Tick-Tock Hedgehog-Mutual crosstalk with liver circadian clock promotes liver steatosis.
(2019) Tick-Tock Hedgehog-Mutual crosstalk with liver circadian clock promotes liver steatosis. J Hepatol 70(6), 1192-1202.
Background & Aims: The mammalian circadian clock controls various aspects of liver
metabolism and integrates nutritional signals. Recently, we described Hedgehog (Hh) signaling
as a novel regulator of liver lipid metabolism. Here, we investigated crosstalk between hepatic
Hh signaling and circadian rhythm.
Methods: Diurnal rhythms of Hh signaling were investigated in liver and hepatocytes from mice
with ablation of Smoothened (SAC-KO) and crossbreeds with PER2::LUC reporter mice. By
using genome-wide screening, qPCR, immunostaining, ELISA and RNAi experiments in vitro we
identified relevant transcriptional regulatory steps. Shotgun lipidomics and metabolic cages were
used for analysis of metabolic alterations and behavior.
Results: Hh signaling showed diurnal oscillations in liver and hepatocytes in vitro.
Correspondingly, the level of Indian Hh, oscillated in serum. Depletion of the clock gene Bmal1
in hepatocytes resulted in significant alterations in the expression of Hh genes. Conversely,
SAC-KO mice showed altered expression of clock genes, confirmed by RNAi against Gli1 and
Gli3. Genome-wide screening revealed that SAC-KO hepatocytes showed time-dependent
alterations in various genes, particularly those associated with lipid metabolism. The
clock/hedgehog module further plays a role in rhythmicity of steatosis, and in the response of the
liver to a high fat diet or to differently timed starvation.
Conclusions: For the first time, Hh signaling in hepatocytes was found to be time-of-day
dependent and to feed back on the circadian clock. Our findings suggest an integrative role of
Hh signaling, mediated mainly by GLI factors, in maintaining hepatic lipid metabolism
homeostasis by balancing the circadian clock.
doi: 10.1016/j.jhep.2019.01.022 PMID: 30711403