The Biological Clock: A Pivotal Hub in Non-alcoholic Fatty Liver Disease Pathogenesis

Gianluigi Mazzoccoli, Salvatore De Cosmo, Tommaso Mazza, Gianluigi Mazzoccoli, Salvatore De Cosmo, Tommaso Mazza

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most frequent hepatic pathology in the Western world and may evolve into steatohepatitis (NASH), increasing the risk of cirrhosis, portal hypertension and hepatocellular carcinoma. NAFLD derives from the accumulation of hepatic fat due to discrepant free fatty acid metabolism. Other factors contributing to this are deranged nutrients and bile acids fluxes as well as alterations in nuclear receptors, hormones, and intermediary metabolites, which impact on signaling pathways involved in metabolism and inflammation. Autophagy and host gut-microbiota interplay are also relevant to NAFLD pathogenesis. Notably, liver metabolic pathways and bile acid synthesis as well as autophagic and immune/inflammatory processes all show circadian patterns driven by the biological clock. Gut microbiota impacts on the biological clock, at the same time as the appropriate timing of metabolic fluxes, hormone secretion, bile acid turnover, autophagy and inflammation with behavioural cycles of fasting/feeding and sleeping/waking is required to circumvent hepatosteatosis, indicating significant interactions of the gut and circadian processes in NAFLD pathophysiology. Several time-related factors and processes interplay in NAFLD development, with the biological clock proposed to act as a network level hub. Deranged physiological rhythms (chronodisruption) may also play a role in liver steatosis pathogenesis. The current article reviews how the circadian clock circuitry intimately interacts with several mechanisms involved in the onset of hepatosteatosis and its progression to NASH, thereby contributing to the global NAFLD epidemic.

Keywords: NAFLD; chronodisruption; circadian; clock gene; metabolism; rhythm.

Figures

Figure 1
Figure 1
Schematic representation of the biological clock. The several cogs of the molecular clockwork are connected by lines representing interaction, arrow-headed lines representing activation, bar-headed lines representing inhibition. ARNTL, CLOCK, and RORA encode transcriptional activators; PER1/2, CRY1/2, and Rev-erbα encode transcriptional repressors; CK and Ph symbolize casein kinases and inorganic phosphate operating by post-translational modification of circadian proteins. ARNTL drives the expression of downstream genes encoding transcriptional activators, such as DEC1-2, DBP, TEF, HLF, PPARA. CLOCK acetyltransferase activity and SIRT1 deacetylase activity is crucial for the functioning of the biological clock. Molecular interactions were manually retrieved and curated from the scientific literature.
Figure 2
Figure 2
Gene regulatory network involved in non-alcoholic fatty liver disease pathogenesis. Gene are nodes of the network and are visualized as blue-colored ellipses. Most nodes are involved in multiple signaling pathways and are clustered in functionally related groups. Interaction data are retrieved from the Ingenuity Knowledge Base (QIAGEN Inc., https://www.qiagenbioinformatics.com/). Graphical layout was obtained by Cytoscape 3.4.0 (www.cytoscape.org/).
Figure 3
Figure 3
Visualization of a unifying concept of the involvement of the biological clock in the control of the relevant pathways and biological processes involved in non-alcoholic fatty liver disease pathogenesis. Each pathway/process is represented as a blue-rounded rectangle. Arrow-headed lines represent activation, bar-headed lines represent inhibition. Molecular interactions were manually retrieved and curated from the scientific literature. Graphical layout was obtained by Cytoscape 3.4.0 (www.cytoscape.org/).

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