Figure 7.

DBTD decreases the intracellular TG by promoting fatty acid β oxidation and inhibiting lipogenesis through blocking the mTOR pathway. Fatty acid oxidation is regulated by PPARα. Once activated by their ligands (L), PPARα could dimerize with RXR, recruit coactivators (PGC1α), and release a corepressor (NCoR1) to bind the PPRE of lipolysis genes, such as PPARα, ACOX1, CPT1, and CYP4A11, to activate their transcription. mTORC1 facilitates the accumulation of NCoR1 in the nucleus to depress the transcription of PPARα and inhibit fatty acid oxidation. Lipogenesis are regulated by SREBP1C. In endoplasmic reticulum, the inactive SREBP1C precursor (pre-SREBP1C) binds with SREBP cleavage-activating protein (SCAP) into a complex, which can be cleaved in Golgi to facilitate their entrance into the nucleus. The mature SREBP1C binds to the sterol regulatory elements (SREs) of target genes, such as SREBP1C, SCD1, FASN, and GPAT1. It is required that SREBP1C dimerize with another bHLH protein, such as SREBP1C and upstream stimulatory factor 1 (USF1), to promote transcription of target genes. Rapamycin and DBTD depress the activity of mTORC1, so the transcription of SREBP1C is reduced while the transcription of PPARα is enhanced, which will lead to a TG content decrease.