to prevent high-fat diet or Pten deletion-induced hepatic steatosis. mTORC2 is also insulin-stimulated and is required in the liver for lipid and glucose homeostasis.