Hedgehog signalling pathway is involved in the regulation of circadian rhythm within hepatic lipid metabolism

Entrained and reset by external cues, the internal circadian clock controls innate physiological processes, including liver metabolism. At the cellular level the circadian clock is characterised by a variety of core clock genes, which, acting as transcriptional factors, modulate the fluctuating expression of central metabolic genes [1]

Presenting an extensive biological process the clock is linked to the elements of the cell cycle control and intracellular signalling pathways. Recent analyses identified the hedgehog (HH)-signalling also to be associated with liver clock [2]. Being an evolutionary highly conserved cascade the HH-morphogen pathway functions as an essential modulator of embryogenesis and tissue differentiation, however there are evidences of its role in the adult liver tissue [3].

Our aim was, therefore, to analyse the liver specific function of the HH-signalling and its interaction with the circadian rhythm, using the transgenic knock-out mice, displaying a hepatocyte specific deletion of Smo (Smo-KO), an essential transducer within the HH-signalling pathway. We performed gene microarray analyses, comparing the hepatocytes from transgenic mice and their wild-type littermates, isolated at two different circadian time-points. The identified candidate genes were classified according to the GO categories and its expression intensities were evaluated using the ANOVA statistical analyses. Further, qRT-PCR studies were performed to determine the expression levels of the core clock genes in Smo-KO mouse hepatocytes.

Generally, the results show strong alterations in the expression levels of genes involved in metabolic and transport processes due to Smo-KO, though these alterations seem not to provide a global significant effect. In contrast, especially the circadian rhythm of the lipid metabolism appears to be significantly affected by the loss of function of the HH-pathway. Interestingly, also some core clock genes exhibit strong alterations in their expression due to the deletion of Smo. A putative transcription factor binding site prediction allows us to conclude that in adult liver the HH signalling seems to be closely related to the circadian clock and, thus, might be involved in the regulation of the rhythmicity of lipid metabolic processes. However, the precise function of HH-signalling within the clock regulatory mechanism still has to be evaluated, requiring further investigations.

References:

[1] Reppert & Weaver, Nature, 418:935–941 (2002)

[2] Zhang et al., Cell, 139:199–210 (2009)

[3] Hovhannisyan et al., Planta Med, 75:1371–1380 (2009)