This review describes the transgenic mouse models designed to evaluate the functions of cytochromes P450 involved in cholesterol and bile acid synthesis,and their link to disease. The knockout of cholesterogenic Cyp51 is embrionally lethal with symptoms of Antley-Bixler syndrome in mice, while the evidence for this association is conflicting in humans. Disruption of Cyp7a1 from classic bile acid (BA) synthesis in mice leads to either increased postnatal death or to a milder phenotype with elevated serum cholesterol. The latter is similar to humans, where CYP7A1 mutations associate with high plasmaLDL and hepatic cholesterol content, and a deficient BA excretion. Disruption of Cyp8b1 from alternative BA pathway results in absence of cholic acid and a reduced absorption of dietary lipids, however, the human CYP8B1 polymorphism fails to explain differences in BA composition. Surprisingly, theapparently normal Cyp27a1(-/-) mice still synthesize BAs that originate from the compensatory pathway. In humans CYP27A1 mutations cause cerebrotendinous xanthomatosis, suggesting that only mice can compensate for the loss of alternative BA synthesis. In line with this, Cyp7b1 knockouts are also apparently normal while human CYP7B1 mutations cause congenital bile acidsynthesis defect in children or spastic paraplegia in adults. Mouse knockouts of the brain-specific Cyp46a1 have reduced brain cholesterol excretion, while in humans CYP46A1 polymorphisms associate with cognitive impairment. CYP39 is at present poorly characterized. Despite important physiological differences between humans and mice, mouse models prove to be aninvaluable tool for understanding the multifactorial facets of cholesterol and BA related disorders.
COBISS.SI-ID: 29158105
Most anabolic processes operate in a timely manner when energy intake is the highest, while catabolism takes place in energy spending periods. Circadian regulation is mediated through the suprachiasmatic nucleus (SCN), a master autonomous oscillator of the brain. Although many peripheral organs have their own oscillators, the SCN is important in orchestrating and entraining organs according to the environmental light cues. However, light is not the only signal for entrainment of internal clocks. For endobiotic and xenobitoic detoxification pathways, the food composition and intake regime are equally important. The rhythm of the liver as an organ where the major metabolic pathways intersect depends on SCN signals, signals from endocrine tissues, and, importantly, the type and time of feeding or xenobiotics ingestion. Several enzymes are involved in detoxification processes. Phase I is composed mainly of cytochromes P450, which are regulated by nuclear receptors. Phase II enzymes modify the phase I metabolites, while phase III includes membrane transportersresponsible for the elimination of modified xenobiotics. Phases I-III of drug metabolism are under strong circadian regulation, starting with the drug-sensing nuclear receptors and ending with drug transporters. Disturbed circadian regualtion (jet-lag, shift work, and dysfunction of core clock genes) leads to changed periods of activity, sleep disorders, disturbed glucose homeostasis, breast or colon cancer, and metabolic syndrome. As many xenobiotics influence the circadian rhythm of the liver, bad drug administration timing can worsen the above listed effects.
COBISS.SI-ID: 30024665
The mammalian circadian clock is driven by cell-autonomous transcriptional feedback loops that involve E-boxes, D-boxes, and ROR-elements. In peripheral organs, circadian rhythms are additionally affected by systemic factors. We show that intrinsic combinatorial gene regulation governs the liver clock. With a temporal resolution of 2 h, we measured the expression of 21 clock genes in mouse liver under constant darkness and equinoctial light-dark cycles. Based on these data and known transcription factor binding sites, we develop a six-variable gene regulatory network. The transcriptional feedback loops are represented by equations with time-delayed variables, which substantially simplifies modelling of intermediate protein dynamics. Our modelaccurately reproduces measured phases, amplitudes, and waveforms of clockgenes. Analysis of the network reveals properties of the clock: overcritical delays generate oscillations; synergy of inhibition and activation enhances amplitudes; and combinatorial modulation of transcription controls the phases. The agreement of measurements and simulations suggests that the intrinsic gene regulatory network primarily determines the circadian clock in liver, whereas systemic cues such as light-dark cycles serve to fine-tune the rhythms.
COBISS.SI-ID: 30247385