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1721-P: In Vivo Effect of Perturbations in Hepatic Insulin Signaling on the Synthesis and Export of De Novo Synthesized Fatty Acids and Triglycerides

Hepatic lipid synthesis and Vldl production plays a major role in whole body lipid homeostasis. Insulin imposed regulation of liver metabolism is in large part executed on a transcriptional level. Several published studies focused on the effect of hepatic insulin resistance and the role of mTORC1 in liver lipid metabolism, sometimes with conflicting results. Here we used mouse genetic models with short-term liver specific removal of the insulin receptor (complete signaling pathway inactivation), Tsc1 (mTORC1 activation), Raptor (mTORC1 inactivation), Pten (simultaneous mTORC1 and Akt activation), and Raptor Pten (simultaneous mTORC1 inactivation and Akt activation) to precisely dissect the role of insulin signaling in the regulation of lipid metabolism. In vivo 2H2O administration, 1H and 2H NMR analyses revealed hepatic de novo fatty acid (FA) and triglyceride (TG) synthesis, export, as well as FA profiles both in liver and plasma. By direct examination of in vivo hepatic de novo lipogenesis (DNL), the direction and magnitude of changes observed in lipogenic gene expression did not correlate well with differences observed in DNL flux. For example, PtenLKO mice had a 3-fold increase in DNL flux with little effect on lipogenic gene expression. Our results suggest that in some contexts other factors, possibly including metabolite availability, TCA cycle metabolism, redox state or energy charge impose stronger control over DNL than regulation of gene expression. We also show that triglyceride synthesis and incorporation of de novo synthesized FA into triglycerides is regulated by mTORC1. While mTORC1 positively regulates export of newly synthesized TG it has a negative effect on export of de novo produced FA. Disclosure B. Kucejova: None. S. Deja: None. J. Duarte: None. X. Fu: None. S.C. Burgess: None. Funding National Institutes of Health (R01DK078184)