Hepatocyte Circadian Clocks Control Cholesterol Metabolism and Protect From Metabolic Dysfunction-Associated Steatohepatitis (MASH)

May 12, 2026Cellular and molecular gastroenterology and hepatology

Body Clock in Liver Cells Controls Cholesterol and Protects Against Fatty Liver Disease Linked to Metabolism

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Abstract

Hepatocyte-specific Bmal1 deletion (Hep-Bmal1KO) mice showed faster progression of metabolic dysfunction-associated steatohepatitis (MASH) with increased hepatic cholesterol.

Disruption of the hepatocyte clock is associated with increased liver inflammation and fibrosis in Hep-Bmal1KO mice.
Transcriptomic and lipidomic analyses indicate dysregulated cholesterol metabolism in mice lacking Bmal1.
Key cholesterol-related genes exhibited reduced expression and disrupted rhythmicity in Hep-Bmal1KO mice.
Bioinformatic analyses suggest Chrebp may co-regulate transcriptional changes related to cholesterol.
In vitro studies indicate that Bmal1 specifically regulates cholesterol accumulation, independent of Chrebp.
A shifted circadian phase was observed in a human patient cohort with advanced liver disease, although hepatic cholesterol levels did not show significant differences between MASH and simple steatosis.

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The circadian clock synchronizes physiological processes with the 24-hour light-dark cycle. Clock disruption contributes to metabolic disorders, including metabolic dysfunction-associated steatohepatitis (MASH). Here, we investigated the role of the hepatocyte clock in MASH using hepatocyte-specific Bmal1 deletion (Hep-Bmal1KO) mice. Hep-Bmal1KO mice showed faster MASH 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 co-regulator 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 (i.e., MASH) compared to simple steatosis. Taken altogether, our findings offer a roadmap to understand the hepatocyte clock's role in MASH and its potential as a therapeutic target.

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Hepatocyte Circadian Clocks Control Cholesterol Metabolism and Protect From Metabolic Dysfunction-Associated Steatohepatitis (MASH)

Abstract

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