<scp>SREBP1</scp> Is a Down‐Stream Target of <scp>CLOCK</scp> Mediating Natural Development of <scp>MAFLD</scp> Induced by <scp>HFD</scp>

Biological rhythm output by central and peripheral circadian clock is closely associated with metabolic dysfunction-associated fatty liver disease (MAFLD) development, but the down-stream targets of the hepatic clock are not well known. This work aimed to investigate how hepatic circadian clock regulates MAFLD development. Male mice were fed a 45% high fat diet (HFD) for 8 weeks to screen the lipid metabolism genes regulated by clock factors in natural MAFLD development. Core circadian factor circadian locomotor output cycles kaput (CLOCK) knockdown and over-expression in cellular models were performed to explore the role of its potential target SREBP1 found in vivo. rAAV8-CAG-EGFP-Clock was delivered in mice to validate the role of SREBP1 signaling regulated by CLOCK. HFD induced body weight gain and steatosis in the liver. The hepatic core circadian factor CLOCK was significantly down-regulated and the lipid metabolism was disrupted including up-regulation of Srebf1 which encodes transcription factor SREBP1. In mouse and human cellular models, SREBP1 and the lipid accumulation were increased by CLOCK knockdown and decreased by CLOCK over-expression. When CLOCK was over-expressed in vivo, liver triglyceride and total cholesterol were reversed and hepatic steatosis was attenuated where the transcription factor SREBP1 signaling was down-regulated. In conclusion, SREBP1 signaling is a down-stream target of CLOCK deeply involved in regulating the natural MAFLD development.