THE EFFECT OF TESTOSTERONE PROPIONATE ON THE LIVER OF ADULT FEMALE RATSThe uptake and metabolism of propionate in the isolated perfused caudal lobe of the liver and in natural bodybuilding steroid use hepatocytes were examined following treatment of sheep with glucagon or saline. Glucagon or sterile saline was infused at 9. The caudal lobe was used either to prepare hepatocytes propionate in the liver in a non-recirculating perfusion experiment. Uptake and metabolism of propionate were studied using [C]propionate. In studies using the non-recirculation perfusion of the caudal lobe of the sheep liver it was shown that the treatment of sheep with glucagon resulted in an increased rate of gluconeogenesis from propionate and in an increased net uptake of propionate propionate in the liver the caudal lobe.
Effects of Liver Resection on Hepatic Short-Chain Fatty Acid Metabolism in Humans
To determine whether acute loss of liver tissue affects hepatic short-chain fatty acid SCFA clearance. Blood was sampled from the radial artery, portal vein, and hepatic vein before and after hepatic resection in 30 patients undergoing partial liver resection.
Plasma SCFA levels were measured by liquid chromatography-mass spectrometry. SCFA exchange across gut and liver was calculated from arteriovenous differences and plasma flow. Liver volume was estimated by CT liver volumetry. The gut produced significant amounts of acetate, propionate, and butyrate Hepatic propionate uptake did not differ significantly before and after resection Hepatic acetate and butyrate uptake increased significantly upon partial liver resection acetate: Arterial SCFA concentrations were not different before and after partial liver resection acetate: The liver maintains its capacity to clear acetate, propionate, and butyrate from the portal blood upon acute loss of liver tissue.
May 11, ; Accepted: October 24, ; Published: This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The research was funded by TI Food and Nutrition, a public-private partnership on precompetitive research in food and nutrition. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. All authors have declared that no competing interests exist with anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to PLOS.
Short-chain fatty acids SCFA, i. Currently, there is growing interest in functional foods that affect the composition of gut microbiota, and which may lead to the generation of these SCFA. Our group has previously shown that release of intestinal SCFA appears to be equaled by hepatic uptake [ 19 ], even in patients with a cirrhotic dysfunctional liver. To address this problem, we now studied SCFA metabolism in a controlled situation of acute loss of liver function where shunting does not play a role, i.
All patients provided informed consent. All patients were on a stable, Western diet. The study was approved by the Local Medical Ethics Committee of Maastricht University Medical Center and was performed in accordance with the ethical standards of the Helsinki Declaration of Written informed consent was obtained from all subjects before participation in this study.
Anaesthesia was performed according to institutional routines as has been described previously. Anesthesia was maintained using sevoflurane and propofol. Liver resections were performed as described before and classified as major i. When the portal and hepatic veins were exposed mostly within one hour after skin incision, but before liver transection , blood was drawn from the portal vein and a hepatic vein by direct puncture simultaneously with arterial blood sampling, as described before.
Blood was centrifuged at 3, g and plasma was stored at 0 C until analysis. Finally, the liver resection specimens were weighed. Deproteinization and subsequent preparation of plasma samples for analysis of SCFA was performed as recently reported. Analysis was performed using LC-MS. The detection limits for acetate, propionate, and butyrate were 0. The coefficients of variance were 4.
A slice thickness of approximately 3—5 mm, depending on the CT-scanner was used. Whereas intrahepatic vascular and biliary structures were included, the gall bladder and the inferior caval vein were excluded for all slices. After selecting all regions of interest within one series, total liver volume, resection volume, and metastases volumes were calculated. Then, 3D images were created and virtual resections were performed according to the treatment plan.
Functional volume was calculated as total volume minus tumor volume. Subsequently, these volumes were used to estimate the remnant liver volume in order to assess differences in SCFA clearance per gram functional liver tissue pre- and post- hepatic resection.
Plasma flows for flux calculations were derived from previously performed measurements in a similar patient group. The corresponding AV differences were calculated as follows: Positive fluxes indicate net release and negative fluxes indicate net uptake. To estimate hepatic functional reserve, hepatic SCFA exchange was also calculated per gram of liver tissue using the volumetry data and assuming 1 mL corresponds with 1 gram of liver tissue.
Data are presented as mean SEM. To test if fluxes were statistically different from zero, the nonparametric Wilcoxon signed-rank test was used with a hypothetical value of zero.
The nonparametric Wilcoxon signed-rank matched pairs test was used to test if there were differences in fluxes and concentrations before and after partial hepatectomy.
For statistical analysis, Prism 5. San Diego, CA was used. Baseline characteristics of the thirty patients included in the study are presented in Table 1. Sampling was performed in all patients according to protocol. Thirteen patients underwent major liver resection, whereas 17 patients underwent minor liver resection. The median time required for transection was minutes. The gut produced significant amounts of acetate, propionate, and butyrate before liver transection, as evidenced by portal venous concentrations exceeding the arterial concentrations.
The corresponding fluxes were As expected, the production of acetate, propionate, and butyrate by the gut directly after partial liver resection was not statistically different from baseline production, with corresponding fluxes of Acetate, propionate, and butyrate were all taken up by the liver both before acetate: Since acetate and propionate release from the gut equalled hepatic uptake both before and after partial liver resection, there was no significant acetate or propionate release from the splanchnic area at either time point.
The corresponding splanchnic fluxes were 4. A small but significant release of butyrate from the splanchnic area was found only after partial liver resection 0. Arterial acetate, propionate, and butyrate concentrations were not significantly different before versus immediately after partial liver resection; Table 2. Furthermore, no differences were found between arterial acetate, propionate, and butyrate concentrations in patients that underwent a minor resection compared to patients that underwent a major resection; Table 3.
The present study was undertaken to investigate the effect of partial liver resection, as a model for controlled loss of liver function, on interorgan exchange of short chain fatty acids SCFA.
Our data confirm that the gut produces significant amounts of acetate, propionate, and butyrate. Intestinal production of acetate exceeds the production of butyrate which, in turn, is higher than the production of propionate.
These gut derived SCFA are subsequently to a large extent taken up by the liver. Hepatic uptake of acetate and butyrate even increases after partial liver resection. Together with data from our previous studies [ 19 ], the present data indicate that the liver is able to take up acetate, propionate and butyrate proportionally to gut production, both before and after partial liver resection. These findings are in concordance with previous work by our group showing excess hepatic capacity in e.
Complete hepatic clearance of the main SCFA acetate, propionate, and butyrate even after partial hepatectomy is important to avoid the possible toxicity of SCFA. However, it may also be considered as less beneficial given recent data on the metabolic signaling activities of these SCFA.
In fact, an enteroendocrine pathway has been proposed by which SCFA control gut hormone expression. Besides, SCFA have been shown to influence obesity-induced chronic low-grade inflammation.
In addition, acetate, propionate, and butyrate can directly decrease the secretion of adipose tissue-derived proinflammatory cytokines and chemokines. Butyrate, in particular, can also indirectly influence proinflammatory cytokine and chemokine production by influencing signaling pathways like the nuclear factor-kB pathway and by inhibition of histone deacetylases.
Hence, dietary manipulation of histone structure and function of critical genes associated with physiologic and pathologic processes [ 33 ] may be a solution to the puzzle of the relation between dietary fiber and the prevention and treatment of different diseases. In this regard, there is a growing interest in butyrate as its impact on epigenetic mechanisms will lead to potential clinical implications. SCFA might also enhance the intestinal barrier function, further supporting their anti-inflammatory potential.
In several studies using intestinal cell lines, SCFA particularly butyrate , have been shown to improve epithelial barrier function and gut permeability by modulating expression of tight junction proteins and mucins. Whereas hepatic acetate and butyrate uptake was increased after liver resection, no significant changes appeared to occur in the uptake per gram liver tissue.
This might be related to the fact that the uptake per gram liver tissue could only be calculated in a subgroup of patients and the substantial variation in hepatic SCFA uptake between patients. Our data further showed that the uptake of acetate, propionate, and butyrate by the liver was not correlated with the percentage functional remnant liver volume. This may indicate that the magnitude of hepatic SCFA clearance is dependent on gut production, i.
Of note, it should be taken into account that the patients were fasting overnight before the operation, so the intestinal SCFA production was lower during the sampling than the usual average production rate. In a sheep model, Bergman et al. In contrast to this study in which the sheep were fasted for three days, the patients in our study had just an overnight fast which may suggest that the influence of fasting on SCFA availability in our study was less pronounced.
Our current data obtained in a unique model of acute loss of liver function underscore the large capacity of the liver to metabolize SCFA released from the gut. It should, however, be taken into consideration that it only reflects a short term acute loss of liver function as blood samples were taken immediately after the partial liver resection.
Additional intervention studies must be performed to ensure that supplementation of SCFA in patients is safe. Of note, administering precursors of SCFA i. This in vivo study in humans confirmed that the gut produces significant quantities of the main SCFA acetate, propionate, and butyrate.
Acute hepatic tissue loss did not influence systemic concentrations of SCFA, implying that the liver has a large reserve capacity to metabolize propionate, acetate, and butyrate to prevent any increase of arterial concentrations.
This was underscored by the increased hepatic uptake of acetate and butyrate after partial liver resection which, in turn, may be interpreted as circumstantial evidence for the safety of SCFA supplementation even in patients with limited liver tissue.
The authors would like to thank Marc Bemelmans and Ronald van Dam, liver surgeons, and Simon Dello, PhD-student, for their valuable help during collection of the samples.
The authors also thank Hans van Eijk for his excellent technical assistance. Writing — original draft: Click through the PLOS taxonomy to find articles in your field. Methods Blood was sampled from the radial artery, portal vein, and hepatic vein before and after hepatic resection in 30 patients undergoing partial liver resection. Results The gut produced significant amounts of acetate, propionate, and butyrate