Steatosis GLI code? Highlights Hh signaling shows diurnal oscillations in liver and hepatocytes in vitro and in vivo. Hh signaling feeds-back on the liver clock via GLI transcription factors. The amplitude of the oscillations of the liver clock is decreased in hepatocytes from Smo-knockout mice. Rhythmicity of many metabolic pathways, including hepatic lipid metabolism, is affected by oscillating Hh signaling. Diurnal timing of starvation affects the clock-hedgehog module differently.

Highlights d The Hh and Wnt pathways in healthy liver act largely complementary to each other d The Wnt/Hh module inversely controls spatiotemporal metabolic pathways in the liver d Inhibition of the Hh pathway leads to periportalization of the liver lobe d Liver-derived IHH seems to signal to other peripheral organs

In the liver, energy homeostasis is mainly regulated by mechanistic target of rapamycin (mTOR) signalling, which influences relevant metabolic pathways, including lipid metabolism. However, the Hedgehog (Hh) pathway is one of the newly identified drivers of hepatic lipid metabolism. Although the link between mTOR and Hh signalling was previously demonstrated in cancer development and progression, knowledge of their molecular crosstalk in healthy liver is lacking. To close this information gap, we used a transgenic mouse model, which allows hepatocyte-specific deletion of the Hh pathway, and in vitro studies to reveal interactions between Hh and mTOR signalling. The study was conducted in male and female mice to investigate sexual differences in the crosstalk of these signalling pathways. Our results reveal that the conditional Hh knockout reduces mitochondrial adenosine triphosphate (ATP) production in primary hepatocytes from female mice and inhibits autophagy in hepatocytes from both sexes. Furthermore, in vitro studies show a synergistic effect of cyclopamine and rapamycin on the inhibition of mTor signalling and oxidative respiration in primary hepatocytes from male and female C57BL/6N mice. Overall, our results demonstrate that the impairment of Hh signalling influences mTOR signalling and therefore represses oxidative phosphorylation and autophagy.

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