CHRONOPHARMACOLOGICAL ASPECT ON IMPAIRMENT OF LIVER CIRCADIAN CLOCK AND HEPATIC DYSFUNCTION: A REVIEW

CHRONOPHARMACOLOGICAL ASPECT ON IMPAIRMENT OF LIVER CIRCADIAN CLOCK AND HEPATIC DYSFUNCTION: A REVIEW

Lopamudra Saha, Debarati Kar and Dipanjan Mandal *

Department of Pharmacy, Guru Nanak Institute of Pharmaceutical Science and Technology, 157/F, Nilgunj Road, Sodepur, Kolkata, West Bengal, India.

ABSTRACT: Hepatitis B, Diabetes, Alcoholic and Non-alcoholic Fatty Liver Disease, Cholangiocarcinoma, Cholangioleiomyopathies, and other risk factors for hepatic illness are all becoming more harmful nowadays. In animals, the dysfunction of melatonin levels and an unbalanced circadian rhythm can control physiological processes and cellular mechanisms during periods of rest and activity. The Suprachiasmatic Nucleus (SCN) in the Hypothalamus of the Brain and Melatonin production in the pineal gland control circadian rhythms and clock gene expressions. The main purpose of the study is to summarise the most recent research on the molecular mechanisms underlying Circadian Rhythm, including the core clock genes and melatonin release, and their relationship to chronic liver diseases. Also covered were the future methods for studying Circadian Rhythm's Chronopharmacological Aspects for the Treatment of Hepatic Diseases.

Keywords: Hepatic Diseases, Circadian Rhythms, Clock Genes, Chronopharmacology, Melatonin, Cholangiopathies

INTRODUCTION: Circadian Rhythm is an oscillating biological cycle in which all vital physiological processes, including metabolisms, take place ¹. SCN (suprachiasmatic nucleus) is situated in the hypothalamus works as a pacemaker and that synchronizes circadian clocks through the whole body according to bright and dark phases and is mediated by autoregulatory expression of clock genes like circadian locomotor output cycles kaput (CLOCK), brain and muscle ARNT-like 1 (BMAL1) which acts as activators, period circadian protein homolog 1 (PER1), PER2, cryptochrome circadian regulator CRY1, and CRY2 as repressors ².

Circadian rhythms control a variety of physiological processes, and they are also disrupted and affect the liver's metabolism and circadian rhythms. By analyzing many studies, it was shown that Circadian Clock-controlled mechanisms in the liver sustain physiologicalbile acid metabolism, glucose levels, lipid metabolism, and detoxification ³.

This review highlights the fact that many genes express various levels of participation in hepatic disorders. However, melatonin treatment has shown therapeutic effects in several conditions, including hepatocellular carcinoma, diabetes, cholangiocarcinoma, non-alcoholic fatty liver disease, and alcohol-induced fatty liver diseases ⁴.

By reducing oxidative stress and reestablishing circadian rhythms and functioning, melatonin has the potential to be an innovative medication for liver diseases ⁵.

Chronological Synchronization over Hepatic Function:

Circadian Clock on Glucose Metabolism: Cryptochromes, which encode glucocorticoid receptors, that interact with G protein-coupled receptors, control hepatic gluconeogenesis, and phosphoenolpyruvate carboxykinase (CREB) controls the activation of the transcription of gluconeogenic genes ⁶. According to studies, the overexpression of Cry1 in the liver of previously induced diabetic mice promotes insulin sensitivity and decreases blood glucose levels ⁷. In the hyperglycemic stage, glucocorticoids which also influence the expression of Per2, are guarded against glucose intolerance in glucocorticoid therapy ⁸. Through studies, it was shown that Krüppel-like factor 10 (KLF10) controls the expression of genes related to glycolysis and gluconeogenesis and that in male mice lacking KLF10, postprandial and fasting hyperglycemia resulted, whereas in female mice, it did not ⁹. Bmal1 ablation in hepatocytes decreased the expression of the glucose transporter Glut2 (Slc2a2) in mutant mice Fig. 1, which caused a reduction in post-absorptive glucose absorption ¹⁰. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1a) or Ppargc1a gene acts as a coactivator of the gluconeogenic transcription program and is generally controlled by BMAL1 ¹¹.

FIG. 1: GLUCOSE METABOLISM BY CIRCADIAN CLOCK

Circadian Clock on Lipid Metabolism: The Plasma levels of FFAs, TGs, and cholesterol rise after Rev-Erba/b is specifically targeted for hepatocyte ablation ¹². According to the study, ATP citrate lyase expression is higher level at the start of the active phase ¹³, which is when acetyl coenzyme A (acetyl-CoA) is exported from the mitochondria. According to Fig. 2, Cytosolic acetyl-CoA is carboxylated by acetyl CoA carboxylase to generate the malonyl CoA an essential step in fatty acid synthesis. The AMPK (PRKAA1) inactivates acetyl-CoA carboxylase by phosphorylation. The 'clock' 'temporally gates' acetyl-CoA carboxylase activity the expression of enzymes regulating b-oxidation (Cpt1/2) and ketone-body production (Hmgcs2) and their transcriptional regulators PPARα and β ¹⁴. Several genes, including Gpat2, Agpat1/2, Lpin1/2, and Dgat2, control the many circadian-regulated phases of TG synthesis. Additionally, the Circadian Clock regulates Pnpla3 transcription and also controls the dynamics of lipid droplets ¹⁵. A pronounced crest and trough of TG levels were seen in a study using ad libitum-fed mouse livers to show how the circadian clock regulates lipid metabolism throughout the rest (zt 8) and activity phases (zt 20). In a study, it was discovered that the expression of Insig2 is REV-ERB-controlled, which in turn affects the activity of SREBP1c and the Circadian Clock mechanism on lipogenesis ¹⁶.

FIG. 2: LIPID METABOLISM BY CIRCADIAN CLOCK

Circadian Clock on Carbohydrate Metabolism: Circadian Rhythm of transcription factors to the promoters of targeted genes by PEPCK (phosphoenol pyruvate kinase), FBP1 (fructose-1,6-bisphosphatase), and G6PC (glucose-6-phosphatase, catalytic subunit) includes oscillations of cellular molecular clocks ¹⁷. A high-sugar diet (HSD) was predicted and demonstrated in Fig. 3. To promote the expression of major transcription factors that regulate lipid, carbohydrate metabolism, SREBP1c, ChREBP, LXR, and PPAR ¹⁸. Sucrose separately synchronizes the breakdown of the connection between the metabolic pathways and the molecular circadian clock. By influencing the post-transcriptional processes involved in mRNA stability, fructose or fructose-derived metabolites and energy status play significant roles in raising the circadian oscillation amplitudes of lipogenic genes ¹⁹. A high consumption of sucrose promotes the development of fatty liver, hyperlipidemia, and lipogenesis, and a crucial component of this mechanism is the monosaccharide fructose ²⁰.

FIG. 3: CARBOHYDRATE METABOLISM BY CIRCADIAN CLOCK

Circadian Clock on Bile Acid Metabolism: In general, BAs are needed for intestinal lipid absorption. They are physiological ligands for the FXR (NR1H4) and the G-protein coupled receptor TGR5 (GPBAR1). These can activate the mitogen-activated protein kinase pathway ²¹. The amount levels of TGs, cholesterol, and glucose in the liver are controlled by BAs. The nuclear receptors like FXR and SHP (NR0B2), as well as FGF15 (FGF19 in human hormone), form a transcriptional feedback loop that, as shown in Fig. 4 ²², mainly controls the synthesis of BA. In the Bile acid synthesis pathway, the circadian transcription of cholesterol 7-hydroxylase (Cyp7a1) is driven by the expression of FXR and SHP60 in the liver and also in the intestinal secretion of FGF15 ²³. E4bp4, Shp, REV-ERBa, and other transcription factors all directly control Cyp7-1 expression ²⁴.

FIG. 4: BILE ACID METABOLISM BY CIRCADIAN CLOCK

Detoxification in Liver by Circadian Clock: Circadian Clock regulates practically all liver detoxification processes involving xenobiotics, including absorption, biotransformation, and excretion. In the case of humans, mornings are preferable to evenings for hepatic absorption of lipophilic medicines. The attachment of xenobiotics to nuclear receptors is the first stage of detoxification, mostly followed by transcriptional activation of detoxification pathways. Through different studies, it proved thatthe liver and other organs' circadian clock regulation in this step is controlled by the rhythmic expression levels of nuclear receptor genes ²⁵.

• When it comes to Phase 1 detoxification, different cytochromes involve substrate oxidation and proteins that are controlled in the liver in a circadian fashion. It demonstrated that the expression peaked when animals consumed food and had the greatest likelihood of coming into contact with food that became toxic.
• In the case of the second phase of detoxification, toxins, become excretable by becoming hydrophilic by conjugating enzymes, and the excretion is triggered by transporter proteins ²⁶.
• In the third phase of detoxification occurs at that time all classes of enzyme detoxification are rhythmically triggered through the binding of the liver-specific PAR bZIP proteins DBP, TEF, and HLF expressions ²⁷.

Melatonin Activity on Hepatocytes: The strong antioxidant properties of melatonin help to protect the liver from non-alcoholic fatty liver disease ²⁸. Melatonin supplementation boosted mass and decreased blood levels of total cholesterol and triglyceride in melatonin-deficit patients brought on by radiotherapy or in surgical excision of the pineal gland for three months ²⁹. Oleic acid lowered the expression of the -oxidation genes PPAR and carnitine palmitoyltransferase I (CPT1). It increases the expression of genes such as SREBP-1c, FAS, and stearoyl-CoA desaturase 1 (SCD1) in HepG2 cells Fig. 5 ³⁰. Melatonin therapy eliminated the consequences that prevented fat buildup. Melatonin suppresses the expression of Nuclear Receptor subfamily 4 group A member 1 (NR4A1). The activation of p53 reduces the production of cytokines, inflammation, and apoptosis ³¹.

A recent in-vivo investigation demonstrated, that the gonadotropin-releasing hormone (GnRH) secretion was inhibited by melatonin injection (1 mg/kg per day for 7 days via intracerebroventricular-implanted cannulas), that ameliorated ductular response of liver fibrosis ³². In another study, melatonin improved liver conditions by lowering serum levels of the enzymes alanine aminotransferase (AST) and aspartate aminotransferase (ALT), and that reduced the release of proinflammatory cytokines like IL-1 and TNF in the liver by reducing oxidative stress. The administration of melatonin, which increased Bcl-2 expression and decreased BAX expression, also attenuated the development of cholangiocarcinoma (CCA) ³³.

FIG. 5: OLEIC ACID ON HEPATIC CIRCADIAN RYTHM

Circadian Clock Regulation over Hepatic Disorders:

NAFLD: The spreading epidemic illness of Non-alcoholic Fatty Liver Disease (NAFLD) is currently 32.4% worldwide ³⁴. The pathology of NAFLD and its evolution in one research showed that itis influenced by circadian rhythms and sleep patterns. Bmal1 Clock regulates SREBP-1c, FASN, HMGCR, ELOVL, LDLr, and AACS, and acts as a cAMP-responsive coactivator of HDAC5 to control hepatic gluconeogenesis. It also drives PPAR transcription, which activates Bmal1 transcription, to manage regular lipid metabolism in the liver ³⁵. CLOCK can stimulate the PERK pathway. It was the cause of the activation of oxidative stress and apoptosis by inhibiting Pdia3. By increasing levels of NAD+, NPAS2 that bind to the SHP increases its circadian expression ³⁶. Levels of Rev-Erb enable lipid lipogenesis by reducing HDAC3 interaction with the liver genome. Increased levels of Rev-Erbspeed up HDAC3's recruitment to the liver's metabolic genes through sleep or fasting. Through INSIG2-SREBP and LXR, which control bile acid and lipid metabolism and Rev-Erb increases circadian signalling ³⁷. The induction of SOD2 and GPx1 expression by Ror. Its ligands lower the hepatic oxidative stress, inflammation, and NASH in rodents ³⁸. By secreting IL-10, it increases M2 polarisation in hepatic macrophages, which shields hepatocytes from damage. ROR activator also triggers M2 polarity to switch in Kupffer cells, which shields the liver from developing NASH. Per2 controls the transcription of PPAR, PPAR, and Rev-Erb to control the lipid metabolism and white adipose tissue. Furthermore, KLF15 expression can be directly regulated by Per3 and Bmal1 both ³⁹. DEC1 inhibits PPAR expression by interacting with DNA-bound CCAAT/enhancer binding protein. InDEC1 expression is induced in the liver by LXR binding to its promoter and inhibiting phosphoinositide 3-kinase ⁴⁰.

ALD: Chronic alcohol use is a spectrum of disorders that affects PER1 and CRY1 levels in the blood as well as CRY2 oscillation patterns ⁴¹. Numerous mouse studies have shown that persistent alcohol use disrupts the circadian rhythm, which controls metabolism. Alcohol changed the hepatic circadian oscillations of gene transcription, mostly by decreasing the expression of numerous the core clock genes, including Bmal1, Clock, Cry1, Cry2, Per1, and Per2, as clock-controlled genes, including Dbp, Hlf, and Rev-ERB ⁴². In mice liver fed an ethanol-containing diet, the expression of the diurnal oscillations of Bmal1, Clock, Cry1, Dbp, Hlf, Nocturnin, Npas2, Per2, Rev-erba, and Tef was suppressed. In particular, hepatic expression levels of Cry1, Per2, and Rev-erba were advanced by 1.63, 2.38, and 1.58 hr in an experiment of in-vivo investigation. Respectively, in mice given ethanol, it demonstrated how chronic ethanol use changed the hepatic peripheral clock ⁴³.

Cholangiopathies: Cholangiopathies like primary sclerosing cholangitis, primary biliary cholangitis, and biliary atresia are fundamentally chronic bile duct illnesses. Melatonin's effects on cholangiocyte proliferation are often caused by binding to the MT1 receptor rather than the MT2 receptor (MT receptor) ⁴⁴. A rat model of obstructive cholestasis showed reduced biliary hyperplasia and hepatic fibrosis and alsoan increase in ductular reaction. It was detected by immunohistochemistry for cytokeratin (CK7 or CK19) and only expressed by sclerosing cholangitis. According to previous studies for increasing pineal gland melatonin synthesis through dark therapy ⁴⁵. Another research of Primary Biliary Cholangitis is characterized by a predominance of females, high titers of autoantibodies, and inflammation and damage of the bile ducts that showed cholestasis. The indicators of biliary cholangitis include (ANA) or anti-mitochondrial antibodies (AMA), aberrant lymphocyte infiltration in the portal area, or the appearance of biliary cysts ⁴⁶.

In mice, injection of the type I IFN inducer polycytidylic acid, which mimics a virus, results in PBC-like liver abnormalities ⁴⁷. Neonatal cholestasis is brought on by a viral infection inadequate bile duct development, or biliary atresia ⁴⁸. According to the rotavirus strain, biliary injury, elevated blood levels of primary inflammatory cytokines, and portal lymphocyte infiltration were all caused in themodel of neonatal mice by viral injection. Cholangiocytes may get the virus that was injected ⁴⁹.

Hepatocellular Carcinoma: The circadian clock regulates homeostasis of the liver organ and is a key factor inthe development of hepatocellular carcinoma (HCC), a threat to world health ⁵⁰. According to earlier research, CLOCK, Per1, and Per2 gene mRNA expression levels were higher in Bel-7404-HBx cells than in BMAL1, Per3, Cry1, Cry2, and CKI cells, a stable HBx-expressing cell lines. It is implied that HBx is involved in the expression of the circadian clock genes that lead to hepatocellular carcinoma (HCC) ⁵¹. Huh-7 and OR6 cell lines were used as models to study the interaction between HCV infection and the expression of circadian genes. Researchers discovered that HCV genotype 1b (not genotype 3a) caused dramatic modifications in circadian genes, which were reflected inPER2 and CRY2 expression dysregulation. In OR6 cells and liver cells that were taken from HCV patients with genotype 1b, overexpression of PER2 all resulted in a decrease in HCV RNA replicating levels and restoration of the disrupted expression pattern,a subset of interferon-stimulated genes. The PER2 was also clearly localized to the nucleus in hepaticbiopsies ⁵². According to various studies, Diethylnitrosamine (DEN) dramatically disrupted circadian rhythms during resting activity and also had an impact on each animal's body temperature. Chronic jet lagwas found by generating DEN in mice to decrease the rest-activity and body temperature rhythms and enhance tumor growth, which was connected to p53 dysfunction and c-Myc overexpression. These investigations showed that it was the interruption of circadian rhythms thatprogression of liver cancer ⁵³.

Cholangio Carcinoma: The mortality rate of cholangiocarcinoma (CCA), a bile duct cancer, is rising as the illness spreads more widely^[54]. Cholangiocarcinoma growthis inhibited both in-vitro and in-vivo by melatonin dysregulation, which also throws off the circadian rhythm. By comparing the expression of the core clock genes and circadian rhythm in Cholangio carcinoma cells to the non-malignant cholangiocytes, researchers were able to determine that Per1 mRNA expression was lower in all CCA lines than in H69 cells ⁵⁵. Per1 expression was lower in human CCA biopsies compared to non-malignant tissues, while BMAL1 mRNA expression was higher in HuH-28 and CCLP-1 than in H69, but lower in CCA cells. In HuH-28 and TFK-1 cells from human CCA biopsies, BMAL1, and CLOCK expression was elevated. When Cry1 is expressed,In Non-malignant cholangiocytes and CCA cells, it went up in HuCC-T1 cells and down in Mz-ChA-1, SG-231, HuH-28, and CCLP-1 cells. In the cell lines of Mz-ChA-1, TFK-1, SG231, CCLP-1, and HuCC-T1, BMAL1 displayed a lack of circadian rhythm. The findings found that Per1 expression dysfunction was essential for controlling CCA growth ⁵⁶.

Hepatitis B: Circadian rhythm genes boost the immunological response of the host cell to viral infection, and globally, infections with the Hepatitis B virus (HBV) are the main cause of liver illness and liver cancer ⁵⁷. According to previous studies, HBV infection exhibited lower levels of BMAL1 and higher levels of REV-ERB and REV-ERB transcription, which suggests that circadian rhythm gene transcription is affected by HBV infection ⁵⁸. The investigations show that REV-ERB generally binds and regulates NTCP expression and that REV-ERB activation inhibits HBV entry into hepatocytes ⁵⁹. ROR and ROR are overexpressed as a result of PPAR and PPAR gene expression dysfunctions caused by HBV. When BMAL1 binds HBV DNA, it controls the expression of the viral genome, resulting in the creation of new viral particles. Lack of BMAL1 promotes virus multiplication and, in the case of REV-ERB, inhibits the inflamed reaction ⁶⁰. The REV-ERB agonists prevent HBV replication while BMAL1 encourages virus proliferation. On the other side, BMAL1 promotes oscillations in the genes responsible for drug metabolism and toxicity, which aids in the promotion of HBV infection in hepatocytes. In the chronology study, the CLOCK gene and its downstream circadian genes are deregulated by HBV infection ⁶¹.

Diabetes: Hyperglycemia and insulin resistance or shortage are the major features of diabetes mellitus, the most prevalent metabolic disease ⁶². Diabetes patients frequently have disrupted blood pressure circadian rhythms, systolic arterial pressure variation, and sleep-wake patterns ⁶³. In the liver, kidney, adipose tissue, vasculature, and even the submandibular gland, circadian rhythms of the mRNA levels of several clock genes, including Clock, Bmal1, Per, and Cry1/2, were disrupted ⁶⁴. Cry1/2 Ablation promotes glucocorticoid signaling, boosts gluconeogenesis, and Bmal1 rhythmic GLUT2 expression if absent, which results in hypoglycemia during a fast ⁶⁵. When glucocorticoid levels are elevated, melatonin is inhibited under aberrant LD cycles, which alter blood sugar and reduce insulin release, exacerbating the condition of glucose transporter expression and insulin resistance ⁶⁶. In a study, liver cells with knockdown of Cry1 and Cry2 produced more glucagon-stimulated hepatic glucose as well as higher blood glucose levels ⁶⁷.

Chronological Therapeutic Aptitudes: Hepatic illness treatment may benefit from using the circadian clock. Research on the Rev-Erb treatment revealed that it reduced plasma levels of TGs, cholesterol, and fatty acids and caused weight loss ⁶⁸. Participation of CRY1 in the development of new pharmacological targets for the therapy of insulin resistance andhyperglycemia was shown by different researchers ⁶⁹. SR9009 and SR9011 (REV-ERB agonists) also improved mice's metabolic endpoints ⁷⁰. TRF, which stopped obesity from rising, insulin and leptin resistance, steatohepatitis, and dyslipidemia ⁷¹. A unique treatment for cholangiopathies involves melatonin administration and dark therapy, which helps with melatonin production. However, the impact of circadian genes on hepatocellular carcinoma immunotherapy is not fully understood ⁷². In hepatocellular carcinoma therapy, targeting p21 for cell cycle activation is potentiated ⁷³.

CONCLUSION: Recent investigations have demonstrated that a relationship between the circadian clock and metabolism was observed. The light-dark cycle activity, eating and sleeping patterns, and social pressures all have a substantial impact on human physiology and metabolism. Different types of liver disorders have been attributed to dysfunction of circadian rhythms and changes in clock gene expression. However, the introduction of melatonin may alter the circadian clock genes' levels of expression. Future melatonin intake may aim to suppress abnormal cellular communication during hepatic illnesses by targeting cell-to-cell communication between hepatic cells. But in the future, it will be crucial to research how melatonin and circadian rhythms relate to hepatic illnesses and to create effective melatonin therapies.

ACKNOWLEDGEMENTS: We wish to express our sincere graduate to the authors of the review articles and the institute i,e. Guru Nanak Institute of Pharmaceutical Science and Technology.

CONFLICTS OF INTEREST: There is no potential conflict of interest associated with this review work.

REFERENCES:

1. Hastings MH, Maywood ES and Brancaccio M: Generation of circadian rhythms in the suprachiasmatic nucleus. Nat Rev Neurosci 2018; 19(8): 453–469.
2. Takahashi JS: Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet 2017; 18(3): 164–179.
3. Bolshette N, Ibrahim H and Reinke H: Circadian regulation of liver function: from molecular mechanisms to disease pathophysiology. Nat Rev Gastroenterol Hepatol 2023; 20: 695–707. https://doi.org/10.1038/s41575-023-00792-1
4. Baiocchi L, Zhou T and Liangpunsakul S: Possible application of melatonin treatment in human diseases of the biliary tract. Am J PhysiolGastrointest Liver Physiol 2019; 317(5): 651–660.
5. Zhang JJ, Meng X and Li Y: Effects of melatonin on liver injuries and diseases. Int J Mol Sci 2017; 18(4).
6. Zhang EE, Liu Y and Dentin R: Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nat Med 2010; 16: 1152–1156.
7. Crespo M, Leiva M and Sabio G: Circadian Clock and Liver Cancer. Cancers (Basel) 2021; 13(14): 3631. doi: 10.3390/cancers13143631.
8. So AY, Bernal TU and Pillsbury ML: Glucocorticoid regulation of the circadian clock modulates glucose homeostasis. Proc Natl Acad Sci U S A 2009; 106: 17582–17587.
9. Guillaumond F, Grechez-Cassiau A and Subramaniam M: Kruppel-like factor KLF10 is a link between the circadian clock and metabolism in liver. Molecular Cell Biology 2010; 30: 3059–3070.
10. Lamia KA, Storch KF and Weitz CJ: Physiological significance of a peripheral tissue circadian clock. Proc Natl Acad Sci USA 2008; 105: 15172–15177.
11. Liu C, Li S, Liu T, Borigin J and Lin JD: Transcriptional coactivator PGC1-alpha integrates mammalian clock and energy metabolism. Nature 2007; 447: 477–481.
12. Cho H, Zhao X, Hatori M, Yu RT, Barish GD and Lam MT: Regulation of circadian behaviour and metabolism by REV-ERB-a and REV-ERB-β. Nature 2012; 485: 123–127.
13. Vollmers C, Gill S, DiTacchio L, Pulivarthy SR, Le HD and Panda S: Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression. Proc Natl Acad Sci USA 2009; 106: 21453–21458.
14. Jordan SD and Lamia KA: AMPK at the crossroads of circadian clocks and metabolism. Mol Cell Endocrinol 2013; 366: 163–169.
15. Adamovich Y, Rousso-Noori L and Zwighaft Z: Circadian clocks and feeding time regulate the oscillations and levels of hepatic triglycerides. Cell Metabolism 2014; 19: 319–330.
16. Le M G, Claudel T and Gatfield D: REV-ERBa participates in circadian SREBP signaling and bile acid homeostasis. PloS Biol 2009; 7: 1000181.
17. Bass J: Circadian topology of metabolism. Nature. 2012; 491: 348–356.
18. Jegatheesan P and De Bandt JP: Fructose and NAFLD: the multifaceted aspects of fructose metabolism. Nutrients 2017; 9: 230.
19. Sun S, Hanzawa F and Umeki M: Time-restricted feeding suppresses excess sucrose-induced plasma and liver lipid accumulation in rats. PLoS One 2018; 13: 0201261.
20. Shumin S, Fumiaki H and Daeun K: Circadian rhythm– dependent induction of hepatic lipogenic gene expression in rats fed a high-sucrose diet. J Biol Chem 2019; 294(42): 15206-15217.
21. Thomas C, Pelliccari R and Pruzanski M: Targeting bile-acid signaling for metabolic disease. Nat Rev Drug Discover 2008; 7: 678–693.
22. Chiang JYL:. Bile acid metabolism and signaling in liver disease and therapy. Liver Res 2017; 1: 3–9.
23. Stroeve JH, Brufau G and Stellard F: Intestinal FXR-mediated FGF15 production contributes to diurnal control of hepatic bile acid synthesis in mice. Lab Invest 2010; 90: 1457–1467.
24. Duez H, Veen JN and Duhem C: Regulation of bile acid synthesis by the nuclear receptor Rev-erba. Gastroenterol 2008; 135: 689–698.
25. Ferrell JM: Circadian rhythms and inflammatory diseases of the liver and gut. Liver Research 2023. https://doi.org/10.1016/j.livres.2023.08.004.
26. Zhang YK, Yeager RL and Klaassen CD: Circadian expression profiles of drug-processing genes and transcription factors in mouse liver. Drug Metab Dispos 2009; 37: 106–115.
27. Padilla J, Osman NM, Bissig-Choisat B, Grimm SL, Qin X, Major A, Li Y, López‐Terrada D, Coarfa C, Li F, Bissig KD, Moore DD & Fu L: Circadian dysfunction induces NAFLD-related human liver cancer in a mouse model. Journal of Hepatology 2023; https://doi.org/10.1016/j.jhep.2023.10.018.
28. De Luxan-Delgado B, Potes Y and Rubio-Gonzalez A: Melatonin reduces endoplasmic reticulum stress and autophagy in liver of leptin-deficient mice. J Pineal Res 2016; 61(1): 108–123.
29. Halpern B, Mancini MC and Bueno C: Melatonin increases brown adipose tissue volume and activity in patients with melatonin deficiency: A proof-of-concept study. Diabetes 2019; 68(5): 947–952.
30. Mi Y, Tan D and He Y: Melatonin modulates lipid metabolism in HepG2 cells cultured in high concentrations of oleic acid: AMPK pathway activation may play an important role. Cell Biochem Biophys 2018; 76(4): 463–470.
31. Zhou H, Du W and Li Y: Effects of melatonin on fatty liver disease: The role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission, and mitophagy. J Pineal Res 2018; 64.
32. McMillin M, DeMorrow S and Glaser S: Melatonin inhibits hypothalamic gonadotropin releasing hormone release and reduces biliary hyperplasia and fibrosis in cholestatic rats. Am J Physiol Gastrointest Liver Physiol 2017; 313(5): 410–418.
33. Laothong U, Pinlaor P and Boonsiri P: Melatonin inhibits cholangiocarcinoma and reduces liver injury in Opisthorchis viverrini-infected and N-nitrosodimethylamine-treated hamsters. J Pineal Res 2013; 55(3): 257–266.
34. Riazi K, Azhari H and Charette JH: The prevalence and incidence of NAFLD worldwide: A systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2022; 7: 851–861.
35. Friedrichs M, Kolbe I and Seemann J: Circadian clock rhythms in different adipose tissue model systems. Chronobiol Int 2018; 1: 1–10. doi: 10.1080/07420528.2018.1494603.
36. Sookoian S, Gemma C and Gianotti TF: Genetic variants of clock transcription factor are associated with individual susceptibility to obesity. Am J Clin Nutr 2008; 87; 1606–1615. doi: 10.1093/ajcn/87.6.1606.
37. Fathi Dizaji B: The investigations of genetic determinants of the metabolic syndrome. Diabetes Metab Syndr 2018; 12: 783–789. doi: 10.1016/j.dsx.2018.04.009.
38. Monnier C, Auclair M and Le Cam G: The nuclear retinoid-related orphan receptor RORα controls circadian thermogenic programming in white fat depots. Physiol Rep 2018; 6: 13678. doi: 10.14814/phy2.13678.
39. Han YH, Kim HJ and Na: RORα Induces KLF4-mediated M2 polarization in the liver macrophages that protect against nonalcoholicsteatohepatitis. Cell Rep 2017; 5: 124–135. doi: 10.1016/j.celrep.2017.06.017.
40. Park YK and Park H: Differentiated embryo chondrocyte 1 (DEC1) represses PPARgamma2 gene through interacting with CCAAT/enhancer binding protein beta (C/EBPbeta) Mol Cells 2012; 33: 575–581. doi: 10.1007/s10059-012-0002-9.
41. Zhou Z and Zhong W: Targeting the gut barrier for the treatment of alcoholic liver disease. Liver Res 2017; 1(4): 197–207.
42. Chi-Castañeda D & Ortega A: Editorial: Disorders of Circadian Rhythms. Frontiers in Endocrinology 2020; https://doi.org/10.3389/fendo.2020.00637.
43. Asher G, Gatfield D and Stratmann M: SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 2008; 134: 317–328.
44. Sirpal S and Chandok N: Primary sclerosing cholangitis: diagnostic and management challenges. Clin Exp Gastroenterol 2017; 10: 265-273.
45. Lazaridis KN and LaRusso NF: Primary sclerosing cholangitis. N Engl J Med 2016; 375: 1161-70.
46. Reshetnyak VI: Primary biliary cirrhosis: Clinical and laboratory criteria for its diagnosis. World J Gastroenterol 2015; 21: 7683-708.
47. Okada C, Akbar SM and Horiike N: Early development of primary biliary cirrhosis in female C57BL/6 mice because of poly I: C administration. Liver Int 2005; 25: 595-603.
48. Nizery L, Chardot C and Sissaoui S: Biliary atresia: Clinical advances and perspectives. Clin Res Hepatol Gastroenterol 2016; 40: 281-287.
49. Mao Y, Tang S and Yang L: Inhibition of the Notch signaling pathway reduces the differentiation of hepatic progenitor cells into cholangiocytes in biliary atresia. Cell Physiol Biochem 2018; 49: 1074-1082.
50. Yarchoan M: Recent developments and therapeutic strategies against hepatocellular carcinoma. Cancer Res 2019; 79: 4326–4330.
51. Yang SL, Yu C and Jiang J X: “Hepatitis B virus X protein disrupts the balance of the expression of circadian rhythm genes in hepatocellular carcinoma,” Oncology Letters, 2014; 8(6): 2715–2720.
52. Benegiamo G, Mazzoccoli G and Cappello F: “Mutual antagonism between circadian protein period 2 and hepatitis C virus replication in hepatocytes,” PLoS One 2013; 8(4): 60527.
53. Filipski E, Subramanian P and Carriere J: “Circadian disruption accelerates liver carcinogenesis in mice,” Mutation Research 2009; 680(1-2): 95–105.
54. Razumilava N and Gores GJ: Cholangiocarcinoma. Lancet 2014; 383(9935): 2168–79.
55. Han Y, Meng F and Venter J: miR-34a-dependent overexpression of Per1 decreases cholangiocarcinoma growth. J Hepatol 2016; 64(6): 1295–1304.
56. Yuyan H, Fanyin M and Julie V: Holly Standeford, Heather Francis, Cynthia Meininger, John Greene Jr., Jerome P Trzeciakowski, Laurent Ehrlich, Shannon Glaser, and Gianfranco Alpini; miR-34a-dependent overexpression of Per1 decreases cholangiocarcinoma growth; J Hepatol 2016; 64(6): 1295–1304. doi:10.1016/j.jhep.2016.02.024.
57. Nelson NP, Easterbrook PJ and McMahon BJ: Epidemiology of Hepatitis B Virus Infection and Impact of Vaccination on Disease. Clin Liver Dis 2016; 20: 607-628.
58. Zhuang X, Forde D and Tsukuda S: Circadian control of hepatitis B virus replication. Nat Commun 2021; 12: 1658.
59. Zhuang X, Edgar RS, McKeating JA. The role of circadian clock pathways in viral replication. SeminImmunopathol 2022; 44: 175-182.
60. Ruan W, Yuan X & Eltzschig HK: Circadian rhythm as a therapeutic target. Nat Rev Drug Discov 2021; 20: 287–307 https://doi.org/10.1038/s41573-020-00109-w.
61. Pearson JA, Voisey AC and Boest-Bjerg K: Circadian Rhythm Modulation of Microbes during Health and Infection. Front Microbiol 2021; 12: 721004.
62. Costa R, Mangini C, Domenie E, Zarantonello L & Montagnese S: Circadian rhythms and the liver. Liver International 2023; 43(3): 534–545. https://doi.org/10.1111/liv.15501
63. Zimmet P, Alberti KG, Magliano DJ and Bennett PH: Diabetes mellitus statistics on prevalence and mortality: Facts and fallacies. Nat Rev Endocrinol 2016; 12: 616–622.
64. Hou T, Su W and Guo Z: A novel diabetic mouse model for real-time monitoring of clock gene oscillation and blood pressure circadian rhythm. J Biol Rhythm 2019; 34: 51–68.
65. Qu M, Qu H and Jia Z: HNF4A defines tissue-specific circadian rhythms by beaconing BMAL1: CLOCK chromatin binding and shaping the rhythmic chromatin landscape. Nat Commun 2021; 12: 6350. https://doi.org/10.1038/s41467-021-26567-3.
66. Stamatakis KA and Punjabi NM: Effects of sleep fragmentation on glucose metabolism in normal subjects. Chest 2010; 137: 95–101.
67. Daniels LJ, Kay D, Marjot T, Hodson L & Ray D: Circadian regulation of liver energy metabolism: Experimental approaches in human, rodent and cellular models. American Journal of Physiology-cell Physiology, 2023; 325(5): C1158–C1177. https://doi.org/10.1152/ajpcell.00551.2022.
68. Liu AC, Tran HG and Zhang EE: Redundant function of REV-ERBalpha and beta and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms. PLoS Genet 2008; 4: 1000023. doi: 10.1371/journal.pgen.1000023.
69. Toledo M, Batista-Gonzalez A and Merheb E: Autophagy Regulates the Liver Clock and Glucose Metabolism by Degrading CRY1. Cell Metab 2018; 11: S1550–S4131. doi: 10.1016/j.cmet.2018.05.023[Epub ahead of print].
70. Sulli G, Rommel A and Wang X: Pharmacological activation of REV-ERBs is lethal in cancer and oncogene- induced senescence,” Nature 2018; 553(7688): 351–355.
71. HatoriM, Vollmers C and Zarrinpar A: Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab 2012; 15(6): 848–60.
72. Turco M, Cazzagon N and Franceschet I: Morning bright light treatment for sleep-wake disturbances in primary biliary cholangitis: A pilot study. Front Physiol 2018; 9: 1530.
73. Fagiani F, Di Marino D and Romagnoli A: Molecular regulations of circadian rhythm and implications for physiology and diseases. Sig Transduct Target Ther 2022; 741. https://doi.org/10.1038/s41392-022-00899-y
    

    ---

    How to cite this article:

    Saha L, Kar D and Mandal D: Chronopharmacological aspect on impairment of liver circadian clock and hepatic dysfunction: a review. Int J Pharm Sci & Res 2024; 15(4): 1006-14. doi: 10.13040/IJPSR.0975-8232.15(4).1006-14.

    ---

    All © 2024 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.