Fig. 6: Proposed molecular mechanism. | Laboratory Investigation

Fig. 6: Proposed molecular mechanism.

From: SIRT6 regulates SREBP1c-induced glucolipid metabolism in liver and pancreas via the AMPKα-mTORC1 pathway

Fig. 6

Only after the proteolytic nucleation processing in endoplasmic reticulum can SREBP1 (specifically expressed SREBP1c in liver) become a mature karyotype nSREBP1c participating in downstream transcription. Insig1 and Insig2 block SREBP1c processing by binding to SCAP, thus preventing SCAP from escorting SREBPs to the Golgi. AMPK can prevent nSREBP1c from entering the nucleus, whereas mTORC1 can affect SREBP1c processing and nSREBP1c formation through Lipin-1. Previously, SREBP1c is regulated by LXR in the classical pathway. Here, we found that SIRT6 regulates glycolipid metabolism (ACC, FASN, and LDLR for lipid metabolism in liver; GCK and PCK1 in glucose metabolism in pancreas) through the AMPKα-mTORC1 complex (T172 p-AMPKα, mTOR, Raptor, and Rheb) regulating SREBP1c in the liver and pancreas induced by overnutrition and starvation, independently of LXR.

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