Circadian Rhythms in Liver Physiology and Liver Diseases

Abstract

In mammals, circadian rhythms function to coordinate a diverse panel of physiological processes with environmental conditions such as food and light. As the driving force for circadian rhythmicity, the molecular clock is a self-sustained transcription-translational feedback loop system consisting of transcription factors, epigenetic modulators, kinases/phosphatases, and ubiquitin E3 ligases. The molecular clock exists not only in the suprachiasmatic nuclei of the hypothalamus but also in the peripheral tissues to regulate cellular and physiological function in a tissue-specific manner. The circadian clock system in the liver plays important roles in regulating metabolism and energy homeostasis. Clock gene mutant animals display impaired glucose and lipid metabolism and are susceptible to diet-induced obesity and metabolic dysfunction, providing strong evidence for the connection between the circadian clock and metabolic homeostasis. Circadian-controlled hepatic metabolism is partially achieved by controlling the expression and/or activity of key metabolic enzymes, transcription factors, signaling molecules, and transporters. Reciprocally, intracellular metabolites modulate the molecular clock activity in response to the energy status. Although still at the early stage, circadian clock dysfunction has been implicated in common chronic liver diseases. Circadian dysregulation of lipid metabolism, detoxification, reactive oxygen species (ROS) production, and cell-cycle control might contribute to the onset and progression of liver steatosis, fibrosis, and even carcinogenesis. In summary, these findings call for a comprehensive study of the function and mechanisms of hepatic circadian clock to gain better understanding of liver physiology and diseases.

Bile Acid Signaling in Metabolic Disease and Drug Therapy

“…Fasting and refeeding as well as the time of feeding have profound effects on circadian rhythms of hepatic lipid and glucose metabolism (Vollmers et al, 2009;Asher and Schibler, 2011;Hatori et al, 2012;Tong and Yin, 2013). During fasting, glucagon stimulates fatty acid mobilization from adipose tissues to the liver for generation of energy.…”

Maternal obesity programs offspring non-alcoholic fatty liver disease through disruption of 24-h rhythms in mice

“…A high fat diet in rodents has also been reported to alter locomotor activity and the rhythmic expression of canonical chronobiology-related genes in the hypothalamus, adipose, muscle and liver tissue. Nuclear receptors which regulate CLOCK gene transcription factors in peripheral tissues including the liver are similarly perturbed by a high fat diet (11) and expression of genes encoding lipogenesis, lipolysis and gluconeogenesis have been shown to possess circadian rhythmicity (12,13). These studies indicate an intimate and reciprocal association between feeding behaviour, metabolism and chronobiology (14)(15)(16)(17)(18).…”

Stress oxidativo e alterações enzimáticas induzidas por nanotubos de carbono de paredes múltiplas (MWCNTs) funcionalizados com polietileno glicol no tecido hepático de camundongos

“…As espécies de oxigênio são importantes nos estímulos oxidativos necessários para a homeostase fisiológica normal dos hepatócitos e na expressão gênica (DIESEN; KUO, 2010). No entanto, também é correto indicar que o excesso de espécies reativas de oxigênio é prejudicial e deletério para a fisiologia hepática (TONG;YIN, 2013). De fato, há evidências abundantes que associam estresse oxidativo e distúrbios e evolução das doenças, dentre as quais a toxicidade hepática induzida por MWCNT, tanto em estudos in vitro como in vivo (DARNE et al, 2014;POLAND, 2012;PATLOLLA et al, 2011).…”