About the Article
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[This article belongs to Volume - 69, Issue - 12]
Published on : 2024-12-11 13:35:47
Article Code: AMJ-11-12-2024-12306
Title : Circadian Disruption of the CLOCK-BMAL1 Axis in Hepatic Stellate Cells Promotes Fibrosis Progression in Non-Alcoholic Steatohepatitis
Author(s) : Dr. Helena Costa, Dr. James Wilson
Abstract :
Non-alcoholic steatohepatitis (NASH) progression exhibits diurnal patterns, yet the molecular clock's role in hepatic
fibrogenesis is unknown. We demonstrate that hepatic stellate cells (HSCs) possess autonomous circadian clocks that
regulate collagen synthesis and autophagy. Disruption of Clock or Bmal1 in HSCs through genetic knockout or
environmental circadian disruption (chronic jet-lag) accelerated fibrosis in methionine-choline deficient (MCD) diet
fed mice. Mechanistically, CLOCK-BMAL1 directly bound the Col1a1 promoter and repressed TGF-β signaling through
period protein interactions. Chronotherapeutic administration of losartan during the active phase maximized HSC
quiescence restoration. Targeting circadian pathways offers a temporal therapeutic strategy for NASH fibrosis.