Figure 2.

Putatively beneficial and harmful effects of HIF2 activation in hepatocytes in NAFLD and NASH. HIF2 activation leads to lower expression of FAO genes, including Ppara, which encodes PPARα. This decreases FAO, leading to increased lipid accumulation. Higher levels of fibrogenic mediators such as LOX and potentially PAI-1, which are involved in ECM deposition, also occur as a result of HIF2 activation. Increased production of HSC activators may also occur but this has not yet been demonstrated in NAFLD/NASH. HIF2 mediated upregulation of the pro-inflammatory cytokine HRGP worsens inflammation. Interplay between HIF2 and NF-κB appears likely, but details of this interaction are unknown. Finally, increased transcription of the insulin signalling component Irs2 appears to improve insulin signalling to prevent insulin resistance. ECM, extracellular matrix; FAO, fatty acid oxidation; HIF, hypoxia-inducible factor; Hrgp, histidine rich glycoprotein; HSC, hepatic stellate cell; Irs2, insulin receptor substrate 2; Lox, lysyl oxidase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Ppara, peroxisome proliferator-activated receptor α; Fas, fatty acid synthase; CD36, cluster of differentiation 36; Pdgfb, platelet derived growth factor b.