FIG. 3.

Porphyrin accumulation and oxidative stress in CEP. CEP is an autosomal recessive disorder of heme synthesis characterized by reduced activity of UROIIIS and the accumulation of nonphysiologic porphyrin metabolites (UROgen I and URO I). This results in ineffective erythropoiesis, iron deposition, mitochondrial dysfunction, and enhanced generation of reactive oxygen species (ROS), leading to the release of molecular danger signals triggering apoptosis in neighbor cells, probably erythroid cells. The diagram also shows the activation of glycolysis caused by mitochondrial dysfunction (Warburg effect) and how the excess of carbon units may be used for the various branching pathways that originate from glycolysis, like the de novo lipogenesis. This, together with the decrease of phosphatidylcholine (PC), which is required for VLDL synthesis and export, and the increased generation of ROS can explain the development of steatohepatitis in CEP mice. Abbreviations: ALA, aminolevulinate; COPROgen, coproporphyrinogen; CYP1A2, cytochrome P450 1A2; G3P, glyceraldehyde 3‐phosphate; HEME, heme group; HMB, hydroxymethylbilane; PGB, porphobilinogen; PROTO, protoporphyrin; PROTOgen, protoporphyrinogen; PYR, pyruvate; URO, uroporphyrin; UROgen, uroporphyrinogen; UV, ultraviolet radiation.