Hepatocyte Circadian Clocks Control Cholesterol Metabolism and Protect From Metabolic Dysfunction-Associated Steatohepatitis.

BACKGROUND & AIMS: The circadian clock synchronizes physiological processes with the 24-hour light-dark cycle. Clock disruption contributes to metabolic disorders, including metabolic dysfunction-associated steatohepatitis.

METHODS

We investigated the role of the hepatocyte clock in metabolic dysfunction-associated steatohepatitis using hepatocyte-specific Bmal1 deletion (Hep-Bmal1KO) mice.

RESULTS

Hep-Bmal1KO mice showed faster metabolic dysfunction-associated steatohepatitis progression with increased hepatic cholesterol, inflammation, and fibrosis. Transcriptomic and lipidomic analyses revealed dysregulated cholesterol metabolism in Hep-Bmal1KO mice, marked by reduced expression and disrupted rhythmicity of key cholesterol-related genes. Bioinformatic analyses identified Chrebp as a potential coregulator of these transcriptional changes. In an in vitro model with palmitate exposure and gene silencing, we found that Bmal1, but not Chrebp, regulated cholesterol accumulation, indicating Bmal1's specific role in hepatic cholesterol metabolism. Translating our findings to a human patient cohort revealed a significantly shifted circadian phase, despite no marked effect on hepatic cholesterol levels in the livers of patients with more advanced liver disease (ie, metabolic dysfunction-associated steatohepatitis) compared with simple steatosis.

CONCLUSIONS

Taken altogether, our findings offer a roadmap to understand the hepatocyte clock's role in metabolic dysfunction-associated steatohepatitis and its potential as a therapeutic target.