Livers with Constitutive mTORC1 Activity Resist Steatosis Independent of Feedback Suppression of Akt

<div><p>Insulin resistance is an important contributing factor in non-alcoholic fatty liver disease. AKT and mTORC1 are key components of the insulin pathway, and play a role in promoting <i>de novo</i> lipogenesis. However, mTORC1 hyperactivity <i>per se</i> does not induce steatosis in mouse livers, but instead, protects against high-fat diet induced steatosis. Here, we investigate the <i>in vivo</i> mechanism of steatosis-resistance secondary to mTORC1 activation, with emphasis on the role of S6K1-mediated feedback inhibition of AKT. Mice with single or double deletion of <i>Tsc1</i> and/or <i>S6k1</i> in a liver-specific or whole-body manner were generated to study glucose and hepatic lipid metabolism between the ages of 6–14 weeks. Following 8 weeks of high-fat diet, the <i>Tsc1-/-;S6k1-/-</i> mice had lower body weights but higher liver TG levels compared to that of the <i>Tsc1-/-</i> mice. However, the loss of <i>S6k1</i> did not relieve feedback inhibition of Akt activity in the <i>Tsc1-/-</i> livers. To overcome Akt suppression, <i>Pten</i> was deleted in <i>Tsc1-/-</i> livers, and the resultant mice showed improved glucose tolerance compared with the <i>Tsc1-/-</i> mice. However, liver TG levels were significantly reduced in the <i>Tsc1-/-;Pten-/-</i> mice compared to the <i>Pten-/-</i> mice, which was restored with rapamycin. We found no correlation between liver TG and serum NEFA levels. Expression of lipogenic genes (<i>Srebp1c</i>, <i>Fasn</i>) were elevated in the <i>Tsc1-/-;Pten-/-</i> livers, but this was counter-balanced by an up-regulation of <i>Cpt1a</i> involved in fatty acid oxidation and the anti-oxidant protein, Nrf2. In summary, our <i>in vivo</i> models showed that mTORC1-induced resistance to steatosis was dependent on S6K1 activity, but not secondary to AKT suppression. These findings confirm that AKT and mTORC1 have opposing effects on hepatic lipid metabolism <i>in vivo</i>.</p>