Bile Acid Balance Research Articles

Effect of carbohydrate source, feeding level (restricted vs. satiation) and their combination on nutrient digestibility, bile acid balance, faecal waste production and characteristics of yellowtail kingfish (Seriola lalandi)

The effect of carbohydrate source on nutrient digestibility, bile acid balance, faecal waste production and characteristics were investigated in yellowtail kingfish (Seriola lalandi). A starch diet and two non-starch polysaccharides (NSP) diets with different NSP sources were used in this study. A diet containing 12 % gelatinized wheat flour as the starch diet, and two diets with distinct non-starch polysaccharides (NSP) sources: soybean hulls (SH) and sugar beet pulp (SBP) at an inclusion level of 10 %, were studied. Each diet was tested in triplicate fish tanks. To determine if feeding level affects diet, restricted and satiation feeding levels were used. After four weeks of restrictive feeding, fish were fed satiation for two weeks. The dietary effect on nutrient digestibility and faecal waste production was dependent on feeding level, whereas the dietary effect on faecal waste characterises was independent of feeding level. SBP diet protein and fat digestibility was highest during restricted and satiation feeding. Satiation feeding reduced nutrient digestibility in all diets, most pronounced in SH and least in SBP. Faecal bile acid loss did not explain fat digestibility differences between the three diets. Both NSP diets increased faecal waste production but decreased bile acid content, resulting in similar bile acid loss to the starch diet. SBP had the highest faecal removal efficiency and the lowest non-removed faeces despite high waste production SH resulted in similar amount of non-removed faeces compared to the starch diet. To conclude, NSP type affected nutrient digestibility, bile acid balance, faecal waste production, and faecal characteristics differently than starch in yellowtail kingfish. Starch resulted in higher FCR and thus lower growth performance in yellowtail kingfish compared to NSP despite higher organic matter digestibility. Adding NSP to their RAS diet may improve faecal integrity without affecting macronutrient digestibility. However, different NSP forms affect nutrient digestion and faeces integrity differently.

Effect of emulsifier supplementation on nutrient digestibility, bile acid balance, faecal waste production and faecal characteristics of yellowtail kingfish (Seriola lalandi)

Yellowtail kingfish (Seriola lalandi), a marine species, has recently been cultured in recirculation aquaculture systems (RAS). A challenge regarding faecal waste management of farming yellowtail kingfish in RAS is their poor faecal integrity. One approach to improve faecal waste management is to enhance nutrient digestibility and thus faecal waste production, which can be achieved through the addition of emulsifiers to the feed. We assessed the effect of emulsifier supplementation on nutrient digestibility, bile acid balance, faecal waste production and characteristics of yellowtail kingfish. This was investigated by using four experimental diets differing in emulsifier supplementation, where fish were fed restrictively (36 days). One diet without emulsifying supplements served as control. Three types of emulsifiers were tested (1) E484, composed of Glyceryl polyethyleneglycol ricinoleate; (2) Lysophospholipids (LPL) combined with lecithin; (3) Sodium taurocholate (STC). The results showed that the STC diet numerically improved fat digestibility and had a positive bile acid balance, which indicated an accumulation of dietary bile acids in the body bile acid pool. Despite a negative bile acid balance, the LPL diet improved fat digestibility as well. A negative bile acid balance shows that the daily amount of faecal bile acid loss exceeds the daily amount of dietary bile acid intake. Fish fed the E484 diet had more faeces removed than the other diets, whilst non-recovered faeces or faecal characteristics were not affected. In conclusion, the current study shows that supplementing both sodium taurocholate (STC), and the combination of Lysophospholipids (LPL) and lecithin can improve fat digestibility in yellowtail kingfish, but emulsifier supplementation does not improve faecal waste management.

The Impact of the Association Between Nonalcoholic Fatty Liver Disease and Intrahepatic Cholestasis of Pregnancy on Maternal and Fetal Outcomes.

Backgroundː Intrahepatic cholestasis of pregnancy (ICP), a hepatic condition that causes severe itching in late pregnancy, is linked to nonalcoholic fatty liver disease (NAFLD) due to disrupted bile acid balance. It poses maternal risks such as preterm labor and gestational diabetes and fetal risks such as preterm birth and respiratory distress. The study examined NAFLD's impact on ICP in pregnant women, highlighting management and research implications. Methodsː This retrospective study examined pregnant women (≥18 years) with ICP, assessing fatty liver with follow-up ultrasounds. Participants were divided into ICP only and ICP with fatty liver (FL) groups, excluding heavy alcohol users and incomplete data. Maternal age, medical history, and comorbidities were evaluated alongside abdominal ultrasounds to identify FL. Resultsː In this study of 43 pregnant women, the mean maternal age was 27 years. Patients with ICP and FL had significantly higher bile acid levels than those with ICP alone. However, no significant differences were found between the two groups regarding the history of gestational diabetes mellitus (GDM), dyslipidemia, polycystic ovarian syndrome (PCOS), parity, and hypothyroidism. Among women with ICP and FL, 51.85% underwent lower segment cesarean section (LSCS), while 43.75% with ICP without FL underwent LSCS. Conclusionsː ICP with FL did not show significant adverse effects on maternal and neonatal outcomes, including mode of delivery, gestational age, maternal complications, neonatal intensive care unit (NICU) admissions, and low birth weight (LBW) with asphyxia. However, additional research is required to fully comprehend the relationship between ICP, NAFLD, and their impact on pregnancy outcomes.

Psoraleae induces hepatotoxicity by affecting bile acid balance

Psoraleae induces hepatotoxicity by affecting bile acid balance

The effect of dietary non-starch polysaccharide level and bile acid supplementation on fat digestibility and the bile acid balance in rainbow trout (Oncorhynchus mykiss)

This study investigated in rainbow trout (Oncorhynchus mykiss) if dietary bile acid supplementation is effective in restoring hampered fat digestibility related to conditions that enhance fecal bile acid loss (i.e., high dietary non-starch polysaccharide (NSP) level and high feeding level). Four diets were formulated according to a two-by-two factorial design. A Low- and High-NSP level (0 vs. 160 g kg-1 inclusion of a NSP-rich ingredient mixture) and two bile acid supplementation levels (0 vs. 2 g kg-1 inclusion of sodium taurocholate) were tested. A contrast in feeding level (i.e., feed intake) was created by subsequently feeding fish restrictively (1.1% BW d-1) for four weeks and to satiation for three weeks. The apparent digestibility coefficient (ADC) of all nutrients was affected by feeding period (i.e., restricted vs. satiation feeding), but the effect was dependent on diet composition with the ADC decline between feeding periods being larger for the High-NSP diets. The ADC of all macronutrients decreased alongside dietary NSP level, but this decrease was much more pronounced for fat compared to starch and protein, especially during satiation feeding (6.7%). This large drop in fat ADC during satiation feeding of NSP-rich diets occurred alongside enhanced fecal bile acid loss and correlated with a negative bile acid balance. The correlation between the bile acid balance and fat ADC found during satiation feeding of diets without bile acid supplementation was not present in fish fed diets with bile acid supplementation. In contrast to fat ADC, the ADC of protein and starch were independent from bile acid supplementation. In conclusion, dietary bile acid supplementation is an effective way to remediate decreased fat ADC related to enhanced fecal bile acid loss in rainbow trout, but is not effective in improving protein and starch ADC.

Natural products for the prevention and treatment of cholestasis: A review.

Cholestasis is a common manifestation of decreased bile flow in various liver diseases. It results in fibrosis and even cirrhosis without proper treatment. It is believed that a wide range of factors, including transporter dysfunction, oxidative stress, inflammatory damage, and immune disruption, can cause cholestasis. In recent years, natural products have drawn much attention for specific multiple-target activities in diseases. Many attempts have been made to investigate the anticholestatic effects of natural products with advanced technology. This review summarizes recent studies on the biological activities and mechanisms of recognized compounds for cholestasis treatment. Natural products, including various flavonoids, phenols, acids, quinones, saponins, alkaloids, glycosides, and so on, function as comprehensive regulators via ameliorating oxidative stress, inflammation, and apoptosis, restoring bile acid balance with hepatic transporters, and adjusting immune disruption. Moreover, in this progress, nuclear factor erythroid 2-related factor 2, reactive oxygen species production, heme oxygenase-1, NF-κB, cholesterol 7 alpha-hydroxylase, and farnesoid X receptors are thought as main targets for the activity of natural products. Therefore, this review presents the detailed mechanisms that include multiple targets and diverse signalling pathways. Natural products are the valuable when seeking novel therapeutic agents to treat cholestatic liver diseases.

HuangQin Decoction Attenuates CPT-11-Induced Gastrointestinal Toxicity by Regulating Bile Acids Metabolism Homeostasis.

Irinotecan (CPT-11) is a potent chemotherapeutic agent, however, its clinical usage is often limited by the induction of severe gastrointestinal (GI) toxicity, especially late-onset diarrhea. HuangQin Decoction (HQD), commonly used for the treatment of GI ailments, has been proved could significantly ameliorate the intestinal toxicity of CPT-11. To reveal the mechanisms of CPT-11-induced toxicity and the modulation effects of HQD, a previous untargeted metabolomics study was performed and the results indicated that HQD may protect the GI tract by altering the metabolism of bile acids (BAs). Nevertheless, the untargeted assays are often less sensitive and/or efficient. In order to further confirm our previous findings, here in this paper, serum and tissues metabolic profiles of 17 BAs were analyzed using liquid chromatography-tandem mass spectrometry based targeted metabolomics. The results indicated that serum and tissues levels of most BAs were significantly decreased after CPT-11 administration, except some hydrophobic BAs. Co-treatment with HQD could markedly attenuate CPT-11-induced GI toxicity and reverse the alterations of hydrophobic BAs. Despite the fact that the BAs pool size remained unchanged, the balance of BAs had shifted leading to decreased toxicity after HQD treatment. The present study demonstrated for the first time that the precise interaction between HQD, CPT-11-induced intestinal toxicity and BAs’ homeostasis.

Agonist of farnesoid X receptor protects against bile acid induced damage and oxidative stress in mouse placenta – A study on maternal cholestasis model

IntroductionIntrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder, which is characterized by raised serum bile acid level and potential adverse fetal outcome. Farnesoid X receptor (FXR), also known as a bile acid receptor, was found to be expressed in placenta with low level. Whether activation of FXR by specific agonists could regulate the pathogenesis of ICP is still unclear. MethodsA model of maternal cholestasis was induced by administration of 17α-ethynylestradiol (E2) in pregnant mice for 6 days. We explored the regulatory effect of WAY-362450 (W450), a highly selective and potent FXR agonist on placenta. ResultsIn this study, we demonstrated that administration of E2 increased bile acid levels in mouse serum, liver and amniotic fluid. Bile acid levels were significantly decreased after W450 treatment. W450 protected against the impairment of placentas induced by E2, including severe intracellular edema and apoptosis of trophoblasts. Moreover, W450 significantly induced the expressions of FXR target bile acid transport gene ATP-binding cassette, sub-family B (MDR/TAP), member 11 (Abcb11;Bsep) in placenta. W450 could also attenuate placental oxidative stress and increase the expressions of antioxidant enzymes Prdx1 and Prdx3. Discussion and conclusionIn conclusion, our data demonstrated that FXR agonist W450 modulated bile acid balance and protected against placental oxidative stress. Thus, our results support that potent FXR agonists might represent promising drugs for the treatment of ICP.

Molecular insights into the promiscuous interaction of human pregnane X receptor (hPXR) with diverse environmental chemicals and drug compounds

The nuclear receptor member human pregnane X receptor (hPXR) regulates enzymes and transporters involved in xenobiotic detoxification as well as maintains homeostatic balance of bile acids, thyroid and steroid hormones. hPXR can be recognized and activated by a structurally diverse array of environmental chemicals and drug compounds to initiate adverse biological effects, such as perturbing normal physiological functions and causing dangerous drug–drug interactions and exhibiting a high promiscuity in its ligand spectrum. Understanding of the molecular mechanism and biological implication underlying the promiscuous interaction of hPXR with its diverse ligands is fundamentally important for toxicological and pharmaceutical researches. In the current study, molecular docking and hybrid quantum mechanics/molecular mechanics (QM/MM) were employed to investigate the binding mode, structural basis and energetic property of hPXR interactions with various activators and non-activators. It was found that, as compared to non-activators, the activators adopt few dominant modes to tightly interact with hPXR, which are specified by few polar spots located on the hydrophobic surface of hPXR active pocket. Based on the findings, a novel method called multiple binding mode-based quantitative structure-activity relationship (MBMB-QSAR) that characterizes the nonbonded interaction profile of hPXR with its ligand in multiple binding modes was proposed to model and predict the activating potency of small-molecule compounds on hPXR. Several partial least square (PLS) predictors derived from the MBMB-QSAR modeling were demonstrated to be effective for quantitative characterization of the biological behavior of experimentally confirmed activators, and for qualitatively differentiating the activators from a large number of non-activators. From the predictor models it is suggested that the hydrophobic force and electrostatic interaction play an important role in hPXR–ligand binding, while steric factor contributes moderately to the binding.

Aggregation Behavior of Indomethacin, Cholic Acid & POPC

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used class of drugs for the treatment of inflammation, fever and pain. One of their major side effects, especially if used chronically, is ulceration and bleeding of the lower gastrointestinal (GI) tract. It has been reported that NSAIDs cause surface injury by perturbing the integrity of membranes of the intestinal mucosa which can be abrogated by phosphatidylcholine (PC). Moreover, it has been shown that the toxic effect of NSAIDs to the lower gut is related to the presence of bile acid, suggesting that the mixture, not NSAID alone, constitutes the agent that destabilizes lower-gut membranes in a COX-independent manner. Several biochemical studies further indicated that NSAIDs form mixed micelles with bile salts. NSAIDs may also alter the physiological balance of bile acids and phospholipids in the lumen of the small intestine. In order to understand the molecular mechanism by which NSAIDs form mixed micelles with bile salts, and to understand how NSAID-bile salt interaction might be modulated by phospholipids, we studied the binary and ternary mixtures of indomethacin (one of the most commonly used NSAIDs), cholate (a bile salt) and palmitoyloleoylphosphatidylcholine (POPC) lipid in a various molar ratios. Initial results from extensive all-atom molecular dynamics simulations indicate that the binary mixtures have distinct aggregation behaviors and morphology than the ternary mixtures, providing clues about the physical basis for the toxicity of NSAID/Cholic Acid mixtures and how this might be modulated by phospholipids.

Metabolomic investigation of cholestasis in a rat model using ultra‐performance liquid chromatography/tandem mass spectrometry

Metabolomics follows the changes in concentrations of endogenous metabolites, which may reflect various disease states as well as systemic responses to environmental, therapeutic, or genetic interventions. In this study, we applied metabolomic approaches to monitor dynamic changes in plasma and urine metabolites, and compared these metabolite profiles in Eisai hyperbilirubinemic rats (EHBR, an animal model of cholestasis) with those in the parent strain of EHBR - Sprague-Dawley (SD) rats - in order to characterize cholestasis pathophysiologically. Ultra-performance liquid chromatography/tandem mass spectrometry-based analytical methods were used to assay metabolite levels. More than 250 metabolites were detected in both plasma and urine, and metabolite profiles of EHBR differed from those of SD rats. The levels of antioxidative and cytoprotective metabolites, taurine and hypotaurine, were markedly increased in urine of EHBR. The levels of many bile acids were also elevated in plasma and urine of EHBR, but the extent of elevation depended on the particular bile acid. The levels of cytoprotective ursodeoxycholic acid and its conjugates were markedly elevated, while that of cytotoxic chenodeoxycholic acid remained unchanged, suggesting the balance of bile acids had shifted resulting in decreased toxicity. In EHBR, reduced biliary excretion leads to increased systemic exposure to harmful compounds including some endogenous metabolites. Our metabolomic data suggest that mechanisms exist in EHBR that compensate for cholestasis-related damage.

Derived chromatographic indices as effective tools to study the self-aggregation process of bile acids

Reversed-phase high-performance liquid chromatography (RP-HPLC) is more and more adopted as a fruitful tool for the estimation of several physico-chemical properties of diverse classes of organic compounds. In this frame, derived chromatographic indices have been proposed as effective parameters to measure the lipophilicity (log P or log D) of compounds. Instead, a limited attention has been directed towards the chromatographic evaluation of the Critical Micellar Concentration (CMC), one of the most important parameters employed to study the bile acid physico-chemical profile. We have recently reported on the effectiveness of the derived chromatographic index φ 0 for the study of the self-aggregation process of bile acids. Here we show that this index is independent upon the adopted chromatographic environment so as to be instrumental for the evaluation of the hydrophobic/hydrophilic balance of bile acids. Molecular modelling studies have also been undertaken with the aim of rationalizing the experimental findings.

Correlation between CMC and chromatographic index: simple and effective evaluation of the hydrophobic/hydrophilic balance of bile acids

The discovery that bile acids are involved in the modulation of nuclear steroid receptors has prompted renewed interest in this field of research. Due to the nature of research in this field, a technique that enables simple and effective assessment of the hydrophobic/hydrophilic balance, thus improving and speeding up evaluations of the biological profiles of these compounds, is greatly needed. In this context, both CMC value determination and RP-HPLC mobility evaluation were explored as possible approaches. While the CMC was calculated using the noninvasive conductimetric method, the RP-HPLC mobility was assessed by measuring the retention factor at several mobile phase compositions and extrapolating back to the pure aqueous mobile phase. The correlation of the CMC with the derived chromatographic hydrophobic index phi0 was satisfactory.

Effect of bile duct obstruction on the expression of intestinal mRNA related to cholesterol and bile acid metabolism in the rat

The liver and small intestine play an important role in maintaining cholesterol and bile acid balance within the body. The purpose of this study was to evaluate the effect of bile duct ligation (BDL) on the expression of intestinal and hepatic genes that are important for cholesterol and bile acid metabolism. Rats were allocated to the BDL group or the sham operation group. Blood, liver and small intestine were obtained after 24, 72 and 168 h from both groups. Serum and hepatic lipids were measured by colorimetric assays and hepatic and intestinal mRNA related to lipid metabolism was studied by reverse transcription-polymerase chain reaction (RT-PCR). Hepatic apolipoprotein (Apo) AIV, multidrug resistant protein (Mrp)2, adenosine triphosphate (ATP) binding cassette transporter (Abc)g5 and Abcg8 expression constantly decreased after BDL. Intestinal Apo AIV, Apo CIII, Mrp2, Abcg5 and Abcg8 expression remarkably decreased 24 h after BDL and recovered 72 and 168 h after BDL. Hepatic small heterodimer partner (Shp) expression did not change after BDL. Conversely, intestinal Shp expression remarkably decreased 24 h after BDL (16% of sham operation) and slightly recovered 168 h after BDL (58% of sham operation). Several intestinal mRNA expressions important for lipid (Apo AIV, Apo CIII, Abcg5 and Abcg8) and bile acid (Mrp2 and Shp) metabolism were decreased in the early phase of obstructive jaundice and the expression of these intestinal mRNA recovered in the late phase of obstructive jaundice.

Chronic renal failure-induced changes in serum and urine bile acid profiles.

Although the kidney is believed to play a minor role in bile acid (BA) excretion, chronic renal failure (CRF) has been reported to be accompanied by alterations in the BA balance. The aim of the present work was to evaluate the changes in BA serum concentrations and renal excretion in patients with different stage of CRF or after kidney transplantation and to elucidate whether these might play a role in the development of pruritus, a common symptom in this disease. This study was carried out on 125 patients. None of them had a history or signs of hepatobiliary malfunction. They belonged either to a control group (N = 31) or to one of the three following CRF groups: patients maintained only on a low-protein diet (diet group, N = 23); the same, together with periodic sessions of hemodialysis (dialysis group, N = 42); and patients who had undergone a kidney transplant more than 1 and less than 2 years before (transplanted group, N = 29). Serum and urine BA concentrations were assayed by gas chromatography-mass spectrometry. Pruritus was quantified by means of a questionnaire answered at the time of sample collection. A marked hypercholanemia together with a reduction in BA output into urine and profound alterations in the profiles of these compounds in both serum and urine in patients with CRF were observed. The levels of total BAs in serum, but not the proportions of molecular species, were corrected by hemodialysis. By contrast, kidney transplant reversed BA serum patterns to normality but, due to immunosuppressive therapy with cyclosporin A, total serum BA concentrations were consistently elevated in this group. Pruritus was more frequent in patients with impaired kidney function and hypercholanemia, although no significant correlation between the degree of this symptom and the magnitude of the serum concentrations of total or individual BAs were found. By contrast, in spite of hypercholanemia, once renal function had been restored by kidney transplantation, none of the patients suffered from pruritus. These results suggest that the kidney plays an important role in determining the serum BA pool size and composition and that hypercholanemia may be a contributing factor, but not the only one, determining the development of pruritus in patients with CRF.

Evaluation of hydrophobic/hydrophilic balance of bile acids by comparative molecular field analysis (CoMFA)

A comparative molecular field analysis (CoMFA) model, employing standard steric and electrostatic fields, is able to predict the hydrophobic/hydrophilic balance, expressed as reverse-phase HPLC capacity factor, for a series of both naturally occurring and semi-synthetic bile acids. The very high values of cross-validated R 2 (Q 2) demonstrate that the CoMFA method can give useful information on the hydrophobic balance of newly synthesized bile acids.

Soy Protein, Isoflavones and Cardiovascular Disease Risk

Since the early 1940s, scientists have examined the effect of soy protein on blood cholesterol concentrations. Although studies in animals have suggested that soy protein lowers blood cholesterol concentrations, similar studies in humans have yielded less consistent results. The presence or absence of the soybean isoflavone fraction may be a confounding factor. This fraction, consisting primarily of genistein, daidzein and glycetein, has been shown to have a hypocholesterolemic effect in animals and humans. Potential mechanisms by which soy protein and/or isoflavones induce lowering of blood cholesterol concentrations include thyroid status, bile acid balance and the estrogenic effects of genistein and daidzein. Some studies have suggested that isoflavones exhibit antioxidant properties and have favorable effects on arterial compliance. In addition to the aforementioned potential beneficial effects, the increased consumption of products containing soy protein may displace foods relatively high in saturated fat and cholesterol from the diet and hence have an indirect blood cholesterol–lowering effect.

Effects of synthetic glycosides on steroid balance in Macaca fascicularis.

The predominantly beta-anomer of diosgenin glucoside (DG) was synthesized and its effects on cholesterol homeostasis were tested in monkeys. Cynomolgus macaques (Macaca fascicularis) were fed, during two 3-week periods, a semipurified diet with 0.1% cholesterol and a similar ration containing 1% DG, respectively. A Chow diet was given for 5 weeks between the experimental periods. Cholesterol and bile acid balance were analyzed during the last week of each semipurified diet. Diosgenin glucoside reduced cholesterolemia from 292 mg/dl to 172 mg/dl, decreased intestinal absorption of exogenous cholesterol from 62.4% to 26.0%, and increased secretion of endogenous cholesterol from -0.8 to 93.5 mg/day. The fecal excretion of neutral steroids rose from 40.7 to 157.3 mg/day; that of bile acids changed, nonsignificantly, from 23.1 to 16.0 mg/day. The cholesterol balance was -44 mg/day in the control period, and 88 mg/day in the DG-fed animals. No toxic signs were observed. Thus, when long-term studies demonstrate that the glucoside is well tolerated, DG and other synthetic glycosides with similar activities may be of use in the management of hypercholesterolemia and atherosclerosis.

Bile acid-induced liver toxicity: Relation to the hydrophobic-hydrophilic balance of bile acids

Hypertransaminasemia is a frequent side effect during chenodeoxycholic administration for gallstone dissolution. Evidence suggests that this effect is not mediated by lithocholic acid, the intestinal metabolite of chenodeoxycholic acid, but that toxicity is due to the chenodeoxycholic acid itself. In vitro cytotoxicity of bile salts is positively proportional to their detergent effect, which is, on the other hand, related to their hydrophobic-hydrophilic balance. We hypothesize that in vivo also liver injury can occur when the liver is perfused by an high proportion of strongly detergent bile salts. The more detergent bile salts are unconjugated or glycine conjugated, while the lesser are taurine conjugated and sulfated. Within each class the following order of decreasing detergent power can be indicated: lithocholic > deoxycholic > chenodeoxycholic > cholic > ursodeoxycholic acid. Besides chronic exogenous administration of chenodeoxycholic or deoxycholic acids, conditions in which the liver is perfused by an high mass of highly detergent bile salts are those characterized by an enhanced intestinal biodegradation of bile salts. These conditions, which are common features of some chronic inflammatory bowel diseases, are frequently associated with liver damage. On the other hand, a normally detergent bile salt pool can become hepatotoxic for liver cells which have already been injured. In this respect, as already reported for increased sulfation, the increased proportion of taurine conjugates and the reduced formation of deoxycholic acid in liver cirrhosis can be regarded as protective mechanisms. Liver toxicity induced by bile salts' detergency can be prevented by favouring tauroconjugation or reducing the intestinal degradation of bile salts or by administering poorly detergent bile salts.

Cholesterol and bile acid balance in Macaca fascicularis. Effects of alfalfa saponins.

We determine the effects of alfalfa top saponins on cholesterol and bile acid balance in eight cynomolgus macaques (Macaca fascicularis). The monkeys ate semipurified food containing cholesterol with or without added saponins. The saponins decreased cholesterolemia without changing the levels of high density lipoprotein-cholesterol; hence, they reduced the total cholesterol/high density lipoprotein-cholesterol ratio. Furthermore, they decreased intestinal absorption of cholesterol, increased fecal excretion of endogenous and exogenous neutral steroids and bile acids, and decreased the percent distribution of fecal deoxycholic and lithocholic acids. The fecal excretion of fat was also slightly increased, but steatorrhea did not occur. We saw no signs of toxicity in the monkeys after 6 or 8 wk of saponin ingestion. The data suggest that alfalfa top saponins may be of use in the treatment of patients with hypercholesterolemia, but long-term studies on possible toxicity are needed before this therapy can be recommended for humans.