Circadian clock core component Bmal1 dictates cell cycle rhythm of proliferating hepatocytes during liver regeneration

Abstract

Following partial hepatectomy (PH), the majority of remnant hepatocytes synchronously enter and rhythmically progress through the cell cycle for three major rounds to regain the lost liver mass. Whether and how the circadian clock core component Bmal1 modulates this process remains elusive. We performed PH on wild-type and hepatocyte-specific Bmal1 knockout (Bmal1hep-/-) mice and compared the initiation and progression of the hepatocyte cell cycle. After PH, wild-type hepatocytes exhibited three major waves of nuclear DNA synthesis. In contrast, in Bmal1hep-/- hepatocytes, the first wave of nuclear DNA synthesis was delayed by 12 hours, the third wave of nuclear DNA synthesis was lost. Following PH, wild-type hepatocytes underwent three major waves of mitosis, whereas Bmal1hep-/- hepatocytes fully abolished the oscillation of mitosis. These Bmal1-dependent disruptions in the rhythmicity of hepatocyte cell cycle after PH were accompanied with prevented expression peaks of a group of the cell cycle components and regulators, dysregulated activation patterns of mitogenic signaling molecules c-Met and EGFR. Moreover, wild-type hepatocytes rhythmically accumulated fat as they expanded following PH, whereas this event was largely prohibited in Bmal1hep-/- hepatocytes. In addition, during the late stage of liver regrowth, Bmal1 absence in hepatocytes caused the activation of redox sensor Nrf2, suggesting an oxidative stress state in regenerated livers. Collectively, we demonstrate that, during liver regeneration, Bmal1 partially modulates the oscillation of S-phase progression, fully controls the rhythmicity of M-phase advance, and largely govern the fluctuation of fat metabolism of replicating hepatocytes, and eventually determines the redox state of regenerated livers.

PPAR-γ Agonist Pioglitazone Restored Mouse Liver mRNA Expression of Clock Genes and Inflammation-Related Genes Disrupted by Reversed Feeding

“…Clock/Bmal1-dependent Nrf2 regulation gives rise to diurnal patterns in Nrf2 signaling, which underlies the rhythmic expression of antioxidant and metabolic enzymes. In the mouse knockout model, Bmal/absence in hepatocytes caused the activation of redox sensor Nrf2 [ 34 , 40 ].…”

The circadian rhythm: an influential soundtrack in the diabetes story

“…Additional evidence have shown that hepatic clocks are critical mediators of glucose homeostasis since most of the binding sites were located/mapped in promoter areas of genes related to the metabolism of hepatic glucose (like Glut2 and G6pc ) and lipid (such as Agpat6 and Dgat2 ). This finding is supported by the in vivo test observation that showed mice with a liver-specific deletion of Bmal1 exhibit systemic glycemia and glucose intolerance due to the absence of rhythmic regulation of glucose metabolism related genes (e.g Glut2 ) ( 146 , 147 ). Newer studies built on these observations, demonstrating that hepatic Bmal1 is essential for controlling hepatic oxidative capacity through orchestrating intracellular mitochondrial dynamics such as mytophagy and fission ( 146 , 148 ).…”

“…This finding is supported by the in vivo test observation that showed mice with a liver-specific deletion of Bmal1 exhibit systemic glycemia and glucose intolerance due to the absence of rhythmic regulation of glucose metabolism related genes (e.g Glut2 ) ( 146 , 147 ). Newer studies built on these observations, demonstrating that hepatic Bmal1 is essential for controlling hepatic oxidative capacity through orchestrating intracellular mitochondrial dynamics such as mytophagy and fission ( 146 , 148 ).…”

Endogenous Circadian Clock Machinery in Cortical NG2-Glia Regulates Cellular Proliferation

“…We then sought to confirm our TRAP findings with small-molecule fluorescent RNA ISH (RNAscope). We initially focused on Bmal1 expression as it is an essential, nonredundant component of the mammalian circadian clock ( Haque et al, 2019 ) and is an integral regulator of circadian physiology in several cell types ( Lefta et al, 2012 ; Jiang et al, 2021 ). Cortical NG2-glia, identified by Cspg4 + nuclei, demonstrated increased Bmal1 RNA expression at a circadian time of day near the expected peak of Bmal1 expression (CT 0000) versus the daily nadir (CT 1200; Fig.…”