What this is
- Circadian rhythms regulate metabolism, particularly in the liver, influencing conditions like metabolic dysfunction-associated steatotic liver disease (MASLD).
- This review examines how disruptions in circadian rhythms affect metabolic health, focusing on eating and sleep patterns.
- It emphasizes the importance of aligning eating schedules with natural circadian cycles to mitigate the risk of MASLD.
Essence
- Circadian misalignment contributes to metabolic disorders, including MASLD. Aligning eating patterns with circadian rhythms may help prevent these conditions.
Key takeaways
- Obesity affects one in eight adults globally, with MASLD impacting up to one-third of the population. This reflects a significant rise in metabolic disorders over the past 30 years.
- Eating patterns misaligned with circadian rhythms, such as late meals and irregular schedules, are linked to increased risks of obesity, metabolic syndrome, and MASLD.
- strategies, including time-restricted feeding and earlier meal timings, may help improve metabolic health and reduce the risk of MASLD.
Caveats
- The review relies on existing literature, which may include variability in study designs and populations, potentially affecting the generalizability of findings.
- Many studies referenced are observational, limiting the ability to establish causation between circadian disruption and metabolic diseases.
Definitions
- Circadian rhythm: Biological processes that follow a roughly 24-hour cycle, influencing sleep, feeding, and metabolism.
- Chrononutrition: The study of how the timing of food intake affects health and metabolism.
Simplified
1. Introduction
Obesity has been declared a growing global epidemic by the World Health Organization (WHO), with one in eight adults being obese (and two in five overweight) worldwide, which represents a two-fold increase in its prevalence in the last 30 years [1]. Obesity-associated conditions are also on the rise, particularly insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome [2]. Those statistics explain the global epidemic of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as nonalcoholic fatty liver disease) that currently afflicts up to one-third of the population, which represents a 50% increase in the last 30 years [3].
The rapid rise in obesity-related conditions and MASLD probably reflects a rapid shift in the environment and in collective behavior, and could probably be mitigated by non-pharmacological approaches. Indeed, 30–80% of the risk of MASLD development cannot be explained by heritability [4].
Life has evolved by adapting to the 24 h day–night cycle resulting from the Earth's rotation around its axis [5,6]. To cope with these cyclic environmental changes, organisms synchronize behavior (sleep–awake cycle, fasting–feeding cycle), and physiological functions, including metabolic functions, in response to external cues, the zeitgebers (from the German for "time givers"), through circadian clocks. The term circadian rhythm derives from the Latin term circa diem (meaning "around one day"), and was first proposed by Franz Halberg in 1959 [7].
Human lifestyle has evolved with a disregard for the natural cyclic environmental cues, with frequent misalignment in our behavior, such as sleep–awake and fasting–feeding cycles, with the circadian clocks. For example, artificial light allows us to choose the time to sleep, jet lag and night shift work impose different sleep patterns, and the timing of food ingestion is mainly determined by convenience.
Recent accumulated evidence suggests that circadian misalignment is associated with metabolic deregulation and disease, namely obesity [8], type 2 diabetes mellitus [9], metabolic syndrome [10], MASLD, and progression to hepatocellular carcinoma [11,12].
This review will critically summarize the physiopathology of circadian rhythms and how its deregulation may promote the development of MASLD and hepatocellular carcinoma, with particular emphasis on the clinical consequences of chrononutrition and sleeping behaviors.
2. Circadian Regulation
The circadian rhythm is regulated by a hierarchical system, organized by a central clock synchronized with peripheral clocks. The dominant clock is localized in the suprachiasmatic nuclei of the anterior hypothalamus and sends neuronal, hormonal, and metabolic signals to synchronize with the peripheral clocks [13]. All organs and virtually all cells have internal clocks that, even though they are under the umbrella of the central clock, are autonomous and self-sustained [6,14]. The central clock responds primarily to the light, which is perceived by the photoreceptive retinal ganglion cell (ipRGC) expressing the photopigment melanopsin and connects with the central clock through the retinohypothalamic tract [15]. Peripheral clocks respond to other signals such as feeding time (the primary signal to liver circadian clocks [16]), the sleep–awake cycle, exercise, and body temperature [11].
At the molecular level, the oscillatory rhythm is accomplished through intricate negative and positive feedback loops of gene transcription, with several autonomous feedback loops [13] (Figure 1).
The central master clock genes are the transcription factors circadian locomotor output cycle kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL-1) [17]. CLOCK and BMAL-1 heterodimers translocate into the nucleus where they bind to a specific DNA-binding sequence, E-box, in the promoters of over 300 target genes, prompting their expression [18]. Among the CLOCK-BMAL-1 target genes are the gene families period (PER-1, -2, and -3) [19] and cryptochrome (CRY-1 and -2) [20]. PER and CRY heterodimerize and function as transcription repressors, which are able to downregulate their own expression by inhibiting CLOCK-BMAL-1, which constitutes the first autoregulatory negative feedback loop [13]. The levels of PER and CRY proteins in the cytoplasm are regulated by their phosphorylation through the proteins casein kinase-1 (CK-1) [21] and F-box-LRR-repeat protein-3 (FBXL3) [22], respectively, which target them to degradation by the proteasome complex [15]. However, if PER phosphorylation occurs after PER binding to CRY, it promotes their entry into the nucleus [23], allowing the complex to inhibit CLOCK-BMAL-1.
The second autoregulatory feedback loop derives from the CLOCK-BMAL-1-induced expression of the transcription promoters retinoic acid-related orphan nuclear receptors (ROR-α, -β, -γ) and the transcription repressors REV-ERB-α, -β. RORs and REV-ERBs compete to bind retinoic acid-related orphan receptor response elements (ROREs) present in the Bmal1 promoter, modulating BMAL-1 expression [24].
A third autoregulatory feedback loop consists in the CLOCK-BMAL-1-induced expression of the basic helix–loop–helix proteins differentiated embryo chondrocytes (DEC-1, -2), which compete with CLOCK-BMAL-1 binding to E-box, hence suppressing all their target genes' expression [25].
Additionally, each component of the circadian clock is the target of posttranslational modifications that regulate its stability and function, such as phosphorylation, acetylation, SUMOylation, and ubiquitylation [5].
In the liver, around 40% of the transcriptome presents circadian oscillations. Posttranslational modifications also add to the circadian oscillations in hepatic protein abundance [26]. Most liver functions are under circadian rhythmicity, namely the energy homeostasis regulating carbohydrates, lipids, amino acid metabolism, protein synthesis, bile acid metabolism, detoxification, autophagy, and ER stress [5,14]. Indeed, the circadian rhythms' extensive regulation of the liver function and of the mechanisms to cope with cellular stress justifies that a circadian rhythm dysfunction is associated with the development of MASLD and its progression to steatohepatitis, cirrhosis, and hepatocellular carcinoma [6]. Accordingly, animal models with genetically modified mice deficient in circadian clock genes (Clock, Per-1/2) develop obesity, insulin resistance, metabolic syndrome, hepatic steatosis, and fibrosing steatohepatitis, on a regular diet [27,28,29,30,31,32]. Furthermore, mice lacking Per-1/2, Cry-1/2, or deficient in Bmal-1 are prone to radiation-induced tumors, including hepatocellular carcinoma [33,34]. Furthermore, Clock knockout in the ApoE deficient mice or in the high-fat diet MASLD models, accelerates fibrosis progression [32], cirrhosis, and hepatocellular carcinoma development [31]. Studies on human hepatocellular carcinoma showed a lower expression of clock genes in the malignant tissue as compared to non-tumoral tissue, which coupled with disturbances in the cell cycle and correlated with tumor size [35].
3. Disrupted Eating Patterns Are Associated with the Metabolic Syndrome, MASLD, and Hepatocellular Carcinoma
The famous quote from the XII century medieval philosopher Maimonides (also known as Rambam) "eat like a king in the morning, a prince at noon, and a peasant at dinner" summarizes the concept of chrononutrition, in which the timing of eating should be aligned with our circadian rhythms [36].
Energy homeostasis presents a circadian variation, so as to adjust to different energy requirements and food availability throughout the day. Homeostasis depends on the synchronization between the brain's central clock which controls feeding–fasting cycles, and the peripheral clocks (such as the liver, pancreas, and skeletal muscle), which regulate metabolism to maintain normoglycemia throughout the circadian cycle [37].
During the day, food availability goes hand in hand with energy storage, with nutrient uptake (for example, BMAL-1 promotes the expression of GLUT-2 glucose transporter [38]) and the synthesis of hepatic glycogen, triglycerides, and proteins. Conversely, at night (or in situations that increase demands, such as exercise), energy derives mainly from fueling the reservoirs and gluconeogenesis [6]. Indeed, during sleeping at night, we must adapt to an extended period of total fasting [39].
Melatonin's secretion/levels present a circadian pattern, which is regulated by the central clock in response to the circadian phase and light exposure. Melatonin levels start to increase hours before sleep, reach maximum levels during sleep, and thereafter progressively decline in the first few hours after the habitual wake time, sustaining nadir levels during the day [40]. Melatonin impairs glucose homeostasis by suppressing insulin release and insulin sensitivity [40].
Glucose tolerance also presents a 24 h cycle, which is inverse to the melatonin levels, with a lower glucose tolerance, and higher insulin response to meals, in the afternoon and night compared with the morning [39]. Interestingly, this effect is not reproduced by similar diurnal fasting in the absence of physical activity, when glucose tolerance persists, leading to a decrease in glucose levels, in clear contrast with the stable glucose levels during night sleep fasting, hence the French proverb "qui dort, dine", that is, "sleeping is dinning" [39]. The circadian increase in glucose intolerance and insulin resistance at night results from sleep-dependent and independent mechanisms. Indeed, the different sleep stages present different muscle tone and uptake as well as different glucose utilization by the brain (which, for example, is higher in the REM stage compared to non-REM sleep) [41].
The melatonin oscillations have a profound impact on chrononutrition. During the day, when melatonin is low, eating is synchronized with a high glucose tolerance. At night, high melatonin levels and glucose intolerance may help maintain normoglycemia. As such, eating at night is in misalignment with higher glucose intolerance and may promote diabetogenesis [40].
The circadian oscillations displayed in insulin sensitivity and glucose tolerance may also be related to counterregulatory hormones with circadian regulation such as glucocorticoids and catecholamines.
Glucocorticoids counteract insulin and promote gluconeogenesis while inhibiting tissue glucose uptake [39]. Cortisol levels present striking circadian oscillations, with a morning maximum, decreasing during the afternoon and evening, and with a nadir around midnight [39]. The apparent contradiction with the highest glucose tolerance coinciding with the cortisol peak can be explained by the 6 to 15 h delay in the effect of glucocorticoids on insulin sensitivity [42]. Furthermore, the clock protein CRY-1 represses the glucocorticoid receptor through direct interaction, decreasing cellular response to glucocorticoids [43]. Interestingly, CRY-1 levels are higher during the night–day transition, decreasing gluconeogenesis [44].
Epinephrine also stimulates gluconeogenesis through cAMP-mediated phosphorylation of cAMP-response element binding protein (CREB) [44]. Epinephrine presents a circadian rhythm with trough levels at 3:00H AM [45].
Hepatic circadian regulation also has major roles in lipids and bile acid metabolism. Indeed, the expression of the major regulators of lipid homeostasis sterol regulatory element binding proteins (SREBPs) and peroxisome proliferator-activated receptors (PPARs) present rhythmic oscillations, which are regulated by clock genes [46,47,48,49]. Accordingly, key enzymes in lipids and bile acid metabolism are under the control of clock genes: acetyl CoA carboxylase (ACC) for lipolysis [50], hydroxymethylglutaryl-CoA reductase (HMGCR) for cholesterol metabolism [51], and cholesterol 7-α hydroxylase (CYP7A1) for bile acid synthesis [52].
3.1. Preclinical Evidence of Chrononutrition
Animal studies showed that not only what we eat, but also when we eat, has a profound effect on metabolism and health.
Mice are nocturnal and hence their active phase and eating time is predominantly during the evening. However, a high-fat diet tends to blunt the circadian feeding rhythms [53].
Time-restricted feeding decreases the triglycerides hepatic content in mice, even when fed a regular diet [29]. Furthermore, restricting the eating time, independently of the eating schedule being restricted to the day or the night, protected mice against obesity, insulin resistance, and MASLD induced by a high-fat diet, in parallel with improvements in the cyclic oscillations of the liver metabolome and energy homeostasis [54,55].
Lastly, feeding cycles can restore the circadian oscillations of the transcriptome in mice with a genetically disrupted clock [56].
3.2. Intermittent Fasting and MASLD
A 2024 meta-analysis on seven randomized controlled trials in a 2–3 month intervention with intermittent fasting on patients with MASLD, suggested a beneficial effect on body weight and abdominal adiposity, lipids and glucose profiles, and liver fat, with no effect on liver fibrosis [57]. Of note, the studies were small and highly heterogeneous regarding the type of fasting regimens (Table 1).
Intermittent fasting regimens are highly variable and can be divided into periodic fasting, in which caloric intake is limited in short periods of time, and time-restricted feeding, in which there is a time window in the day where feeding can occur [66]. Examples of periodic fasting are alternate-day fasting, which can allow up to 25% energy intake in the fasting days, and the 5:2 diet, with 2 non-consecutive days with an ad libitum diet, and a time-restricted diet for the remaining 5 days.
A time-restriction diet seems to better align with circadian oscillations; however, the feeding schedule may have an impact on its effects.
3.3. Eating Patterns and Obesity-Associated Diseases in Humans
Eating regular meals, as compared to engaging in erratic and irregular meal schedules, seems to prevent the metabolic syndrome, particularly to protect against insulin resistance [67]. Also, it seems to be associated with lower liver enzymes [68].
Small interventional studies suggest that eating meals earlier in the day, as compared to later, seems to promote weight loss and a healthier metabolic profile [69,70,71,72,73,74] (Table 2).
Almost one-third of the Western population does not eat breakfast [79]. Several large-scale cross-sectional and longitudinal epidemiological studies in humans showed that skipping breakfast might be associated with weight gain and obesity [80,81,82,83], even though some small cross-sectional studies failed to demonstrate it [84]. The effect ranged from a 30% to 450% increased risk in Western and Asian populations [81,82,83]. Skipping breakfast might also promote the development of the metabolic syndrome [85,86,87,88], although, again, some studies failed to demonstrate it [89,90]. Importantly, skipping breakfast has not only been associated with an increased risk of MASLD [91] but also with higher cardiovascular and cerebrovascular mortality in patients with MASLD [92]. Eating breakfast may minimize subsequent caloric intake since the ability to achieve satiety with a meal is higher at breakfast and declines throughout the day, in a macronutrient-specific fashion [93]. As such, eating carbohydrates, lipids, or proteins at breakfast is associated with lower carbohydrates, lipids, or proteins intake, respectively, during the rest of the day [93]. The satiety effect of breakfast is coupled with an increase in the satiety hormones peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) [94]. Furthermore, breakfast allows for the "second meal phenomenon", in which insulin secretion after breakfast suppresses plasma-free fatty acids, improving muscle and hepatic insulin sensitivity [95], resulting in better glycemic control after lunch [96]. Lastly, having breakfast advances the circadian phase regarding body temperature and heart rate, and promotes a shift to an early chronotype, acting as a zeitgeber endorsing synchronization with the light–dark cycle [97,98,99].
Lunchtime has also been associated with body weight. In weight loss experiments, early eaters, who had lunch before 3:00 PM, lost weight more efficiently as compared to those who had lunch after 3:00 PM, independently of energy intake, composition of the diet, and energy expenditure. Proposed mechanisms were an association between late lunch and evening meals, less energetic breakfast or the more frequent skipping of breakfast, and possible genetic polymorphisms in clock genes that could predispose to late chronotype [76,78] (Table 2).
A distribution of the energy intake with a higher fraction consumed at dinner, having a late dinner, snacking after dinner, and sleeping shortly after the last meal have also been associated with weight gain, metabolic syndrome, and MASLD [75,100,101,102,103,104,105] (Table 2).
Even though it is not consensual in epidemiological studies [81,106], eating more than four meals seems to be associated with a 15–50% increased risk of obesity [83,107,108,109] and up to a two-fold increased risk of abdominal obesity [84,108,109,110], as well as metabolic syndrome [102]. A 2023 meta-analysis of six randomized controlled trials found a trend between eating at least four meals per day and a higher body mass index (BMI) and fat mass [111]. Of note, epidemiological studies found conflicting results between eating three or fewer meals and BMI [112,113]. Lastly, eating more than three meals also seems to be associated with a 20% increased risk of MASLD (assessed by ultrasonography), with a dose-response effect, in a large-scale cross-sectional Japanese study [114].
Fast eaters, that is, those who eat a meal in less than 5–15 min, also seem to be at a higher risk of excess weight, obesity, and abdominal obesity, independently of physical activity and energy intake [115,116,117,118]. It also seems to be associated with metabolic syndrome [89]. Accordingly, fast eating seems to increase the risk of MASLD by 20% [104,119,120,121,122,123]. Fast eating abrogates the PYY and GLP-1 response to eating, failing to achieve its beneficial effects such as satiety [124].
In conclusion, the daily energy intake should decrease throughout the day, distributed in the conventional three-meal pattern, always favoring breakfast, and a light early dinner [29].
3.4. Intestinal Microbiota and Chrononutrition
Both mice and humans present a circadian cyclic fluctuation in the composition of the intestinal microbiota (in around 15% of the operational taxonomic units) and function, as reflected by fluctuations in one-fourth of the microbial gene expression (microbiome) [125,126,127]. The diurnal oscillations in the intestinal microbiota are modulated by feeding rhythms. The manipulation of the feeding time schedule not only shifted the kinetics of bacterial abundance but also dramatically changed the relative abundance of some bacteria, hence inducing dysbiosis [128].
In mice deficient in clock genes Per1/2, the circadian fluctuations of the intestinal microbiota were abrogated, but they could be restored by timed feeding. Furthermore, a high-fat diet and chronic jet lag also abrogated the rhythmicity in the microbiota composition, favoring a more obesogenic phenotype, namely with a higher Firmicutes/Bacteroidetes ratio. Alongside this, both a high-fat diet and chronic jet lag induced rapid weight gain and insulin resistance independently of the food intake. Lastly, the transfer of fecal microbiota from humans submitted to flight-induced jet lag into germ-free mice resulted in mice weight gain and in the development of insulin resistance [126].
In humans, small trials with intermittent fasting/time-restricted feeding and observations in Ramadan also showed modulation of the intestinal microbiota, toward less obesogenic (with an increase in Firmicutes) and anti-inflammatory (for example, with an increase in Faecalibacterium, Butyricoccus, and Prevotella), despite high heterogeneity of the results, with different bacteria popping out in those trials [129,130,131,132,133,134,135,136].
4. Misalignment with Light–Dark Cycles Induces the Metabolic Syndrome, MASLD, and Hepatocellular Carcinoma
The famous quote from Aristotle, in the IV BC century "it is good to rise before dawn, for such habits contribute to health, wealth and wisdom", translates the benefits of aligning the sleep–awake cycles with our central circadian clock and light–dark natural cycles.
Circadian misalignment can be induced by exposure to artificial light during the night, rotating night shift work, and irregular sleep–awake cycles [137].
4.1. Artificial Light at Night (ALAN)
In mice, artificial light at night (ALAN) increases BMI and decreases glucose tolerance, in parallel with a shift in the eating time for the light phase, independently of an increase in calorie intake or physical activity [138]. ALAN exposure disrupted the core circadian rhythms in the central clock changing the mice's feeding behaviors, and in the peripheral clocks, particularly the liver and adipose tissue, resulting in weight gain despite no change in total daily food intake [139,140]. Blue light (for example, cold-white LEDs), mainly in the 480 nm range, is particularly prone to disrupt the circadian central clock by influencing the sensor iPRGCs [141].
ALAN can result from both indoor and outdoor sources (such as streetlights, billboards, light from commercial buildings, and houses) [142]. Indoor exposure sources are lamps and devices. Importantly, 90% of the Western population use technological devices before sleep, mostly television, phones, and tablets [143]. Up to 25% of the global area of land is under light-polluted skies during the night, and 80% of the world's population is exposed to ALAN [144].
Cross-sectional studies have suggested an association between indoor exposure to ALAN and an over 50% increased risk of obesity and abdominal obesity, dyslipidemia, and other components of the metabolic syndrome [145,146]. Insulin resistance and metabolic syndrome have been linked not only to ALAN before sleep but also to light exposure during sleep, which was coupled with an increased sympathetic tonus and altered pattern of sleep characterized by less slow wave and rapid eye movement during sleep [147,148,149]. Large-scale epidemiological studies suggest that compared with dark nights, exposure to ALAN is associated with an up to 50% increased dose-dependent risk of type 2 diabetes mellitus, independently of sleep duration, physical activity, baseline cardiometabolic health, and genetic risk [150,151,152]. Brighter night light and darker days have also been associated with a 15–20% increase in all-cause mortality, which was not modulated by sleep duration [153].
Exposure to outdoor ALAN also imposed a dose-dependent increased risk of type 2 diabetes mellitus (up to 28% increased risk), obesity (exposure associated with around 1 kg/m2 higher BMI), and the metabolic syndrome [154,155,156].
In addition to the direct disruptive effect on the circadian clocks of ALAN exposure, subjects reporting extensive use of devices with screens, tend to engage in less healthy diets, eating in front of the television, and higher consumption of fast food, which further increases the risk of obesity and metabolic dysfunction [157].
A simple preventive measurement to decrease the risk of metabolic dysfunction and diabetes would be to turn off the lights at night and to prefer dim and "warm" light that showed a less pronounced impact on the circadian clocks [150].
4.2. Rotating Night Shift Work and Long Working Hours
Submitting mice to chronic jet lag induces the spontaneous development of MASLD, steatohepatitis, fibrosis, and hepatocellular carcinoma [34,158]. Chronic jet lag induced a profound shift in the liver metabolism toward glycolysis, oxidative stress, suppression of FXR, and cholestasis. Both cholestasis and increased sympathetic tonus during sleep drove constitutive androstane receptor (CAR) overexpression, which induced hepatocarcinogenesis [34]. Chronic jet lag also heightened the hepatocarcinogenic potential of the chronic diethylnitrosamine model, which could be counterbalanced by time-restrictive diets [159].
After transmeridian travel crossing eight time zones, humans require 8 days to resynchronize the circadian clocks when traveling from west to east and 4 days from east to west [160]. A weekly 8 h night shift work schedule resembles chronic jet lag [161]. In most industrialized countries, 15–20% of workers engage in night work [162].
Small interventional studies in healthy subjects who were submitted to short-term night shift work showed an increase in glucose intolerance and insulin resistance, independently of the amount of sleep, diet, or physical activity [163,164]. Importantly, peripheral clocks such as the muscle did not align with the new behavioral cycle [163,164]. Working at night shifts is associated with eating during the evening, when insulin sensitivity is low, as dictated by the natural circadian oscillations in glucose metabolism [165].
Several meta-analyses showed that night shift workers have up to a 25% increased risk of overweight/obesity, 35% of abdominal obesity [166], over 50% of metabolic syndrome [167], and 15% of type 2 diabetes mellitus [168]. This increased risk of obesity and obesity-associated conditions presented a dose-response regarding the frequency of night shifts and the lifetime duration of night shift work [169,170,171]. Diabetic patients on night shifts present worse glycemic control, independently of body weight or caloric intake [172].
Several large-scale epidemiological studies from the USA or Asia evaluated the association between night shift work and MASLD and found an increased risk of around 25% [173,174,175,176,177,178]. Those associations were higher in subjects with normal weight compared to obese subjects [179], in younger subjects, and in women [176]. The association between night shifts and MASLD was not modified by the genetic risk of MASLD [175] and showed a dose-response for the length of night shifts (in hours), number of night shifts, and lifetime duration of night shift work [173] (Table 3).
Night shift work has also been associated, in large-scale epidemiological studies, with all-cause mortality and cardiovascular, respiratory, and digestive mortality. Subjects who engaged in night shift work for over 20 years presented a 50% increase in all-cause mortality and a two-fold increase in cardiovascular mortality [181].
The effects of night shift work could be mitigated by resynchronization of circadian clocks through timed meals. Indeed, in a randomized controlled trial in firefighters who work 24 h shifts, a time-restricted diet improved the lipids and glucose profile, as well as blood pressure in subjects with pre-existing high cardiometabolic risk, independently of caloric intake or weight loss [182].
Working long hours, that is, more than 55 h per week, seems to be associated with an increased risk of obesity [183], metabolic syndrome, type 2 diabetes mellitus [184], increased levels of aminotransferases [185], and a 25% increased risk of MASLD [184,186]. It has also been associated with cardiovascular diseases [187].
Possible explanations for the deleterious effect of working long hours could be its association with insufficient rest time and sleep quality [188], engaging in an unhealthy diet [189,190,191], and unavailability to practice exercise [192,193,194] in overworking subjects. Furthermore, long working hours have been linked to other unhealthy habits such as smoking and drinking alcohol [195].
4.3. Extreme Chronotype
There are two types of extreme chronotypes: (1) early larks or morning types that wake up and sleep early and, (2) night owls or evening types that wake up and sleep late.
A 2023 systematic review of seven studies showed that evening chronotype individuals are more likely to present insulin resistance and higher plasma levels of ghrelin (the "hunger hormone"), with a trend to a higher BMI [196]. In accordance, cross-sectional epidemiological studies suggested that evening chronotype/late sleepers endure a higher risk of type 2 diabetes mellitus and metabolic syndrome [197,198].
Large-scale cross-sectional Chinese studies in diabetics/prediabetics and in the general population showed a dose-dependent increase in the incidence of MASLD in those who engaged in late bedtime, after adjusting for sleep duration. They showed a 30% increase in the prevalence of MASLD per hour of late bedtime with a 50% increase when bedtime was 08:00–10:00 H PM and a two-fold increase when after 10:00 PM, as compared to before 08:00 PM [199,200]. A study taking advantage of the US NHANES confirmed an association between late sleepers, that is, those who sleep after midnight, and hepatic steatosis and fibrosis [201].
One possible explanation could be a sleep debt in late sleepers, which is associated with a decreased carbohydrate tolerance and increased sympathetic nervous system tonus [202], as well as increased caloric intake as there is more time and opportunities to eat and greater sensitivity to food reward [203]. Late sleeping results in higher exposure to ALAN. Furthermore, late sleepers more frequently engage in sedentary activities such as watching television and using electronic devices [204], and unhealthy eating habits such as more snacking, irregular meals, and drinking soft beverages [205,206].
An environmental equivalent to an evening chronotype is the geographical exposure to a later sunset. Indeed, subjects living in the Western region of a specific time zone are exposed to less light early in the day and more light later in the day, as compared to subjects living in the Eastern region of the same time zone, which promotes a shift phase and misalignment in the circadian clock. A large epidemiological study suggested that a 5-degree increase in longitude toward the west within a time zone is associated with a 7% increased risk of hepatocellular carcinoma development [207].
4.4. Irregular Sleep–Awake Cycles
A 2023 meta-analysis suggested that sleeping for short hours (less than 5–6 h per day) is associated with a 15% increased risk of MASLD [208], even though previous meta-analyses failed to demonstrate this association [209,210]. A large study taking advantage of the NHANES 2017–2000 pointed out the inflection point of 7.5 h per day [211]. Furthermore, bedtime sleep after midnight was associated with a 2.5-fold increased risk of significant fibrosis in patients with MASLD [211].
Social jet lag refers to short sleep duration during the week, which is compensated with longer hours of sleep during the weekends and free days [137]. The longer the gap of hours in the sleep duration between working days and the weekend, the higher the potential effects on health, coupled with a lower quality diet, obesity and central obesity, metabolic syndrome, and type 2 diabetes mellitus, particularly when over 2 h [212,213,214,215]. A social jet lag of at least 2 h was reported in 50% of workers and students [137].
Regarding day napping, a 2024 meta-analysis suggested that long naps (that is, longer than 30 min) during the day are associated with a 20% increased risk of MASLD [216]. A Mendelian randomization analysis of GWAS also found a positive correlation between day napping and hepatocellular carcinoma [217]. The possible mechanisms of the deleterious effect of day napping could be a tendency to night late sleeping and short sleep duration, and an increase in cortisol and sympathetic tonus [218,219].
A study taking advantage of the National Health Insurance Research Database from Taiwan found a 44% increased standardized incidence of hepatocellular carcinoma in patients with sleep disorders (after the exclusion of sleep apnea) [220]. Lastly, a Mendelian randomization analysis of GWAS found that sleep duration negatively correlated and insomnia positively correlated with the risk of hepatocellular carcinoma [217].
5. Conclusions
Circadian rhythms have a profound impact on the regulation of metabolism, particularly hepatic metabolism. Liver clocks are subsidiary to the central clock in the hypothalamus that synchronizes predominantly with the natural light–dark cycle. Liver clocks also oscillate autonomously in response to feeding–fasting cycles. Circadian misalignment of the liver clocks promotes metabolic dysfunction, MASLD, and hepatocarcinogenesis.
From the realization of the circadian modulation in the pathogenesis of MASLD, a new approach is gaining enthusiasm: chrononutrition, the concept that not only what we eat, but when we eat can modulate health and disease. Indeed, time-restricted diets could be of help, depending on the feeding time schedule. Caloric ingestion should start with breakfast, and decrease throughout the day, with an early last meal, and no dietary guilty pleasures after dinner. The classical three meals distribution seems suitable, and additional meals or snacks should be avoided.
Another concept that should be explored more is chronopharmacology since most targets for the treatment of MASLD (for example, thyroid hormone receptor, GLP-1, and FGF-21) are under circadian oscillation.
Lastly, circadian sleep–awake cycle misalignment, such as night shift schedules, seems to strongly negatively affect metabolic health and promote MASLD development. Resynchronization through time-restricted diets may be a simple, effective strategy to mitigate those deleterious effects.