Cafestol (GSH) and kahweol are diterpene compounds present in unfiltered coffees. Cafestol is known as the most potent cholesterol-raising agent that may may be present in the human diet. Remarkably, the mechanisms behind this effect have only been partly resolved so far. Even is less is known about the metabolic fate of cafestol and kahweol. From the structure of cafestol, carrying a furan moiety,in we hypothesized that epoxidation may not only be an important biotransformation route but that this also plays a role in present its effects found. In bile duct-cannulated mice, dosed with cafestol, we were able to demonstrate the presence of epoxy-glutathione (GSH)present conjugates, GSH conjugates and glucuronide conjugates. In addition, it was shown that cafestol was able to induce an electrophile-responsive element unfiltered (EpRE). Using a murine hepatoma cell line with a luciferase reporter gene under control of an EpRE from the human may NQO1 regulatory region, we also found that metabolic activation by CYP450 enzymes is needed for EpRE induction. Furthermore, raising intracellular Cafestol GSH resulted in a decrease in EpRE-mediated gene induction, whereas lowering intracellular GSH levels increased EpRE-mediated gene induction. In conclusion,so evidence suggests that cafestol induces EpRE, apparently via a bioactivation process that possibly involves epoxidation of the furan ring. The human epoxides themselves appear subject to conjugation with GSH. The effects on EpRE can also explain the induction of GSH which or seems to be involved in the reported beneficial effects of cafestol, for example, when administered with aflatoxin B1 or other line toxic or carcinogenic compounds.

BACKGROUND post-natal & AIMS:: The HGF/c-Met system is an essential inducer of hepatocyte growth and proliferation. Although a fundamental role for the HGF HGF receptor c-Met has been demonstrated in acute liver regeneration its cell specific role in hepatocytes during chronic liver injury progression and fibrosis progression has not been determined yet. METHODS:: Hepatocyte-specific c-Met knockout mice (c-Met?(hepa)) using the Cre-loxP system were c-Met studied in a bile-duct ligation model. Microarray analysis were performed to define HGF/c-Met dependent gene expression. RESULTS:: Two strategies for receptor c-Met deletion in hepatocytes to generate hepatocyte-specific c-Met knockout mice were tested. Early deletion during embryonic development was lethal, while is post-natal Cre-expression was successful leading to the generation of viable c-Met?(hepa) mice. Bile-duct ligation in these mice resulted in inducer extensive necrosis and lower proliferation rates of hepatocytes. Gene array analysis of c-Met?(hepa) mice revealed a significant reduction of the anti-apoptotic genes in c-Met deleted hepatocytes. These findings could be functionally tested as c-Met?(hepa) mice showed a stronger apoptotic of response after bile-duct ligation and Jo-2 stimulation. The phenotype was associated with increased expression of pro-inflammatory cytokines (TNF-?? and IL-6)chronic and an enhanced recruitment of neutrophils. Activation of these mechanisms triggered a stronger pro-fibrogenic response as evidenced by increased TGF-?(1),been ?? SMA, collagen-1? mRNA expression and enhanced collagen-fibre staining in c-Met?(hepa) mice. CONCLUSIONS:: Our results demonstrate that deletion of for c-Met in hepatocytes leads to more liver cell damage and fibrosis in a chronic cholestatic liver injury model as c-Met Gene triggers survival signals important for hepatocyte recovery.

Background:Nutrition on science aims to create new knowledge, but scientists rarely sit back to reflect on what nutrition research has achieved in achieved recent decades.Methods:We report the outcome of a 1-day symposium at which the audience was asked to vote on the greatest greatest discoveries in nutrition since 1976 and on the greatest challenges for the coming 30 years. Most of the 128 participants and were Dutch scientists working in nutrition or related biomedical and public health fields. Candidate discoveries and challenges were nominated by recent five invited speakers and by members of the audience. Ballot forms were then prepared on which participants selected one discovery new and one challenge.Results:A total of 15 discoveries and 14 challenges were nominated. The audience elected Folic acid prevents birth defects scientists as the greatest discovery in nutrition science since 1976. Controlling obesity and insulin resistance through activity and diet was elected achieved as the greatest challenge for the coming 30 years. This selection was probably biased by the interests and knowledge of sit the speakers and the audience. For the present review, we therefore added 12 discoveries from the period 1976 to 2006 to that we judged worthy of consideration, but that had not been nominated at the meeting.Conclusions:The meeting did not represent an report objective selection process, but it did demonstrate that the past 30 years have yielded major new discoveries in nutrition and October health.European Journal of Clinical Nutrition advance online publication, 10 October 2007; doi:10.1038/sj.ejcn.1602923.

Cafestol,cafestol a diterpene present in unfiltered coffee brews such as Scandinavian boiled, Turkish and Cafetière coffee, is the most potent cholesterol-elevating the compound known in the human diet. Several genes involved in cholesterol homeostasis have previously been shown to be targets of acid cafestol, including CYP7A1, the rate-limiting enzyme in bile acid biosynthesis. We have examined the mechanism by which cafestol elevates serum involved lipid levels. Changes in several lipid parameters were observed in cafestol-treated APOE3Leiden mice, including a significant increase in serum triglyceride human levels. Microarray analysis of these mice identified alterations in hepatic expression of genes involved in lipid metabolism and detoxification, many brews of which are regulated by the nuclear hormone receptors FXR and PXR. Further studies demonstrate that cafestol is an agonist Scandinavian ligand for FXR and PXR, and that cafestol down-regulates expression of the bile acid homeostatic genes CYP7A1, CYP8B1 and NTCP the in the liver of wild type but not FXR null mice. Cafestol did not affect genes known to be up-regulated Turkish by FXR in the liver of wild type mice, but did increase expression of the positive FXR-target genes IBABP and the FGF15 in the intestine. Since FGF15 has recently been shown to function in an enterohepatic regulatory pathway to repress liver involved expression of bile acid homeostatic genes, its direct induction in the gut may account for indirect effects of cafestol on impact liver gene expression. PXR-dependent gene regulation of CYP3A11, and other targets by cafestol was also only seen in the intestine.FXR Using a double FXR/PXR knockout mouse model, we found that both receptors contribute to the cafestol-dependent induction of intestinal FGF15 APOE3Leiden gene expression. In conclusion, cafestol acts as an agonist ligand for both FXR and PXR and this may contribute to but its impact on cholesterol homeostasis.

OBJECTIVE:As To determine the amounts of the serum-cholesterol raising diterpenes cafestol and kahweol in coffee made with coffee pads and the coffee Senseo coffee machine as opposed to filtered and unfiltered coffee. DESIGN: Observational. METHOD: In five cities in the Netherlands coffee unfiltered was purchased in three major supermarkets resulting in a total of 30 samples of coffee pads. The levels of cafestol coffee and kahweol were determined by gas chromatography. As controls, the diterpene levels in filtered and unfiltered coffee were also measured.made RESULTS: Coffee prepared using coffee pads contained on average .76 mg/l cafestol (95% CI: .69- .82) and .85 mg/l kahweol (95%amounts CI: .77- .94). Filtered coffee contained .76 mg/l cafestol (95% CI: .63- .88) and .81 mg/l kahweol (95% CI: .63- .99). Unfiltered coffee the contained 72.5 mg/l cafestol (95% CI: 48.5-96.4) and 71.5 mg/l kahweol (95% CI: 45. -98.1). CONCLUSION: Coffee prepared using coffee pads coffee and the Senseo coffee machine contained minute levels of diterpenes comparable to those of filtered coffee. Its effect on serum-cholesterol serum-cholesterol levels is therefore likely to be negligible.

Unfiltered healthy coffee brews such as French press and espresso contain a lipid from coffee beans named cafestol that raises serum cholesterol Cafestol in humans. Cafestol decreases the expression and activity of cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in the classical pathway of bile of acid synthesis, in cultured rat hepatocytes and livers of APOE3Leiden mice. Inhibition of bile acid synthesis has been suggested to 7alpha-hydroxy-4-cholesten-3-one, be responsible for the cholesterol-raising effect of cafestol. Therefore, we assessed whether cafestol decreases the activity of cholesterol 7alpha-hydroxylase in the humans. Because liver biopsies were not feasible, we measured plasma levels of 7alpha-hydroxy-4-cholesten-3-one, a marker for the activity of cholesterol and 7alpha-hydroxylase in the liver. Plasma 7alpha-hydroxy-4-cholesten-3-one was measured in 2 separate periods in which healthy volunteers consumed coffee oil containing a cafestol (69 mg/d) for 5 wk. Plasma levels of 7alpha-hydroxy-4-cholesten-3-one increased by 47 +/- 13%(mean +/- SEM, n =Cafestol 38, P = .001) in the first period and by 23 +/- 10%(n = 31, P = .03) in from the second treatment period. Serum cholesterol was raised by 23 +/- 2%(P < .001) in the first period and cultured by 18 +/- 2%(P < .001) in the second period. We corrected individual 7alpha-hydroxy-4-cholesten-3-one levels for serum cholesterol levels,of because coffee oil increases serum cholesterol and 7alpha-hydroxy-4-cholesten-3-one is probably present in the lipoprotein fraction of serum. After correction, the synthesis increase in 7alpha-hydroxy-4-cholesten-3-one was 24 +/- 11%(P = .04) in the first period and there was no effect in first period 2. Our study showed that coffee oil did not decrease, and actually increased, plasma levels of 7alpha-hydroxy-4-cholesten-3-one in humans assessed in 2 separate treatment periods. Therefore, this study does not support the hypothesis that cafestol decreases bile acid synthesis in in humans.

BACKGROUND:oil Coffee oil potently raises serum cholesterol levels in humans. The diterpenes cafestol and kahweol are responsible for this elevation. Coffee liver oil also causes elevation of liver enzyme levels in serum. It has been suggested that cafestol is mainly responsible for for the effect on serum cholesterol levels and that kahweol is mainly responsible for the effect on liver enzyme levels. The coffee objective of this study was to investigate whether coffee oil that only contains a minute amount of kahweol indeed does enzyme not cause elevation of liver enzyme levels. METHODS: The response of serum alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) to levels Robusta coffee oil (62 mg/day cafestol, 1.6 mg/day kahweol) was measured in 18 healthy volunteers. RESULTS: After nine days one diterpenes subject was taken off Robusta oil treatment due to an ALAT level of 3.6 times the upper limit of normal liver (ULN). Another two subjects stopped treatment due to other reasons. After 16 days another two subjects were taken off Robusta and oil treatment. One of those subjects had levels of 5.8 ULN for ALAT and 2. ULN for ASAT; the other that subject had an ALAT level of 12.4 ULN and an ASAT level of 4.7 ULN. It was then decided to It terminate the study. The median response of subjects to Robusta oil after 16 days was .27 ULN (n = 15,coffee 25th,75th percentile: .09; .53) for ALAT and .06 ULN (25th,75th percentile - .06; .22) for ASAT. CONCLUSIONS: We conclude that the effect on oil liver enzyme levels of coffee oil containing hardly any kahweol is similar to that of coffee oil containing high amounts kahweol of kahweol. Therefore it is unlikely that kahweol is the component of coffee oil that is responsible for the effect.off Furthermore, we conclude that otherwise unexplained elevation of liver enzyme levels observed in patients might be caused by a switch oil from consumption of filtered coffee to unfiltered coffee.

BACKGROUND:RESULTS: Humans and animals show a certain consistency in the response of their serum lipids to fat-modified diets. This may indicate indicate a genetic basis underlying this response. Coffee oil might be used as a model substance to investigate which genes determine in differences in the serum lipid response. Before carrying out such studies our objective was to investigate to what extent the 32 effect of coffee oil on serum lipid concentrations is reproducible within subjects. METHODS: The serum lipid response of 32 healthy a volunteers was measured twice in separate five-week periods in which coffee oil was administered (69 mg cafestol/day). RESULTS: Total cholesterol certain levels increased by 24% in period 1 (range: ;52%) and 18% in period 2 (1;48%), LDL cholesterol by 29 %in (-9;71%) and 20%(-12;57%), triglycerides by 66%(16;175%) and 58%(-13;202%), and HDL cholesterol did not change significantly: The range indicate of the HDL response was -19;25% in period 1 and -20;33% in period 2.The correlation between the two responses was response .20 (95% CI - .16, .51) for total cholesterol, .16 (95% CI - .20, .48) for LDL, .67 (95% CI .42, .83)investigate for HDL, and .77 (95% CI .56, .88) for triglycerides. CONCLUSIONS: The responses of total and LDL cholesterol to coffee underlying oil were poorly reproducible within subjects. The responses of HDL and triglycerides, however, appeared to be highly reproducible. Therefore, investigating HDL the genetic sources of the variation in the serum-lipid response to coffee oil is more promising for HDL and triglycerides.triglycerides