Figure 4.

De novo lipogenesis drives both VLDL secretion and liver steatosis. Hepatic expression of the DNL enzymes depends on nutritional state. After food intake, increased glucose metabolism and elevated insulin signaling increase the activity of the transcription factors ChREBP and SREBP1, respectively. Under conditions of chronic energy excess and hyperinsulinemia prevalent in MAFLD, both lipogenic transcription factors and thus de novo lipogenesis are constantly active, which leads to elevated triglyceride synthesis from saturated fatty acids (SAFA) and monounsaturated fatty acids (MUFA). Stearoyl-CoA desaturase (SCD) catalyzes the generation of MUFA-CoA that are efficiently incorporated into triglycerides via diacylglycerol acyl transferase-2 (DGAT2) that directly associates with SCD. Of note, induction of SCD was observed to go along with increased VLDL secretion, and ChREBP promotes expression of proteins important for VLDL assembly (MTTP, TM6SF2). Together these findings indicate a strong link of DNL to VLDL secretion and dyslipidemia.