Fig. 11

PPARα and CREB3L3 cooperate to regulate hepatic lipid metabolism. a The cartoon illustrates the distinct roles of CREB3L3 and PPARα in the regulation of hepatic lipid metabolism during fasting. CREB3L3 stimulates genes involved in lipoprotein metabolism (Apoc2, Apoa5, Apoa1), lipid storage (Cidec), fatty acid binding (Fabp2), fatty acid desaturation and elongation (Fads1, Fads2, Elovl2, Elovl5), gluconeogenesis (Pck1,G6pc), and fatty acid oxidation (Cpt1a, Hsd17b10). PPARα stimulates genes involved in peroxisomal fatty acid oxidation (Acaa1, Decre2, Ehhadh, Ech1), mitochondrial fatty acid oxidation (Slc25a20, Cpt2, Acadvl, Hadh), microsomal fatty acid oxidation (Cyp4a10, Cyp4a14), fatty acid binding and (de)activation (Fabp1, Acsl5, Acot1), triglyceride hydrolysis (Plin5, Fitm1, G0 s2, Mgll). Genes significantly decreased in CREB3L3−/− mice in the fasted state are in blue (IBMT P-value< 0.001). Genes significantly decreased in PPARα−/− mice in the fasted state are in red. Genes significantly decreased in both genotypes are shown in green. b Overview of the effect of CREB3L3 deficiency after 4 days of ketogenic diet feeding. It is hypothesized that CREB3L3 deficiency during ketogenic diet leads to accumulation of certain lipid species that (ligand) activate PPARα. In turn, PPARα activation leads to hepatocyte proliferation and hepatomegaly. Additional effects of CREB3L3 deficiency include steatosis and enhanced liver damage