Heyde, I. | bioRxiv Science

bioRxiv2025

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

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 Bmal1s 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 clocks role in MASH and its potential as a therapeutic target.

pathology↗

bioRxiv2025

A systemic clock brake: Period1 stabilizes the circadian network under environmental stress

Precise alignment between internal circadian clocks and environmental light cycles is essential for physiological homeostasis and survival. However, the molecular mechanisms that preserve this synchrony across central and peripheral tissues remain poorly defined. Here, we uncover an unexpected role for the core clock gene Period1 (Per1) as a systemic modulator of circadian stability, regulating light-induced re-entrainment across the brain and body. In Per1-deficient mice, we show that loss of Per1 accelerates clock realignment, influencing transcriptomic, metabolic, hormonal, and behavioral indicators of circadian realignment across multiple organ systems, including the suprachiasmatic nucleus (SCN) and peripheral tissues such as the liver, adipose tissue, and adrenal glands. Notably, this accelerated adaptation confers protection against jetlag-induced sleep disturbances, weight gain, and metabolic imbalance, underscoring a systemic role for Per1 in maintaining circadian network stability. Mechanistically, unbiased spatial transcriptomics identified reduced expression of the arginine vasopressin (AVP), a key neuropeptide mediating SCN intercellular coupling, as the driver of circadian network instability. Weakened SCN synchrony permits enhanced flexibility of peripheral oscillator responses, expediting whole-body adaptation to shifted light-dark schedules. These findings position Per1 as a critical regulator of circadian robustness, a buffer against light over-responsiveness, identifying a potential molecular target for mitigating circadian misalignment in contexts such as jetlag, shift work, and metabolic disease. TeaserWhat if beating jetlag was as simple as switching off a gene? Researchers show that disabling Per1, a core circadian regulator, accelerates body clock realignment and protects against sleep and metabolic disruption--highlighting new therapeutic possibilities for jetlag and shift work.

neuroscience↗