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. 2017 Nov 6;9:55–66. doi: 10.2147/HMER.S125718

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© 2017 Bruschi et al. This work is published and licensed by Dove Medical Press Limited

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Differential molecular mechanisms of PNPLA3 I148M in HSCs and hepatocytes.

Notes: HSCs are depicted in the left panel, in which activation and increase of proinflammatory FFAs directly activates JNK/AP-1 pathway, increasing HSCs proliferation and secretion of inflammatory mediators. On the right side, a different scenario is represented in regard to hepatocytes: ubiquitination of PNPLA3 does not take place because of the I148M variant, and this results in an increase in PNPLA3 and FFA content, because the proteasome is not able to degrade PNPLA3 protein efficiently. The augmented amount of FFAs cannot be released in the form of VLDL from the hepatocytes to the blood stream.

Abbreviations: AP-1, activator protein 1; FFA, free fatty acids; HSC, hepatic stellate cell; JNK, c-Jun activated kinase; LXR, liver X receptor; PPARg, peroxisome proliferator activated receptor gamma; PNPLA3, patatin-like phospholipase domain-containing 3 gene; RXR, retinoid X receptor; SMA, smooth muscle actin; TAG, triacylglycerol; VLDL, very-low-density lipoprotein; Ub, ubiquitin.