Many hepatic cytochrome P450 enzymes and their associated drug metabolizing activities are down-regulated in disease states, and much of this has been associated with inflammatory cytokines and their signaling pathways. One such pathway is the induction of inducible nitric oxide synthase (NOS2) and generation of nitric oxide (NO) in many tissues and cells including the liver and hepatocytes. Experiments in the 1990s demonstrated that NO could bind to and inhibit P450 enzymes, and suggested that inhibition of NOS could attenuate, and NO generation could mimic, the down-regulation by inflammatory stimuli of not only P450 catalytic activities but also of mRNA expression and protein levels of certain P450 enzymes. This review will summarize and examine the evidence that NO functionally inhibits and down-regulates P450 enzymes in vivo and in vitro, with a particular focus on the mechanisms by which these effects are achieved.
Nonalcoholic fatty liver disease (NAFLD) is the most frequent liver disease in the world. It describes a term for a group of hepatic diseases including steatosis, fibrosis, and cirrhosis that can finally lead to hepatocellular carcinoma. There are many factors influencing NAFLD initiation and progression, such as obesity, dyslipidemia, insulin resistance, genetic factors, and hormonal changes. However, there is also lean-NAFLD which is not associated with obesity. NAFLD is considered to be a sexually dimorphic disease. In most cases, men have a higher prevalence for the disease compared to premenopausal women. Areas covered: In this review, we first summarize the NAFLD disease epidemiology, pathology, and diagnosis. We describe NAFLD progression with the focus on sexual and genetic differences for disease development and pharmacological treatment. Personalized treatment for multifactorial NAFLD is discussed in consideration of different factors, including genetics, gender and sex. Expert opinion: The livers of female and male NAFLD patients have different metabolic capacities which influence the metabolism of all drugs applied to such patients. This aspect is not yet sufficiently taken into account. The liver computational models might quicken the pace toward assessing personalized disease progression and treatment options.
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.
We developed a simple and robust liquid chromatographic/mass spectrometric method (LC-MS) for the quantitative analysis of 10 sterols from the late part of cholesterol synthesis (zymosterol, dehydrolathosterol, 7-dehydrodesmosterol, desmosterol, zymostenol, lathosterol, FFMAS, TMAS, lanosterol, and dihydrolanosterol) from cultured human hepatocytes in a single chromatographic run using a pentafluorophenyl (PFP) stationary phase. The method also avails on a minimized sample preparation procedure in order to obtain a relatively high sample throughput. The method was validated on 10 sterol standards that were detected in a single chromatographic LC-MS run without derivatization. Our developed method can be used in research or clinical applications for disease-related detection of accumulated cholesterol intermediates. Disorders in the late part of cholesterol synthesis lead to severe malformation in human patients. The developed method enables a simple, sensitive, and fast quantification of sterols, without the need of extended knowledge of the LC-MS technique, and represents a new analytical tool in the rising field of cholesterolomics.
While the role of cholesterol in liver carcinogenesis remains controversial, hepatocellular carcinoma generally prevails in males. Herein, we uncover pathways of female-prevalent progression to hepatocellular carcinoma due to chronic repression of cholesterogenic lanosterol 14α-demethylase (CYP51) in hepatocytes. Tumors develop in knock-out mice after year one, with 2:1 prevalence in females. Metabolic and transcription factor networks were deduced from the liver transcriptome data, combined by sterol metabolite and blood parameter analyses, and interpreted with relevance to humans. Female knock-outs show increased plasma cholesterol and HDL, dampened lipid-related transcription factors FXR, LXRα:RXRα, and importantly, crosstalk between reduced LXRα and activated TGF-β signalling, indicating a higher susceptibility to HCC in aging females. PI3K/Akt signalling and ECM-receptor interaction are common pathways that are disturbed by sex-specific altered genes. Additionally, transcription factors (SOX9)2 and PPARα were recognized as important for female hepatocarcinogenesis, while overexpressed Cd36, a target of nuclear receptor RORC, is a new male-related regulator of ECM-receptor signalling in hepatocarcinogenesis. In conclusion, we uncover the sex-dependent metabolic reprogramming of cholesterol-related pathways that predispose for hepatocarcinogenesis in aging females. This is important in light of increased incidence of liver cancers in post-menopausal women.
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