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This review focuses on the role of oxidized sterols in three major gastrointestinal cancers (hepatocellular carcinoma, pancreatic, and colon cancer) and how the circadian clock affects the carcinogenesis by regulating the lipid metabolism and beyond. While each field of research (cancer, oxysterols, and circadian clock) is well-studied within their specialty, little is known about the intertwining mechanisms and how these influence the disease etiology in each cancer type. Oxysterols are involved in pathology of these cancers, but final conclusions about their protective or damaging effects are elusive, since the effect depends on the type of oxysterol, concentration, and the cell type. Oxysterol concentrations, the expression of key regulators liver X receptors (LXR), farnesoid X receptor (FXR), and oxysterol-binding proteins (OSBP) family are modulated in tumors and plasma of cancer patients, exposing these proteins and selected oxysterols as new potential biomarkers and drug targets. Evidence about how cholesterol/oxysterol pathways are intertwined with circadian clock is building. Identified key contact points are different forms of retinoic acid receptor related orphan receptors (ROR) and LXRs. RORs and LXRs are both regulated by sterols/oxysterols and the circadian clock and in return also regulate the same pathways, representing a complex interplay between sterol metabolism and the clock. With this in mind, in addition to classical therapies to modulate cholesterol in gastrointestinal cancers, such as the statin therapy, the time is ripe also for therapies where time and duration of the drug application is taken as an important factor for successful therapies. The final goal is the personalized approach with chronotherapy for disease management and treatment in order to increase the positive drug effects.

Recent research has indicated that dysbiosis of the gut microbiota can lead to an altered circadian clock of the mammalian host. Herein we developed an original system that allows real-time circadian studies of human HepG2 hepatoma cells co-cultured with bacteria. The HepG2 cells with stably integrated firefly luciferase reporter under the control of PERIOD2 promoter were co-cultured with E. coli strains isolated from human fecal samples from healthy individuals. The two E. coli strains differ in the phylogenetic group and the number of ExPEC virulence-associated genes: BJ17 has only two, and BJ23 has 15 of 23 tested. In the first 24 h, the E. coli BJ17 affected the HepG2 circadian clock more than BJ23. Cosinor analysis shows a statistically significant change in the amplitude of PER1 and 2 and the phase advance of PER3. A high percentage of necrotic and apoptotic cells occurred at 72 h, while a correlation between the number of ExPEC genes and the influence on the HepG2 core clock gene expression was observed. Our study reveals that the E. coli genetic background is important for the effect on the mammalian circadian clock genes, indicating possible future use of probiotic E. coli strains to influence the host circadian clock.

Deregulation of the circadian system in humans and animals can lead to various adverse reproductive outcomes due to genetic mutations and environmental factors. In addition to the clock, lipid metabolism may also play an important role in influencing reproductive outcomes. Despite the importance of the circadian clock and lipid metabolism in regulating birth timing few studies have examined the relationship between circadian genetics with lipid levels during pregnancy and their relationship with preterm birth (PTB). In this study we aimed to determine if single nucleotide polymorphisms (SNPs) in genes from the circadian clock and lipid metabolism influence 2nd trimester maternal lipid levels and if this is associated with an increased risk for PTB. We genotyped 72 SNPs across 40 genes previously associated with various metabolic abnormalities on 930 women with 2nd trimester serum lipid measurements. SNPs were analyzed for their relationship to levels of total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL) and triglycerides (TG) using linear regression. SNPs were also evaluated for their relationship to PTB using logistic regression. Five SNPs in four genes met statistical significance after Bonferroni correction (p < 1.8 × 10-4) with one or more lipid levels. Of these, four SNPs were in lipid related metabolism genes: rs7412 in APOE with total cholesterol, HDL and LDL, rs646776 and rs599839 in CELSR2-PSRC1-SORT1 gene cluster with total cholesterol, HDL and LDL and rs738409 in PNPLA3 with HDL and TG and one was in a circadian clock gene: rs228669 in PER3 with TG. Of these SNPs only PER3 rs228669 was marginally associated with PTB (p = 0.02). In addition, PER3 rs228669 acts as an effect modifier on the relationship between TG and PTB.

Non-alcoholic fatty liver disease (NAFLD) is a complex and widely prevalent liver disorder, traditionally characterised by pathological changes ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) that can further progress to cirrhosis and hepatocellular carcinoma. Owing to the epidemics of obesity and metabolic syndrome, NAFLD is the most frequent liver disorder in the Western world. It is considered to be a multifactorial state, leading not only to liver related mortality but also to increased cardiovascular, type 2 diabetes mellitus and the overall mortality. The natural course of NAFLD is highly variable and is influenced by both environmental and genetic factors. Candidate gene and genome wide association studies together with other clinical data reveal the importance of genetic factors in susceptibility to NAFLD where polymorphisms in genes involved in the control of insulin resistance, lipid metabolism, inflammation and oxidative stress are linked to the progression of liver damage. To date, polymorphisms in PNPLPA3, the patatin-like phospholipase domain containing 3 gene, remain the most consistent genetic association with NAFLD while a number of other genetic polymorphisms have been associated with the disease in case–control studies. It is now necessary to explore the molecular mechanism underlying associations between gene variants and pathogenesis of various stages of NAFLD. Key Concepts NAFLD is a complex disease influenced by both genetic and environmental factors which interact to determine the disease phenotype and its progression. The pathogenesis of NAFLD remains poorly understood. It is under debate if the development of simple steatosis and NASH is the result of two or multiple hits, or whether it is a more complex network phenomenon. Susceptibility to and progression of NAFLD differ according to race, ethnicity, gender and lifestyle. Several SNPs in the human genome associate with susceptibility to and progression of NAFLD. The most consistently replicated genetic risk factor for NAFLD disease is the rs738409 polymorphism in the human PNPLA3, the patatin-like phospholipase domain containing gene 3, also called adiponutrin. Other SNPs in genes influencing lipid metabolism, insulin resistance, inflammation, oxidative stress, extracellular matrix synthesis, degradation, apoptosis, and so on associate with NAFLD; however, they require conformation before being formally associated with NAFLD stages. Keywords: non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); hepatocellular carcinoma; genetics; single nucleotide polymorphism (SNP); genome wide association studies (GWAS); clinical studies