1. Nat. Rev. Endocrinol. doi:10.1038/nrendo.2017.91
Figure 3 Nutritional and growth signalling to sterol regulatory element-binding proteins
Figure 3 | Nutritional and growth signalling to sterol regulatory element-binding proteins. Anabolic states activate sterol regulatory element-binding protein (SREBP)-mediated lipogenesis. As nutritional and growth signals, insulin and growth factors such as epidermal growth factor (EGF) signal via the PI3K–AKT pathway and further link to the mechanistic target of rapamycin (mTOR) pathway, which leads to SREBP activation. AKT is also phosphorylated and activated by mTOR complex 2 (mTORC2). Many branches of the PI3K–AKT–mTORC1 pathway link to SREBP activation or regulatory processes, which include transcription of SREBP genes (SREBF); SREBP mRNA stability; translation to a SREBP precursor form in the endoplasmic reticulum (ER); retention by insulin-induced gene proteins (INSIGs); translocation of SREBPs to the Golgi membrane escorted by SREBP cleavage-activating protein (SCAP) via COPII vesicle proteins; cleavage into active SREBPs by site 1 protease (SIP) and S2P at the Golgi membrane and, ultimately, nuclear entry and binding and transactivation of target gene promoters. mTORC1 functions as the metabolic integrator of nutritional, energy and redox states by regulating protein synthesis. mTOR signalling branches to SREBP1 and lipogenesis via ribosomal protein S6 kinase (S6K), phosphatidate phosphatase lipin-1, CREB-regulated transcription coactivator 2 (CRTC2) and E4 promoter-binding protein 4 (E4BP4). Amino acids and energy hub molecules also influence mTOR–SREBP pathways. Other nutrients, liver X receptor (LXR) and atypical protein kinase C (PKC) isoforms (λ, ζ and β) activate the SREBP1c promoter for nutritional regulation. Signals involved in energy depletion, such as cAMP–protein kinase A (PKA), 5′-AMP-activated protein kinase (AMPK) and sirtuins, generally inhibit SREBP1c expression. Polyunsaturated fatty acids (PUFAs) suppress SREBP1c at multiple levels including its expression and cleavage. Black arrowsand T-bars denote stimulatory and inhibitory actions, respectively.
Shimano, H. & Sato, R. (2017) SREBP-regulated lipid metabolism: convergent physiology — divergent pathophysiology
Nat. Rev. Endocrinol. doi: /nrendo