The hepatic circadian clock fine-tunes the lipogenic response to feeding through ROR?/?.

ABSTRACT: Liver lipid metabolism is under intricate temporal control by both the circadian clock and feeding. The interplay between these two mechanisms is not clear. Here we show that liver-specific depletion of nuclear receptors ROR? and ROR?, key components of the molecular circadian clock, up-regulate expression of lipogenic genes only under fed conditions at Zeitgeber time 22 (ZT22) but not under fasting conditions at ZT22 or ad libitum conditions at ZT10. ROR?/? controls circadian expression of Insig2, which keeps feeding-induced SREBP1c activation under check. Loss of ROR?/? causes overactivation of the SREBP-dependent lipogenic response to feeding, exacerbating diet-induced hepatic steatosis. These findings thus establish ROR/INSIG2/SREBP as a molecular pathway by which circadian clock components anticipatorily regulate lipogenic responses to feeding. This highlights the importance of time of day as a consideration in the treatment of liver metabolic disorders.

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC5558923 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature