Tick-tock hedgehog-mutual crosstalk with liver circadian clock promotes liver steatosis

Abstract

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.

Hedgehog signaling keeps liver clock in check

“…Several Hh pathway genes (Ihh, Ptch1, Smo, Hhip1, Fu, SuFu) showed circadian fluctuations in the liver and hepatocytes in vitro, the genes encoding Gli transcription factors (Gli1, Gli3) exhibited only tiny fluctuations and the serum levels of Indian, the ligand encoded by Ihh, oscillated with 24-hour periodicity. 15 Bmal1 downregulation in hepatocytes provoked important alterations in the expression of Hh pathway genes (upregulation of Gli1 and Ihh, downregulation of Ptch1) and, in turn, altered expression of clock genes in SAC-KO mice was demonstrated and corroborated in vitro using RNA interference against Gli1 and Gli3. Rhythmicity of many metabolic pathways, including hepatic lipid metabolism, was affected by Smo knockout in SAC-KO hepatocytes, as evidenced using genome-wide screening.…”

“…Rhythmicity of many metabolic pathways, including hepatic lipid metabolism, was affected by Smo knockout in SAC-KO hepatocytes, as evidenced using genome-wide screening. 15 Interestingly, nutritional challenge represented by high-fat diet or starvation applied at diverse zeitgeber time differently impacted the biological clock-Hh signaling interplay and these results could supply a mechanistic explanation for the dissimilar effect of differently timed eating/fasting on the liver.…”

“…In the present issue, Marbach-Breitrück et al 15 report the results of an original study investigating the interplay between Hh signaling and the biological clock in the regulation of lipid metabolism in the liver. They assessed time-related patterns of expression of Hh signaling pathway and core clock components in liver and hepatocytes from controls and mice with ablation of Smoothened (SAC-KO) and crossbreeds with PER2:: LUC reporter mice.…”

Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver

“…Moreover, specifically in hepatocytes, we recently found that Gli1 is part of a Gli-network and behaves different than in other cell types [25]. Furthermore, it is known that the expression of both genes is subject to pronounced diurnal oscillation [11]. Thus, measurements at a single time point may not be the best choice for estimating Hh pathway activity.…”

“…Although the molecular mechanisms driving the regulation of metabolic processes via mTOR signalling are well understood in principle, there are still major gaps in the research on the crosstalk of mTOR with signalling pathways known to serve as gatekeepers for lipid metabolism in the liver. Recently, we discovered that the Hedgehog (Hh) pathway is an essential player in liver lipid metabolism and metabolic zonation, influencing circadian rhythms [9][10][11]. The Hh pathway can be induced by binding of the Hh ligands Indian Hh, Sonic Hh and Dessert Hh to the receptors Patched (PTCH).…”