Inhibit Bile Acid Synthesis Research Articles

Dimethyl Sulfoxide Inhibits Bile Acid Synthesis in Healthy Mice but Does Not Protect Mice from Bile-Acid-Induced Liver Damage.

Bile acids serve a vital function in lipid digestion and absorption; however, their accumulation can precipitate liver damage. In our study, we probed the effects of dimethyl sulfoxide (DMSO) on bile acid synthesis and the ensuing liver damage in mice induced by bile acids. Our findings indicate that DMSO efficaciously curbs bile acid synthesis by inhibiting key enzymes involved in the biosynthetic pathway, both in cultured primary hepatocytes and in vivo. Contrarily, we observed that DMSO treatment did not confer protection against bile-acid-induced liver damage in two distinct mouse models: one induced by a 0.1% DDC diet, leading to bile duct obstruction, and another induced by a CDA-HFD, resulting in non-alcoholic steatohepatitis (NASH). Histopathological and biochemical analyses unveiled a comparable extent of liver injury and fibrosis levels in DMSO-treated mice, characterized by similar levels of increase in Col1a1 and Acta2 expression and equivalent total liver collagen levels. These results suggest that, while DMSO can promptly inhibit bile acid synthesis in healthy mice, compensatory mechanisms might rapidly override this effect, negating any protective impact against bile-acid-induced liver damage in mice. Through these findings, our study underscores the need to reconsider treating DMSO as a mere inert solvent and prompts further exploration to identify more effective therapeutic strategies for the prevention and treatment of bile-acid-associated liver diseases.

Colitis ameliorates cholestatic liver disease via suppression of bile acid synthesis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of the biliary tree. The majority of PSC patients suffer from concomitant inflammatory bowel disease (IBD), which has been suggested to promote disease development and progression. However, the molecular mechanisms by which intestinal inflammation may aggravate cholestatic liver disease remain incompletely understood. Here, we employ an IBD-PSC mouse model to investigate the impact of colitis on bile acid metabolism and cholestatic liver injury. Unexpectedly, intestinal inflammation and barrier impairment improve acute cholestatic liver injury and result in reduced liver fibrosis in a chronic colitis model. This phenotype is independent of colitis-induced alterations of microbial bile acid metabolism but mediated via hepatocellular NF-κB activation by lipopolysaccharide (LPS), which suppresses bile acid metabolism in-vitro and in-vivo. This study identifies a colitis-triggered protective circuit suppressing cholestatic liver disease and encourages multi-organ treatment strategies for PSC.

FRI-334 - Cholestatic liver disease is alleviated by colitis-induced inhibition of bile acid synthesis

FRI-334 - Cholestatic liver disease is alleviated by colitis-induced inhibition of bile acid synthesis

Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO mice

Therapeutic reduction of hydrophobic bile acids exposure is considered beneficial in cholestasis. The Cyp2c70 KO mice lack hydrophilic muricholic acids and have a human-like hydrophobic bile acid pool resulting in hepatobiliary injury. This study investigates if combining an apical sodium-dependent bile acid transporter inhibitor GSK2330672 (GSK) and fibroblast growth factor-15 (FGF15) overexpression, via simultaneous inhibition of bile acid synthesis and gut bile acid uptake, achieves enhanced therapeutic efficacy in alleviating hepatobiliary injury in Cyp2c70 KO mice. The effects of GSK, adeno-associated virus (AAV)-FGF15, and the combined treatment on bile acid metabolism and cholangiopathy were compared in Cyp2c70 KO mice. In female Cyp2c70 KO mice with more severe cholangiopathy than male Cyp2c70 KO mice, the combined treatment was more effective in reversing portal inflammation, ductular reaction, and fibrosis than AAV-FGF15, while GSK was largely ineffective. The combined treatment reduced bile acid pool by ∼80% compared to ∼50% reduction by GSK or AAV-FGF15, and enriched tauro-conjugated ursodeoxycholic acid in the bile. Interestingly, the male Cyp2c70 KO mice treated with AAV-FGF15 or GSK showed attenuated cholangiopathy and portal fibrosis but the combined treatment was ineffective despite reducing bile acid pool. Both male and female Cyp2c70 KO mice showed impaired gut barrier integrity. AAV-FGF15 and the combined treatment, but not GSK, reduced gut exposure to lithocholic acid and improved gut barrier function. In conclusion, the combined treatment improved therapeutic efficacy against cholangiopathy than either single treatment in the female but not male Cyp2c70 KO mice by reducing bile acid pool size and hydrophobicity.

Inhibiting Wnt Signaling Reduces Cholestatic Injury by Disrupting the Inflammatory Axis

β-Catenin, the effector molecule of the Wnt signaling pathway, has been shown to play a crucial role in bile acid homeostasis through direct inhibition of farnesoid X receptor (FXR), which has pleiotropic effects on bile acid homeostasis. We hypothesize that simultaneous suppression of β-catenin signaling and activation of FXR in a mouse model of cholestasis will reduce injury and biliary fibrosis through inhibition of bile acid synthesis. To induce cholestasis, we performed bile duct ligation (BDL) on wild-type male mice. Eight hours after surgery, mice received FXR agonists obeticholic acid, tropifexor, or GW-4064 or Wnt inhibitor Wnt-C59. Severity of cholestatic liver disease and expression of target genes were evaluated after either 5 days or 12 days of treatment. We found that although the FXR agonists worsened BDL-induced injury and necrosis after 5 days, Wnt-C59 did not. After 12 days of BDL, Wnt-C59 treatment, but not GW-4064 treatment, reduced both the number of infarcts and the number of inflammatory cells in liver. RNA sequencing analysis of whole livers revealed a notable suppression of nuclear factor kappa B signaling when Wnt signaling is inhibited. We then analyzed transcriptomic data to identify a cholangiocyte-specific signature in our model and demonstrated that Wnt-C59-treated livers were enriched for genes expressed in quiescent cholangiocytes, whereas genes expressed in activated cholangiocytes were enriched in BDL alone. A similar decrease in biliary injury and inflammation occurred in Mdr2 KO mice treated with Wnt-C59. Inhibiting Wnt signaling suppresses cholangiocyte activation and disrupts the nuclear factor kappa B-dependent inflammatory axis, reducing cholestatic-induced injury.

Impact of Coffee Consumption on Cardiovascular Health.

Background: Coffee is a widely available beverage that is enjoyed by individuals of many cultures. The publication of new studies prompts a review of the clinical updates regarding the association between coffee consumption and cardiovascular disease. Methods: We present a narrative review of the literature related to coffee consumption and cardiovascular disease. Results: Recent (2000-2021) studies have shown that regular coffee consumption is associated with a decreased risk of developing hypertension, heart failure, and atrial fibrillation. However, results are inconsistent with regard to coffee consumption and risk of developing coronary heart disease. Most studies show a J-shaped association, wherein moderate coffee consumption resulted in decreased risk of coronary heart disease and heavy coffee consumption resulted in increased risk. In addition, boiled or unfiltered coffee is more atherogenic than filtered coffee because of its rich diterpene content that inhibits bile acid synthesis and ultimately affects lipid metabolism. On the other hand, filtered coffee, which is essentially devoid of the aforementioned compounds, exerts antiatherogenic properties by increasing high-density lipoprotein-mediated cholesterol efflux from macrophages through the influence of plasma phenolic acid. As such, cholesterol levels are principally influenced by the manner of coffee preparation (boiled vs filtered). Conclusion: Our findings suggest that moderate coffee consumption leads to a decrease in all-cause and cardiovascular-related mortality, hypertension, cholesterol, heart failure, and atrial fibrillation. However, no conclusive relationship between coffee and coronary heart disease risk has been consistently identified.

Kuhuang alleviates liver fibrosis by modulating gut microbiota-mediated hepatic IFN signaling and bile acid synthesis.

Background: Liver fibrosis is a common outcome of the pathological progression of chronic liver disease; however, no specific and effective therapeutic agent has been approved for its treatment. We investigated the effects of Kuhuang on liver fibrosis and the underlying mechanisms of action. Materials and methods: To induce hepatic fibrosis, either 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC) diet was administered, or bile duct ligation (BDL) surgery was performed on C57BL/6 mice. Kuhuang was orally administered to mice for 7days before and after bile duct ligation or 4weeks with a DDC diet. Hematoxylin and eosin, Sirius red staining, and immunohistochemical analyses were performed to evaluate hepatic pathology. Hepatic interferon-β (IFN-β) levels were measured using an enzyme-linked immunosorbent assay. RNA sequencing was performed to examine the gene expression profiles of liver tissues. The mRNA expression of inflammatory, profibrotic, and bile acid (BA)-related genes was further validated by qRT-PCR. A targeted metabolomics assay revealed the alteration of the hepatic bile acid (BA) composition. The composition of the gut microbiota was determined via 16S rRNA sequencing. Results: Treatment with Kuhuang attenuated liver fibrosis and reduced the inflammatory response in bile duct ligation and DDC mouse models. In addition, the hepatic IFN signaling pathway was activated following Kuhuang treatment. Kuhuang treatment also significantly decreased hepatic levels of both primary and secondary BAs. In addition, Kuhuang treatment altered gut microbiota composition, with an increased abundance of interferon-inducing Akkermansia and decreased abundance of bile salt hydrolase-producing Lactobacillus, Clostridium, and Bifidobacterium. Furthermore, the abundance of Akkermansia was positively correlated with the hepatic mRNA expression levels of Ifna4, Ifnb, and Isg15, whereas that of Lactobacillus, Clostridium - sensu - stricto - 1, and Bifidobacterium was positively correlated with levels of bile acid synthesis-related genes. Conclusion: Our results suggest that Kuhuang plays a protective role during the progression of liver fibrosis, potentially by altering the composition of the gut microbiota, which consequently activates interferon signaling and inhibits bile acid synthesis in the liver.

Dietary choline prevents high fat-induced disorder of hepatic cholesterol metabolism through SREBP-2/HNF-4α/CYP7A1 pathway in a freshwater teleost yellow catfish Pelteobagrus fulvidraco

Lipid overload-induced hepatic cholesterol accumulation is a major public health problem worldwide, and choline has been reported to ameliorate cholesterol accumulation, but its mechanism remains unclear. Our study found that choline prevented high-fat diet (HFD)-induced cholesterol metabolism disorder and enhanced choline uptake and phosphatidylcholine synthesis in the liver tissues; choline incubation prevented fatty acid (FA)-induced cholesterol accumulation and FA-induced inhibition of bile acid synthesis. Moreover, compared to single FA incubation, choline incubation or FA + choline co-incubation increased the mRNA abundances and protein levels of HNF4α and up-regulated the degradation of cholesterol into bile acids. Mechanistically, choline prevented the FA-induced accumulation of SREBP2 protein and the interaction between SREBP2 and HNF4α, thereby enhancing the DNA binding capacity of the HNF4α to the CYP7A1 promoter, and promoting the degradation of cholesterol into bile acids. Our study elucidated the novel regulatory mechanisms of choline preventing HFD-induced cholesterol accumulation and increasing bile acid synthesis by SREBP-2/HNF-4α/CYP7A1 pathway.

Suppression of bile acid synthesis as a tipping point in the disease course of primary sclerosing cholangitis

Background & AimsFarnesoid X receptor (FXR) agonists and fibroblast growth factor 19 (FGF19) analogues suppress bile acid synthesis and are being investigated for their potential therapeutic efficacy in cholestatic liver diseases. We investigated whether bile acid synthesis associated with outcomes in 2 independent populations of people with primary sclerosing cholangitis (PSC) not receiving such therapy.MethodsConcentrations of individual bile acids and 7α-hydroxy-4-cholesten-3-one (C4) were measured in blood samples from 330 patients with PSC attending tertiary care hospitals in the discovery and validation cohorts and from 100 healthy donors. We used a predefined multivariable Cox proportional hazards model to evaluate the prognostic value of C4 to predict liver transplantation-free survival and evaluated its performance in the validation cohort.ResultsThe bile acid synthesis marker C4 was negatively associated with total bile acids. Patients with fully suppressed bile acid synthesis had strongly elevated total bile acids and short liver transplantation-free survival. In multivariable models, a 50% reduction in C4 corresponded to increased hazards for liver transplantation or death in both the discovery (adjusted hazard ratio [HR] = 1.24, 95% CI 1.06–1.43) and validation (adjusted HR = 1.23, 95% CI 1.03–1.47) cohorts. Adding C4 to established risk scores added value to predict future events, and predicted survival probabilities were well calibrated externally. There was no discernible impact of ursodeoxycholic acid treatment on bile acid synthesis.ConclusionsBile acid accumulation-associated suppression of bile acid synthesis was apparent in patients with advanced PSC and associated with reduced transplantation-free survival. In a subset of the patients, bile acid synthesis was likely suppressed beyond a tipping point at which any further pharmacological suppression may be futile. Implications for patient stratification and inclusion criteria for clinical trials in PSC warrant further investigation.Lay summaryWe show, by measuring the level of the metabolite C4 in the blood from patients with primary sclerosing cholangitis (PSC), that low production of bile acids in the liver predicts a more rapid progression to severe disease. Many people with PSC appear to have fully suppressed bile acid production, and both established and new drugs that aim to reduce bile acid production may therefore be futile for them. We propose C4 as a test to find those likely to respond to these treatments.

Effect of dietary NSP level and bile acid supplementation on nutrient digestibility and the bile acid metabolism in rainbow trout (Oncorhynchus mykiss)

The effects of dietary bile acid supplementation (BAS) on apparent digestibility coefficients (ADC) and the bile acid metabolism in rainbow trout (Oncorhynchus mykiss) were investigated for diets differing in non-starch polysaccharide (NSP) level. Four experimental diets were formulated according to an 2 by 2 factorial design. A low-NSP and High-NSP diet (0 vs. 160 g kg−1 inclusion of an NSP-rich ingredient mixture) were first formulated. The aim of this was to create differences in the amount of faecal waste produced, and consequently as previously shown in rainbow, the amount of faecal bile acid loss (FBAL). Both NSP-level diets were tested with 0% and 0.3% BAS (0 vs. 3 g kg−1 inclusion of a bile acid mixture). The bile acid mixture contained taurocholic acid (T-CA) and glycocholic acid (G-CA) in a 2:1 ratio. Glycocholic acid does not naturally occur in trout and was used as marker to see if supplemented bile acids are efficiently absorbed and enter enterohepatic circulation (EHC). Fish were fed to apparent satiation for 42 days. Dietary NSP level did not enhance FBAL. BAS was beneficial for fat ADC, but not for the ADC of protein and carbohydrates. BAS improved fat ADC regardless of NSP level, which suggests that bile acids are a limiting factor for fat digestion in rainbow trout. Total bile acid synthesis was a 4-fold lower in fish fed the 0.3% BAS diets compared to the 0% BAS diets. Lower bile acid synthesis with BAS occurred alongside enlarged body and liver + gallbladder bile acid pools and a higher content of bile acids in the chyme. These higher bile acid levels most likely caused a negative feedback inhibition of bile acid synthesis. Negative synthesis rates of G-CA were found when feeding the 0.3% BAS diets, which suggests that this bile acid is catabolised or converted into other bile acid types in rainbow trout. The enlarged pool of T-CA, but especially of the body foreign G-CA, with BAS in both the body and liver + gallbladder shows that dietary bile acids are effectively taking part in EHC. The relative absorption of T-CA and G-CA over the different intestinal compartments was comparable, which shows that EHC does not differentiate between T-CA and G-CA. While relative absorption of bile acids was highest between the distal intestine and the faeces, the absolute decrease in chyme bile acid content was highest between the pyloric region and the mid intestine. The latter shows that significant bile acid absorption occurs more proximal in the intestine of rainbow trout than previously thought.

OS119 - The selective PPAR-delta agonist seladelpar suppresses bile acid synthesis by reducing hepatocyte CYP7A1 through the FGF21 pathway

OS119 - The selective PPAR-delta agonist seladelpar suppresses bile acid synthesis by reducing hepatocyte CYP7A1 through the FGF21 pathway

Abstract 2689: FGF19 is a novel serum colorectal cancer biomarker that exerts endocrine paraneoplastic effects on hepatic tissue

Abstract Despite having excellent prognosis when detected early, colorectal cancer (CRC) remains a leading cause of cancer-related deaths globally. Barriers to screening reduces compliance and negatively impacts patient outcomes, necessitating alternatives. A blood-based approach provides a more convenient and accessible modality, but serum markers are lacking. Using a meta-transcriptomics approach, we identified Fibroblast Growth Factor 19 (FGF19), an enteroendocrine FGF responsible for bile acid (BA) homeostasis, as an attractive CRC marker. However, whether FGF19 is aberrantly secreted into blood by colorectal tumors or induces endocrine-like paraneoplastic effects is unknown. To assess the strength of FGF19 as a CRC biomarker, expression data from the Genotype-Tissue Expression consortium (GTEx), The Cancer Genome Atlas (TCGA-COADREAD), and our curated Meta-dataset (E-MTAB-10089) were downloaded and analyzed for associations with prognostic indicators. Next, in silico FGF19 expression profiles were validated in vitro using a panel of five CRC cell lines via western blot with secretion quantitated by sandwich ELISA. To determine whether colorectal tumors contribute FGF19 to circulation, subcutaneous xenografts of HCT116 and Colo201 cells were established in four male and female NOD Scid gamma (NSG) mice. Tumor volume, as well as serum and urine FGF19 were assessed weekly over a 36-day period. Following euthanasia, murine liver and ileal tissue were processed for downstream mRNA and bile acid quantification. To determine if malignant FGF19 exerts paraneoplastic effects RNA sequencing was performed on hepatic mRNA using the Illumina NovaSeq 6000 system. Reads were processed, aligned, mapped, and analyzed for differential expression and functional enrichment using an integrated informatics pipeline implemented in R. Meta-transcriptomics revealed that ectopic overexpression of FGF19 was highly indicative of CRC and associated with unfavorable prognostic indicators including disease progression, treatment failure, and poor survival. In vitro testing recapitulated in silico findings, showing that that four out of five CRC cell lines constitutively express and secrete FGF19. We also readily detected FGF19 in serum and urine of mice harboring xenografts derived from Colo201, but not HCT116, cells. Moreover, circulating FGF19 levels increased with tumor size and exerted paraneoplastic effects on liver tissue such as suppression of BA synthesis, dysregulation of cholesterol metabolism, and induction of pre-neoplasia. In summary, we describe FGF19 as a putative serum CRC biomarker that exerts novel endocrine-like paraneoplastic effects on the liver. Study limitations included the lack of FGF19 quantification in CRC patient blood, in vivo experimentation using two different cell lines, and gender-related batch effects identified by RNA sequencing. Citation Format: Michael Walter Rohr, Jordan Beardsley, Sai Preethi Nakkina, Dexter Hadley, Deborah Altomare. FGF19 is a novel serum colorectal cancer biomarker that exerts endocrine paraneoplastic effects on hepatic tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2689.

Selective PPARδ agonist seladelpar suppresses bile acid synthesis by reducing hepatocyte CYP7A1 via the fibroblast growth factor 21 signaling pathway

Peroxisome proliferator–activated receptor delta (PPARδ) agonists have been shown to exert beneficial effects in liver disease and reduce total bile acid levels. The mechanism(s) whereby PPARδ agonism reduces bile acid levels are, however, unknown, and therefore the aim of the present study was to investigate the molecular pathways responsible for reducing bile acid synthesis in hepatocytes, following treatment with the selective PPARδ agonist, seladelpar. We show that administration of seladelpar to WT mice repressed the liver expression of cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme for bile acid synthesis, and decreased plasma 7α-hydroxy-4-cholesten-3-one (C4), a freely diffusible metabolite downstream of Cyp7a1. In primary mouse hepatocytes, seladelpar significantly reduced the expression of Cyp7a1 independent of the nuclear bile acid receptor, Farnesoid X receptor. In addition, seladelpar upregulated fibroblast growth factor 21 (Fgf21) in mouse liver, serum, and in cultured hepatocytes. We demonstrate that recombinant Fgf21 protein activated the c-Jun N-terminal kinase (JNK) signaling pathway and repressed Cyp7a1 gene expression in primary hepatocytes. The suppressive effect of seladelpar on Cyp7a1 expression was blocked by a JNK inhibitor as well as in the absence of Fgf21, indicating that Fgf21 plays an indispensable role in PPARδ-mediated downregulation of Cyp7a1. Finally, reduction of CYP7A1 expression by seladelpar was confirmed in primary human hepatocytes. In conclusion, we show that seladelpar reduces bile acid synthesis via an FGF21-dependent mechanism that signals at least partially through JNK to repress CYP7A1.

Modulation of Bile Acid Metabolism to Improve Plasma Lipid and Lipoprotein Profiles.

New drugs targeting bile acid metabolism are currently being evaluated in clinical studies for their potential to treat cholestatic liver diseases, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Changes in bile acid metabolism, however, translate into an alteration of plasma cholesterol and triglyceride concentrations, which may also affect cardiovascular outcomes in such patients. This review attempts to gain insight into this matter and improve our understanding of the interactions between bile acid and lipid metabolism. Bile acid sequestrants (BAS), which bind bile acids in the intestine and promote their faecal excretion, have long been used in the clinic to reduce LDL cholesterol and, thereby, atherosclerotic cardiovascular disease (ASCVD) risk. However, BAS modestly but consistently increase plasma triglycerides, which is considered a causal risk factor for ASCVD. Like BAS, inhibitors of the apical sodium-dependent bile acid transporter (ASBTi’s) reduce intestinal bile acid absorption. ASBTi’s show effects that are quite similar to those obtained with BAS, which is anticipated when considering that accelerated faecal loss of bile acids is compensated by an increased hepatic synthesis of bile acids from cholesterol. Oppositely, treatment with farnesoid X receptor agonists, resulting in inhibition of bile acid synthesis, appears to be associated with increased LDL cholesterol. In conclusion, the increasing efforts to employ drugs that intervene in bile acid metabolism and signalling pathways for the treatment of metabolic diseases such as NAFLD warrants reinforcing interactions between the bile acid and lipid and lipoprotein research fields. This review may be considered as the first step in this process.

Sodium butyrate alleviates cholesterol gallstones by regulating bile acid metabolism

Cholesterol overloading and bile acid metabolic disorders play an important role in the onset of cholesterol gallstone (CGS). Short-chain fatty acids (SCFAs) can regulate bile acid metabolism by modulating the gut microbiota. However, the role and mechanism by which sodium butyrate (NaB) targets bile acids to attenuate CGS are still unknown. In this study, continuous administration of 12 mg/day for 8 weeks was decreased the incidence of gallstones induced by lithogenic diet (LD) from 100% to 25%. NaB modulated SCFAs and improved the gut microbiota. The remodeling of the gut microbiota changed the bile acid compositions and decreased cecal tauro-α-muricholic acid (T-α-MCA) and tauro-β-muricholic acid (T-β-MCA) which are effective farnesoid X receptor (FXR) antagonists. The quantitative real-time PCR examination showed that NaB significantly increased levels of ileal Fxr, fibroblast growth factor-15 (Fgf-15) and small heterodimer partner (Shp) mRNA and subsequently inhibited bile acid synthesis. In addition, NaB enhanced bile acid excretion by increasing the levels of hepatic multidrug resistance protein 2 (Mdr2) and bile salt export pump (Bsep) mRNA, and it enhanced bile acid reabsorption in the intestine by increasing the levels of ileal bile acid transporter (Ibat) mRNA. In addition, NaB reduced the absorption of cholesterol in the intestine and inhibited the excretion of cholesterol in the liver, which reduced the cholesterol concentration in serum and bile. Furthermore, the protective effects of NaB administration were abolished by FXR antagonists.Taken together, our results suggest that NaB mitigates CGS by modulating the gut microbiota to regulate the FXR-FGF-15/SHP signaling pathway.

Genetic Disorders of Bile Acid Transport.

Genetic Disorders of Bile Acid Transport.

Dynamics of the enterohepatic circulation of bile acids in healthy humans.

Regulation of bile acid metabolism is normally discussed as the regulation of bile acid synthesis, which serves to compensate for intestinal loss in order to maintain a constant pool size. After a meal, bile acids start cycling in the enterohepatic circulation. Farnesoid X receptor-dependent ileal and hepatic processes lead to negative feedback inhibition of bile acid synthesis. When the intestinal bile acid flux decreases, the inhibition of synthesis is released. The degree of inhibition of synthesis and the mechanism and degree of activation are still unknown. Moreover, in humans, a biphasic diurnal expression pattern of bile acid synthesis has been documented, indicating maximal synthesis around 3 PM and 9 PM. Quantitative data on the hourly synthesis schedule as compensation for intestinal loss are lacking. In this review, we describe the classical view on bile acid metabolism and present alternative concepts that are based on the overlooked feature that bile acids transit through the enterohepatic circulation very rapidly. A daily profile of the cycling and total bile acid pool sizes and potential controlled and uncontrolled mechanisms for synthesis are predicted. It remains to be elucidated by which mechanism clock genes interact with the Farnesoid X receptor-controlled regulation of bile acid synthesis. This mechanism could become an attractive target to enhance bile acid synthesis at night, when cholesterol synthesis is high, thus lowering serum LDL-cholesterol.

New Drugs on the Horizon for Functional and Motility Gastrointestinal Disorders

New Drugs on the Horizon for Functional and Motility Gastrointestinal Disorders

Pyrrolizidine Alkaloids Disturb Bile Acid Homeostasis in the Human Hepatoma Cell Line HepaRG.

1,2-unsaturated pyrrolizidine alkaloids (PAs) belong to a group of secondary plant metabolites. Exposure to PA-contaminated feed and food may cause severe hepatotoxicity. A pathway possibly involved in PA toxicity is the disturbance of bile acid homeostasis. Therefore, in this study, the influence of four structurally different PAs on bile acid homeostasis was investigated after single (24 h) and repeated (14 days) exposure using the human hepatoma cell line HepaRG. PAs induce a downregulation of gene expression of various hepatobiliary transporters, enzymes involved in bile acid synthesis, and conjugation, as well as several transcription regulators in HepaRG cells. This repression may lead to a progressive impairment of bile acid homeostasis, having the potential to accumulate toxic bile acids. However, a significant intracellular and extracellular decrease in bile acids was determined, pointing to an overall inhibition of bile acid synthesis and transport. In summary, our data clearly show that PAs structure-dependently impair bile acid homeostasis and secretion by inhibiting the expression of relevant genes involved in bile acid homeostasis. Furthermore, important biliary efflux mechanisms seem to be disturbed due to PA exposure. These mole-cular mechanisms may play an important role in the development of severe liver damage in PA-intoxicated humans.

3'quant mRNA-Seq of Porcine Liver Reveals Alterations in UPR, Acute Phase Response, and Cholesterol and Bile Acid Metabolism in Response to Different Dietary Fats.

Animal fats are considered to be unhealthy, in contrast to vegetable fats, which are rich in unsaturated fatty acids. However, the use of some fats, such as coconut oil, is still controversial. In our experiment, we divided experimental animals (domestic pigs) into three groups differing only in the type of fat used in the diet: group R: rapeseed oil (n = 5); group B: beef tallow (n = 5); group C: coconut oil (n = 6). After transcriptomic analysis of liver samples, we identified 188, 93, and 53 DEGs (differentially expressed genes) in R vs. B, R vs. C, and B vs. C comparisons, respectively. Next, we performed a functional analysis of identified DEGs with String and IPA software. We observed the enrichment of genes engaged in the unfolded protein response (UPR) and the acute phase response among genes upregulated in B compared to R. In contrast, cholesterol biosynthesis and cholesterol efflux enrichments were observed among genes downregulated in B when compared to R. Moreover, activation of the UPR and inhibition of the sirtuin signaling pathway were noted in C when compared to R. The most striking difference in liver transcriptomic response between C and B was the activation of the acute phase response and inhibition of bile acid synthesis in the latest group. Our results suggest that excessive consumption of animal fats leads to the activation of a cascade of mutually propelling processes harmful to the liver: inflammation, UPR, and imbalances in the biosynthesis of cholesterol and bile acids via altered organelle membrane composition. Nevertheless, these studies should be extended with analysis at the level of proteins and their function.