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. 2019 Aug 8;4(15):e129397. doi: 10.1172/jci.insight.129397

Figure 6. Model for mTORC1-mediated compensation of obstructed AT lipogenesis.

Figure 6

Insig1 overexpression results in general suppression of lipogenic gene expression, including that of the citrate transporter (CiC). Diminished efflux of citrate from the mitochondria results in a “backup” of the TCA cycle and mitochondrial ROS production, as citrate carbons are abruptly diverted into the TCA cycle for ATP production instead of lipogenesis. ROS activates mTORC1, which stimulates both SREBP1 transcription and the processing of SREBP1 into its nuclear/active from. High levels of glycolytic intermediates may also stimulate ChREBP activity. The consequence is restoration of lipogenic gene expression. This mechanism of compensation is transient, but chronic compensation is maintained by greater uptake of fructose via GLUT5. Both acute and chronic compensation is dependent on DNL substrate availability.