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. 2018 Nov 12;6:150. doi: 10.3389/fcell.2018.00150

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Copyright © 2018 Hou and Syn.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Role of succinate in HSC activation. Succinate, an intermediate in the TCA cycle, functions as a paracrine signal between hepatocytes and HSCs, through binding and activation of its cognate G protein-coupled receptor 91 (GPR91), which resulted in upregulation of fibrogenic markers alpha-smooth muscle actin (α-SMA), transforming growth factor β (TGF-β), and collagen type I. Sirtuin 3 (SIRT3), a NAD+-dependent protein deacetylase, predominantly localized in the mitochondrial matrix, is a key regulator of dehydrogenase (SDH) activity. The SIRT3-SDH-GPR91 axis regulates HSC activation. Repression of succinate-GPR91 signaling by LY2405319, an analog of fibroblast growth factor 21 (FGF21), as well as metformin inhibits HSC activation.