Role of Melatonin in the Pathogenesis of NAFLD

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1		Dimitar Terziev, PhD	--	2923	2023-06-21 15:06:51	\|
2	format correction	Dean Liu	-41 word(s)	2882	2023-06-25 04:01:41	\|

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11061722

Endogenous melatonin, an indoleamine hormone synthesized by the pineal gland mainly at night, is a powerful chronobiotic that probably regulates metabolic processes and has antioxidant, anti-inflammatory, and genomic effects. Extrapineal melatonin has been found in various tissues and organs, including the liver, pancreas, and gastrointestinal tract, where it likely maintains cellular homeostasis. Melatonin exerts its effects on NAFLD at the cellular, subcellular, and molecular levels, affecting numerous signaling pathways.

nonalcoholic fatty liver disease metabolic syndrome melatonin experimental data signaling pathways

1. Introduction

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide, affecting over 25% of the United States and global populations ^[1]. The disease is characterized by the accumulation of droplets of lipids and mainly triglycerides within hepatocytes (steatosis), with the advanced form known as nonalcoholic steatohepatitis (NASH) ^[2]^[3]. The latter is a clinical syndrome of steatosis and hepatic inflammation that is diagnosed via liver biopsy and subsequent histological examination, after other causes of liver disease have been excluded ^[3]. For the diagnosis of NASH, the establishment of three pathognomonic features on liver biopsy is important—hepatocellular ballooning, lobular inflammation, and steatosis ^[2]. The differentiation of NASH from NAFLD is of great importance for determining the prognosis of the disease ^[4]. In NASH, superimposed inflammation can lead to progressive fibrosis and increase the risks of cirrhosis, liver failure, and hepatocellular carcinoma ^[1]^[2]^[3]. From this point of view, it can be noted that NAFLD covers a wide range of liver pathology—from steatosis alone through steatohepatitis to liver cirrhosis and cancer ^[5]. NAFLD is poised to become the leading indication for liver transplantation in North America and areas of Europe ^[6]. According to Charlton et al. ^[7], NASH is the third most common indication for liver transplantation in the United States, and the frequency of NASH as an indication is steadily increasing. NASH is the only indication for liver transplantation that was seen to increase from 1.2% in 2001 to 9.7% in 2009.

Over the past few years, several hypotheses have attempted to explain the role and meaning of a number of risk factors for the development of NAFLD. Although many specific features of the disease have been elucidated, there are still many unanswered questions about the pathogenetic mechanisms underlying the disease. For this reason, it is still believed today that the pathogenesis of NAFLD is not completely characterized ^[8]. Associations between obesity, type 2 diabetes mellitus (T2DM), and fatty liver (steatosis) have long been recognized, as has the high prevalence of cirrhosis in diabetes ^[5]. The best-known risk factors for NASH are obesity, T2DM, and lipid abnormalities (hypertriglyceridemia) ^[3]^[5]. It is widely considered that NASH is thought to be the hepatic manifestation of metabolic syndrome ^[2]. A large proportion of patients with NAFLD have metabolic comorbidities, such as obesity, T2DM, hyperlipidemia, hypertension, and metabolic syndrome ^[9]. However, it should be noted that not all patients with these comorbidities have NAFLD/NASH, and not all patients with NAFLD/NASH suffer from one of these conditions ^[10]. An international panel of experts recommended that when there is evidence of hepatic steatosis coexisting with one of the criteria of overweight/obesity, presence of T2DM, and evidence of metabolic dysregulation, to use the term metabolic dysfunction-associated fatty liver disease (MAFLD) ^[11]. In fact, complex metabolic disorders, such as central obesity, hyperglycemia, hyperlipidemia, hypertension, insulin resistance, and hepatic steatosis, which are risk factors for cardiovascular diseases and T2DM, fill the content of the concept of metabolic syndrome ^[12]. In addition to these disorders and genetic factors, physical inactivity, pro-inflammatory state, and hormonal changes are believed to play a role in the development of metabolic syndrome ^[13]. Essential characteristics of hepatic metabolism are its high dynamics, its influence on fasting/fed state, and circadian rhythms ^[14]. It is believed that, on the one hand, the liver circadian clock is strongly influenced by feeding/fasting rhythms, which is associated with altered activity of genes regulating the metabolism of glucose, lipids and bile acids, autophagy, and stress of the endoplasmic reticulum. Diet and feeding/fasting rhythms also modulate the cyclical change in the gut microbiome. On the other hand, peripheral circadian rhythms, including those of the liver, are regulated by the biological clock located in the hypothalamic suprachiasmatic nucleus ^[15]. It can be concluded that the desynchronization of these processes, both at the central and peripheral level, would be important in a number of metabolic disorders that occupy a leading place in the pathogenesis of NAFLD.

One of the hormones that has a pronounced circadian rhythm of secretion with physiologically high values in the blood at night is melatonin. More than 20 years ago, the presence of high-affinity melatonin receptors in mouse hepatocytes, whose binding affinity to melatonin was affected by blood glucose levels, was established ^[16]. There is evidence that melatonin administration reduces body weight in obese laboratory rats, but melatonin efficiency was time dependent ^[17]. In aged obese rats, insulin sensitivity is increased after melatonin supplementation, suggesting that an age-related decline in melatonin secretion is likely to play a role in the development of insulin resistance in aged organisms ^[18]. The close relationship observed between insulin resistance and NAFLD is confirmed by elevated free fatty acid levels during fasting and a reduced suppression of lipolysis after insulin administration, which strongly correlate with the degree of fatty infiltration of the liver ^[19].

2. Therapeutic Potentials of Melatonin in NAFLD

In 2019, Baiocchi et al. ^[20] expressed the opinion that all studies related to the potential therapeutic effects of melatonin on NASH in rodents and humans did not pinpoint the possible molecular mechanisms by which melatonin protects against NASH but, rather, focused only on the general antioxidant and cytoprotective properties of melatonin in this setting. Two years earlier, Zang et al. ^[21] analyzed the protective effect of melatonin on liver injuries induced by various factors and liver diseases, such as liver steatosis, non-alcohol fatty liver, hepatitis, liver fibrosis, liver cirrhosis, and hepatocarcinoma. According to Sato et al. ^[22], melatonin has potential for novel treatments of liver diseases by decreasing oxidative stress or restoring circadian rhythms and functions. However, related studies of melatonin applied to clinical treatment for liver injuries and diseases are limited ^[21]. Mohammadi et al. ^[23] administered melatonin (10 mg/day), metformin (500 mg/day), and vitamin E (800 IU/day) to patients with NAFLD for six months and found that melatonin reduced serum aminotransferases, triglycerides, cholesterol, and fasting glucose when comparing these parameters before and after medication with melatonin. When comparing these indicators against a control group (received plasibo), only low-density lipoprotein and AST had significant changes. Based on the improvements shown via ultrasonography, the greatest improvement was demonstrated with metformin, and the authors concluded that metformin is a better choice for the treatment of these patients. Mohammadi et al. ^[23] suggested that melatonin can be considered an effective treatment of NAFLD, as this drug made improvements in different aspects of NAFLD injuries. Gonciarz et al. ^[24] evaluated the effects of 24 weeks of lifestyle intervention combined with 10 mg/day melatonin treatment (5 mg at 09:00 h and 5 mg at 21:00 h) on plasma liver enzyme levels of AST, ALT, gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), concentrations of lipids (total cholesterol, triglycerides), glucose, and melatonin in 30 patients with NASH. A control group of 12 patients with NASH who received placebo was used for comparison. The study demonstrates that AST and GGT levels decreased significantly only in the melatonin-treated group. The decrease in median plasma ALT level in the melatonin-treated group at weeks 18 and 24 was significantly more intense (p < 0.5) than that observed in the control group; however, at follow-up, the difference between the two groups was not significant. The higher ALT, AST, and GGT levels shown at follow-up in comparison with those found at the 18th and 24th weeks of treatment reflected the high efficacy of melatonin, linked closely to the period of medicine administration. Plasma concentration of melatonin (pg/mL) in the melatonin-treated group averaged 7.5 ± 3.5 at baseline and increased to 52.5 ± 17.5 at the 24th week, no patients complained of somnolence, and no significant side-effects were observed. Cichoz-Lach et al. ^[25] evaluated the effects of melatonin and L-tryptophan on selected biochemical parameters and proinflammatory cytokines of blood in 45 patients with NASH divided into three groups: the first group received preparation Essentiale forte three times a day and L-tryptophan 500 mg twice a day; the second group received Essentiale forte in the above doses and melatonin 5 mg twice a day; the third group received only Essentiale forte three times a day. The treatment lasted 4 weeks. In all participants, plasma biochemical parameters (ALT, AST, ALP, GGT, bilirubin, total cholesterol, triglycerides, LDL, HDL) and cytokines (IL-1, IL-6, and TNF-α) were measured after 4 weeks of treatment and were compared with the results evaluated at the start of the study. The study showed that the addition of melatonin or its precursor, L-tryptophan, to Essentiale forte therapy resulted in a statistically significant decrease in the plasma levels of key pro-inflammatory cytokines, such as IL-1, IL-6, and TNF-α. This effect can be explained by the antioxidant action of melatonin and leads to an improvement in the therapy of NASH. The beneficial effect is also accompanied by a decrease in GGT and triglyceride levels. Based on the results obtained, these researchers suggested that treatment with melatonin is very important in the prevention of the progression of liver damage in NAFLD and NASH. A similar design was used in the study of Celinski et al. ^[26], which also determined the effects of tryptophan and melatonin on the biochemical parameters in patients with NAFLD. In addition, they evaluated the effects of tryptophan and melatonin in improvements of liver tissue in selected NAFLD patients (n = 9) after 14 months of a treatment period. Significantly reduced activity of GGT and values of triglycerides, LDL-cholesterol, IL-1, IL-6, and TNF-α were found in the groups that received melatonin and tryptophan compared to the group that received only Essentiale forte. The study findings demonstrated that melatonin and tryptophan substantially reduce the levels of pro-inflammatory cytokines and improve some parameters of fat metabolism in patients with NAFLD. In a few patients with NASH, melatonin and tryptophan reduced the inflammation in the liver. It was concluded that melatonin is worth considering for the therapy of NAFLD, especially in patients with impaired fat metabolism (hypertriglyceridemia and hyper-LDL cholesterolemia). No side effects of melatonin and tryptophan were observed; for instance, no patients complained of excessive sleepiness and/or dizziness. Pakravan et al. ^[27] studied the effect of melatonin in 100 patients with NAFLD aged 22 to 65 years, divided into two groups: a case group (n = 50) who received melatonin tablets twice a day for 6 weeks, and a control group (n = 50) who received a placebo twice daily for the same period of time. During the study, the patients followed the same diet and exercise regime. Results showed that in the case group, the mean of weight, waist, systolic and diastolic blood pressure, high-sensitive C-reactive protein, and ALT after treatment was significantly decreased compared to baseline; also, melatonin significantly decreased diastolic blood pressure, AST, and high-sensitive C-reactive protein in case group more than the control group. In addition, most of the patients who received melatonin grade of fatty liver improved more than the controls. These results demonstrated that the use of melatonin in patients with NAFLD was more affected than placebo, with no serious side effects. Melatonin significantly decreases liver enzymes in cases more than the placebo; therefore, the use of melatonin in patients with NAFLD can be effective.

It is hypothesized that new compounds that act as specific melatonin agonists or antagonists will contribute to a better understanding of melatonin’s mechanism of action ^[28]. Melatonin analogues (agonists and antagonists) differ in their chemical structure and affinity for melatonin receptors ^[29]. Currently, powerful, lipophilic, non-selective MT1/MT2 high-exposure agonists in the brain, such as Ramelteon, Agomelatine, Tazimelteon, and prolonged-release melatonin (Circadin), are approved for the treatment of insomnia, depression, and circadian rhythm sleep–wake disorders ^[30]. In a systematic review, Freiesleben and Furczyk ^[31] evaluated the potential risk posed by agomelatine as an antidepressant in inducing liver injury. Agomelatine was found to be associated with higher rates of liver injury than both placebo and the four active comparator antidepressants used in the clinical trials for agomelatine, with rates as high as 4.6% for agomelatine compared to 2.1% for placebo, 1.4% for escitalopram, 0.6% for paroxetine, 0.4% for fluoxetine, and 0% for sertraline. The review also provided evidence for the existence of a positive relationship between agomelatine dose and liver injury. According to researchers, it is essential that clinicians continue to monitor liver function frequently, as prescribed by the manufacturer of agomelatine. Early detection followed by best-practice treatment plan reactions (e.g., treatment discontinuation) remain the most efficient responses toward possible manifestations of liver damage. Ferreira et al. ^[32] reported the discovery of a new powerful melatonin receptor agonist, benzoimidazole derivative compound 10b, which reduced weight gain, liver triglycerides, and steatosis in HFD rats. Two-month oral administration of 10b in high-fat-diet rats led to a reduction in body weight gain, with superior results on hepatic steatosis and triglyceride levels. An early toxicological assessment indicated that 10b (also codified as ACH-000143) was devoid of genotoxicity, and there were behavioral alterations at doses up to 100 mg/kg p.o. Based on its efficacy, oral pharmacokinetics, and safety, compound 10b was selected for further investigation as a candidate drug against NAFLD/NASH.

Melatonin Side Effects

In 2001, Chung ^[33] reported that for 6 weeks, three patients attended the emergency department after attempting suicide by taking an overdose of melatonin. Their hospital stay was uneventful, but the report states that the emergency physicians were still unfamiliar with the management of melatonin “overdose”, and it is advisable to monitor for adverse effects, such as drowsiness, confusion, tachycardia, and hypothermia. In 2005, Waldron et al. ^[34] drew attention to the fact that there was a shortage of randomized controlled trials to demonstrate the efficacy of melatonin therapy, and that the lack of pharmacokinetics, pharmacodynamics, and toxicology data limits knowledge of therapeutic dose ranges, formulations, and adverse effects. Later, in 2017, Erland and Saxena ^[35] quantified melatonin in 30 commercial supplements, comprising different brands and forms, and screened supplements for the presence of serotonin. The melatonin content was found to range from −83% to +478% of the labelled content, and serotonin was identified in eight of the supplements at levels of 1 to 75 μg. The significant variability in the melatonin content of analyzed additives and the presence of serotonin indicate the pressing need for mechanisms to monitor the melatonin content in these products, which will ensure the safety of supplements. In a number of countries (United Kingdom, Japan, Australia, European Union, and, most recently, Canada), exogenous melatonin is regarded as a medicine and available only through prescription ^[36].

Buscemi et al. ^[37] conducted a systematic review of the efficacy and safety of exogenous melatonin in managing secondary sleep disorders and sleep disorders accompanying sleep restriction, such as jet lag and shift-work disorder. The most commonly reported adverse events were headaches, dizziness, nausea, and drowsiness, but the occurrence of these outcomes was similar for melatonin and placebo. Lemoine et al. ^[38] investigated the efficacy, safety, and withdrawal phenomena associated with 6–12 months prolonged-release melatonin treatment in 244 adults with primary insomnia. In 7% of the patients, the adverse events were considered by the investigator to be definitely, probably, or possibly related to the study medication. Of these, the most commonly reported adverse events were dizziness in four patients (1.6%) and headache in three patients (1.2%). No noticeable changes were found in hematologic and biochemical laboratory tests at any timepoint during the study. Khezri and Merate ^[39] evaluated the effects of melatonin premedication on anxiety and pain scores of patients, operating conditions, and intraocular pressure during cataract surgery under topical anesthesia. Sixty patients were randomly assigned to receive either sublingual melatonin 3 mg or placebo 60 min before surgery. Only one patient in the melatonin group complained of mild headache. Ismail and Mowafi ^[40] evaluated the effects of melatonin premedication on pain, anxiety, intraocular pressure, and operative conditions during cataract surgery under topical analgesia. Forty patients undergoing cataract surgery under topical anesthesia were randomly assigned into two groups (twenty patients each) to receive either a melatonin 10 mg tablet (melatonin group) or placebo tablet (control group) as oral premedication 90 min before surgery. One patient in the melatonin group complained of dizziness, and another patient in the control group suffered nausea. In a study by Esmat and Kassim ^[41], 75 patients were randomly divided into three groups: C group (n = 25), each patient received transdermal placebo patch, TDF group (n = 25), each patient received transdermal therapeutic system-fentanyl 50 μg/h, and TDM group (n = 25), each patient received transdermal therapeutic system containing 7 mg of melatonin. All patches were placed 2 h preoperatively and were applied to the skin in the subclavicular area. The patch was removed 12 h postoperatively. As regards side effects, all cases of the three groups were hemodynamically stable, no patient developed hypoxia, and there were no reported intraoperative complications interfering with the course of surgery or interrupting the surgeons. Two patients in the C group suffered from nausea (p = 0.08). Regarding adverse effects in patients who received TDM, patients were more sedated (p < 0.05) and two patients were dizzy (p = 0.08). Baradari et al. ^[42] investigated the effect of preoperative oral melatonin on the severity of postoperative pain after lumbar laminectomy/discectomy; 80 patients were selected and randomly assigned into one of four groups. Patients in groups A, B, C, and D received 3, 5, and 10 mg melatonin or placebo tablets one hour before surgery, respectively. Two patients in group A, one patient in group B, and two patients in the placebo group had postoperative vomiting, but the difference between the groups in terms of postoperative vomiting was not statistically significant (p = 0.524).

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Dimitar Terziev

Dora Terzieva

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1. Introduction

2. Therapeutic Potentials of Melatonin in NAFLD

Melatonin Side Effects

References