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

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.

Nonalcoholic fatty liver disease in CLOCK mutant mice

“…Other factors, such as microbiota and high-fat diets, affect circadian circuitry. Therefore, chronodisruption may play a role in liver steatosis (4,5). Circadian rhythms are controlled by few core transcription factors: circadian locomotor output cycles kaput (CLOCK), brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1), periods (PER1-3), and cryptochromes (CRY1 and CRY2).…”

Perturbation of the circadian clock and pathogenesis of NAFLD

“…Importantly, due to the overwhelming role of the CC in maintaining metabolic homeostasis ( Fig. 2), it can be postulated that disruption in the CCfunctioning can drive NAFLD [1][2][3]15]. In the subsequent chapters we describe some of these functions to further illustrate the link between CC and NAFLD.…”

“…Importantly, in our modern industrialized world, various human behaviors and activities such as shift work, jet lag, energy-dense fatty foods and sleep deprivation often interfere with these rhythms and disrupt Metabolism Clinical and Experimental 111 (2020) 154337 CC-functioning. Unsurprisingly then that disruption of CC functioning has recently emerged as a major contributor to different metabolic diseases, as well as carcinogenesis [1][2][3][4][5][8][9][10][11][12][13][14][15][16]. Therefore, detailed comprehension of the mechanistic basis of the CC-control on gene expression is critical to develop novel therapeutics for metabolic disorders whose therapeutic efficacy may be administration time-of -day dependent.…”

Hedgehog signaling keeps liver clock in check

“…9 It is now clear that biological clock dysfunction accelerates the development of NAFLD, cirrhosis and liver cancer, and in turn, these disorders also disrupt clock function. 9,10 The hepatic clock strictly regulates the pharmacokinetics of xenobiotics through each of its phases, including absorption and uptake, distribution, metabolism and elimination. Most of these studies took advantage of valuable mice models, such as global clockgene-knockout mice, or mice with liver-specific knockout of clock genes or clock-controlled genes.…”

“…In particular, the relationship between food intake and melatonin secretion onset impacts body composition, with augmented body fat and reduced glucose tolerance linked to eating at a later circadian time. 10,16,17 Furthermore as the Hh signaling pathway inhibits autophagy in mammalian cells, 18 established Hh inhibitors, such as the FDA-approved Vismodegib (a potent Smo antagonist) may be studied in the future in combination with chronomodulated nutritional approaches to treat obesity and NAFLD/NASH.…”