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- W4579886 abstract "We are interested in the mechanisms whereby the body senses its nutrient environment and responds to adapt cellular and organismal metabolism to this changing environment. One maladaptive response to excess feeding is excess fat storage driven by the Sterol Response Element Binding Protein-1c (SREBP-1c) transcription factor. SREBP-1c is activated at multiple levels in response to insulin signaling and stimulates the expression of the entire de novo lipogenesis and triglyceride biosynthesis program. The signaling pathway whereby insulin stimulates SREBP-1c activity includes the canonical PI3K-Akt module, but has recently been shown to also depend on the Akt-dependent activation of the mTOR Complex 1 (mTORC1). We have recently characterized a novel component of this pathway that sheds additional light on how feeding-induced lipogenesis is controlled. PAS kinase (PASK) is a highly evolutionarily conserved protein kinase that we have shown to be metabolically regulated and to control glucose-responsive processes in pancreatic beta-cells. A mouse lacking PASK, in addition to modest beta-cell defects, has a profound resistance to the pathological effects of a high-fat diet. Specifically, PASK−/− mice are protected from the obesity, insulin resistance and dyslipidemia observed in wild-type mice on a high-fat diet. The most striking effect that we observed was a loss of the massive hepatic lipid accumulation that occurs on a high-fat diet. This was accompanied by decreased expression of many of the genes that promote lipid uptake and synthesis in the liver. We demonstrated that PASK strongly regulates SREBP-1c in cultured cells using a combination of loss-of-function and gain-of-function approaches and genetics, cell biology and biochemistry. Based on these observations in vitro, we went back to the mouse model and showed that, indeed, the entirety of the SREBP-1c transcriptional program was decreased in PASK−/− mice. Our preliminary data suggests that PASK regulates SREBP-1c at the level of proteolytic maturation. In parallel, we observed that PASK was strongly activated post-translationally by insulin and that mTORC1 activation was necessary and sufficient for this effect. The current evidence suggests that mTORC1 activates PASK through direct interaction with and phosphorylation. Having found that insulin/mTORC1 activates PASK and PASK activates SREBP-1c, we then tested whether PASK is a required mediator of the acute insulin/mTORC1 effects on SREBP-1c and found that it is. My laboratory is now focused on understanding the mTORC1-PASK-SREBP-1c pathway, both the mechanisms of signal transduction and the physiological importance of this pathway." @default.
- W4579886 created "2016-06-24" @default.
- W4579886 creator A5063404794 @default.
- W4579886 date "2012-04-01" @default.
- W4579886 modified "2023-10-16" @default.
- W4579886 title "Hormonal and cellular control of hepatic lipid metabolism" @default.
- W4579886 doi "https://doi.org/10.1096/fasebj.26.1_supplement.231.1" @default.
- W4579886 hasPublicationYear "2012" @default.
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