bims-liverm 2023-02-19 papers

bims-liverm

Biomed News

on Liver Metabolism

Issue of 2023–02–19
eight papers selected by

Ingestion of whey protein and β-conglycinin exerts opposite effects on intestinal FGF15 and serotonin secretion in mice.
Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice.
Bile acid-induced tissue factor activity in hepatocytes correlates with activation of farnesoid X receptor.
Potential therapeutic action of Tauroursodeoxycholic acid against cholestatic liver injury via hepatic Fxr/Nrf2 and CHOP-DR5-caspase-8 pathway.
The PPARα/CYP4A14 bile acid pathway is associated with lipid metabolism disorders caused by low birth weight with high-fat diet.
Increase of liver stiffness and altered bile acid metabolism after triple CFTR modulator initiation in children and young adults with cystic fibrosis.
Bile acid predicts congenital portosystemic venous shunt in patients with pulmonary arterial hypertension.
Gastric bypass alters diurnal feeding behavior and reprograms hepatic clock to regulate endogenous glucose flux.

Front Endocrinol (Lausanne). 2023 ;14 1080790

Ingestion of whey protein and β-conglycinin exerts opposite effects on intestinal FGF15 and serotonin secretion in mice.

Katsunori Nonogaki, Takao Kaji.

  Farnesoid X receptor (FXR) and Takeda G protein-coupled Receptor 5 (TGR5), the intestinal bile acid (BA) receptors, regulate the gut-derived hormones including fibroblast growth factor 15/19 (FGF15/19) and serotonin (5-hydrooxytryptamine, 5-HT). Here we show that ingestion of whey protein isolate, a milk protein, significantly decreased expression of heteromeric organic solute transporter Ostα and Ostβ, which is the basolateral BA transporter in the enterocyte, and increased the expression of FXR and FGF15 in C57BL6J mouse ileum and plasma FGF15 levels. In addition, the ingestion of whey protein isolate significantly suppressed expression of hepatic cholesterol-7α hydroxylase (CYP7A1), which induces the primary BA synthesis, bile salt export pump (BSEP) and sodium-taurocholate cotransporting polypeptide (NTCP), which are the key transporters for the BA excretion and uptake in the liver, and genes involved in gluconeogenesis, and decreased the primary BAs including cholic acid, taurocholic acid, glycocholic acid, and taurochenodeoxycholic acid in the liver compared with controls. Moreover, ingestion of whey protein isolate significantly decreased the expression of TGR5, glucagon-like peptide 1 (GLP-1), and tryptophan hydroxylase1 (Tph1) in the small intestine, leading to decreases in plasma 5-HT and insulin levels. On the other hand, ingestion of the soy protein β-conglycinin significantly increased the expression of Ostα and Ostβ, and decreased the expression of FGF15 in the ileum and plasma FGF15 levels, leading to the increases in expression of hepatic CYP7A1, BSEP, NTCP, and genes involved in gluconeogenesis, and the primary BAs in the liver. Moreover, ingestion of β-conglycinin significantly increased the expression of intestinal TGR5, GLP-1, and Tph1, leading to increases in plasma 5-HT and insulin levels. These findings suggest that whey protein and β-conglycinin have opposite effects on intestinal FGF15 and 5-HT secretion in mice.

Keywords:  Fgf15; bile acids; serotonin; whey protein; β-conglycinin

DOI:  https://doi.org/10.3389/fendo.2023.1080790
JCI Insight. 2023 Feb 14. pii: e149360. [Epub ahead of print]

Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice.

Jennifer K Truong, Jianing Li, Qin Li, Kimberly Pachura, Anuradha Rao, Sanjeev Gumber, Claudia D Fuchs, Andrew P Feranchak, Saul J Karpen, Michael Trauner, Paul A Dawson.

  The pronounced choleretic properties of norursodeoxycholic acid (norUDCA) to induce bicarbonate-rich bile secretion have been attributed to its ability to undergo cholehepatic shunting. The goal of this study was to identify the mechanisms underlying the choleretic actions of norUDCA and role of the bile acid transporters. Here, we show that the apical sodium-dependent bile acid transporter (ASBT), Organic solute transporter-alpha (OSTα), and Organic anion transporting polypeptide 1a/1b (OATP1a/1b) transporters are dispensable for the norUDCA-stimulation of bile flow and biliary bicarbonate secretion. Chloride channels in biliary epithelial cells provide the driving force for biliary secretion. norUDCA potently stimulated chloride currents in mouse large cholangiocytes, which was blocked by siRNA silencing and pharmacological inhibition of the calcium-activated chloride channel transmembrane member 16A (TMEM16A), but unaffected by ASBT inhibition. In agreement, blocking intestinal bile acid reabsorption by co-administration of an ASBT inhibitor or bile acid sequestrant did not impact norUDCA stimulation of bile flow in wildtype mice. The results indicate that these major bile acid transporters are not directly involved in the absorption, cholehepatic shunting, or choleretic actions of norUDCA. Additionally, the findings support further investigation of the therapeutic synergy between norUDCA and ASBT inhibitors or bile acid sequestrants for cholestatic liver disease.

Keywords:  Drug therapy; Gastroenterology; Hepatology; Toxins/drugs/xenobiotics; Transport

DOI:  https://doi.org/10.1172/jci.insight.149360
Lab Invest. 2021 10;pii: S0023-6837(22)00402-0. [Epub ahead of print]101(10): 1394-1402

Bile acid-induced tissue factor activity in hepatocytes correlates with activation of farnesoid X receptor.

Theresa Greimel, Jörg Jahnel, Sina Pohl, Tanja Strini, Martin Tischitz, Nathalie Meier-Allard, Sandra Holasek, Katharina Meinel, Victor Aguiriano-Moser, Joachim Zobel, Harald Haidl, Siegfried Gallistl, Katrin Panzitt, Martin Wagner, Axel Schlagenhauf.

Bile acids (BA) have been found to promote coagulation by increasing tissue factor (TF) activity. The contribution of elevated BA levels and cholestasis to TF decryption within the liver parenchyma and the role of farnesoid X receptor (FXR) in this process remain unclear. We investigated the effects of BA on TF activity and thrombin generation in hepatocytes and correlated these effects with activation of FXR-dependent signaling and apoptosis. HepG2 cells and primary hepatocytes were incubated with chenodeoxycholic acid (CDCA), glycochenodeoxycholic acid (GCDCA), ursodeoxycholic acid (UCDA), or the synthetic FXR agonist GW4064 for 24 h. MTT tests demonstrated cell viability throughout experiments. TF activity was tested via factor Xa generation and thrombin generation was measured by calibrated automated thrombography. Increased TF activity alongside enhanced thrombin generation was observed with CDCA and GW4064 but not with GCDCA and UDCA. TF activity was substantially reduced when FXR activation was blocked with the antagonist DY 268. Quantitative polymerase chain reaction revealed upregulation of FXR target genes only by CDCA and GW4064. Western blot analysis and fluorescence microscopy showed no TF overexpression arguing for TF decryption. Caspase 3 activity measurements and flow cytometric analysis of Annexin V binding showed no signs of apoptosis. Long-term exposure of hepatocytes to nontoxic BA may cause intracellular FXR overstimulation, triggering TF decryption irrespective of the amphiphilic properties of BA. The effect of BA on TF activation correlates with the molecule's ability to enter the cells and activate FXR. TF decryption occurs independently of apoptotic mechanisms. The potential of various bile acids to induce procoagulant tissue factor (TF) activity in viable HepG2 cells and primary human hepatocytes was investigated. Increased TF activity correlated with the molecules' ability to enter the cells and activate the farnesoid X receptor (FXR) suggesting a crucial role of FXR in bile acid-mediated TF activity within the liver parenchyma.

DOI: https://doi.org/10.1038/s41374-021-00628-z
Clin Sci (Lond). 2023 Feb 16. pii: CS20220674. [Epub ahead of print]

Potential therapeutic action of Tauroursodeoxycholic acid against cholestatic liver injury via hepatic Fxr/Nrf2 and CHOP-DR5-caspase-8 pathway.

Guochao Song, Fengyi Weng, Bin Zou, Jing Zhao, Jingyi Jin, Dongming Yan, Kai Huang, Xing Sun, Cheng-Hai Liu, Yi-Yang Hu, Yue Li, Furong Qiu.

  Cholestasis is a pathophysiologic syndrome with limited therapeutic options. Tauroursodeoxycholic acid (TUDCA) has been employed to treat hepatobiliary disorders and is as effective as UDCA in alleviating cholestatic liver disease in clinical trials. Until now, TUDCA's mechanism of action towards cholestasis remains unclear. In this study, cholestasis was induced with a cholic acid (CA)-supplemented diet or alpha-naphthyl isothiocyanate (ANIT) gavage in wild-type and Farnesoid X Receptor (FXR) deficient mice, using obeticholic acid (OCA) as control. The effects of TUDCA on liver histological changes, transaminase level, bile acid composition, hepatocyte death, expression of Fxr and Nuclear factor erythroid 2-related factor 2 (Nrf2) and target genes, as well as apoptotic signaling pathways, were investigated. Treating CA-fed mice with TUDCA markedly alleviated liver injury, attenuated bile acids retention in liver and plasma, increased Fxr and Nrf2 nuclear levels and modulated the expression of targets regulating synthesis and transportation of bile acids, including BSEP, MRP2, NTCP and CYP7A1. TUDCA, but not OCA, activated Nrf2 signaling and exerted protective effects against cholestatic liver injury in Fxr-/- mice fed with CA. Furthermore, in both mice with CA- and ANIT-induced cholestasis, TUDCA decreased expression of GRP78 and CCAAT/enhancer-binding protein homologous protein (CHOP); reduced Death Receptor 5 (DR5) transcription, caspase-8 activation, and BID cleavage; and subsequently inhibited activation of executioner caspases and apoptosis in liver. We confirmed that TUDCA protected against cholestatic liver injury by alleviating BAs burden of dually activating hepatic Fxr and Nrf2. Moreover, inhibiting CHOP-DR5-caspase-8 pathway contributed to the anti-apoptotic effect of TUDCA in cholestasis.

Keywords:  Anti-apoptosis; CCAAT/enhancer-binding protein homologous protein; Cholestasis; Farnesoid X Receptor; Nuclear factor erythroid 2-related factor 2; Tauroursodeoxycholic acid

DOI:  https://doi.org/10.1042/CS20220674
Food Nutr Res. 2023 ;67

The PPARα/CYP4A14 bile acid pathway is associated with lipid metabolism disorders caused by low birth weight with high-fat diet.

Fei Zhou, Linquan Yang, Wenwen Sun, Xing Wang, Na Guo, Huijuan Ma, Linlin Yang.

   Purpose: To investigate possible mechanisms underlying the greater susceptibility of lipid metabolism disorders in low birth weight (LBW) mice fed with high-fat diets (HFDs).
Methods: LBW mice model was established by using the pregnancy malnutrition method. Male pups were selected from LBW and normal-birth weight (NBW) offspring at random. After 3 weeks of weaning, all offspring mice were fed with HFD. Serum triglycerides (TGs), cholesterol (TC), low density lipoprotein (LDL-C), total bile acid (TAB), non-esterified fatty acid (NEFA), and mice fecal bile acid profiles were measured. Lipid deposition in liver sections was visualized by Oil Red O staining. The weight ratio of liver, muscle, and adiposity was calculated. Tandem mass tag (TMT) combined with LC-MS/MS was used to determine the differentially expressed proteins (DEPs) of liver tissue in two groups. Bioinformatics was used for further analysis of DEPs to screen key target proteins, and then Western Blot (WB) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to validate the expressions of DEPs.
Results: LBW mice fed with HFD showed more severe lipid metabolism disorders in the childhood. In contrast to the NBW group, the serum bile acids and fecal ω-muricholic acid (ω-MCA) levels in the LBW group were significantly lower. LC-MS/MS analysis showed that downregulated proteins were associated with lipid metabolism, and further analysis found that these proteins are mainly concentrated in peroxisome proliferation-activated receptor (PPAR) and primary bile acid synthesis signaling pathways and are involved in cellular processes and metabolic processes through binding and catalytic functions. Bioinformatics analysis indicated that the level of Cytochrome P450 Family 46 Subfamily A Member 1 (CYP46A1), PPARα, key factors of cholesterol metabolism and bile acid synthesis, as well as downstream molecules Cytochrome P450 Family 4 Subfamily A Member 14 (CYP4A14), and Acyl-Coenzyme A Oxidase 2 (ACOX2) are markedly different in the liver of LBW individuals fed with HFD, and confirmed by WB and RT-qPCR.
Conclusion: LBW mice are more prone to dyslipidemia probably due to downregulated bile acid metabolism-related PPARα/CYP4A14 pathway, resulting in insufficient metabolism of cholesterol to bile acids, which, in turn, leads to elevated blood cholesterol.

Keywords:  ACOX2; LBW; LC-MS/MS; bile acid; lipid metabolism disorders

DOI:  https://doi.org/10.29219/fnr.v67.8994
Liver Int. 2023 Feb 16.

Increase of liver stiffness and altered bile acid metabolism after triple CFTR modulator initiation in children and young adults with cystic fibrosis.

Alexander Schnell, Jörg Jüngert, Daniel Klett, Hannah Hober, Natalie Kaiser, Renate Ruppel, Annika Geppert, Christina Tremel, Julia Sobel, Erika Plattner, Sabina Schmitt-Grohé, Sabine Zirlik, Deike Strobel, Markus F Neurath, Ferdinand Knieling, Manfred Rauh, Joachim Woelfle, André Hoerning, Adrian P Regensburger.

   BACKGROUND: Novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies (elexacaftor/tezacaftor/ivacaftor - ETI) promise clinically significant and sustained improvements for patients with cystic fibrosis (CF). In this study, we investigated the impact of ETI therapy on liver stiffness and bile acid metabolism in a cohort of children and young adults with CF.
METHODS: A prospective observational study (NCT05576324) was conducted from September 2020 to November 2021 enrolling CF patients naive to ETI. Standard laboratory chemistry, sweat test, lung function, share wave velocity (SWV) derived by Acoustic Radiation Force Impulse Imaging (ARFI) and serum bile acid profiles were assessed before and 6 months after induction of ETI therapy.
RESULTS: A total of 20 patients (10 aged <20 years) completed the study. While lung function and BMI improved after ETI therapy, ARFI SWV increased in CF patients < 20 years of age (from 1.27 to 1.43 m/s, p = 0.023). Bile acid (BA) profiles revealed a decrease in unconjugated (5.75 vs 1.46, p = 0.007) and increase in glycine-conjugated derivatives (GCDCA) (4.79 vs 6.64 p = 0.016). There was a positive correlation between ARFI SWV values and GCDCA (r = 0.80, p <0.0001). Glycine conjugated BA provided high diagnostic accuracy to predict increased ARFI measurements (AUC 0.90) and clinical (Colombo) CFLD grading (AUC 0.97).
CONCLUSIONS: ARFI SWV and bile acid profiles provide evidence for early increase of liver stiffness and altered bile acid metabolism in young CF patients after initiation of ETI and may serve as synergistic measures for detection of hepatic complications during ETI therapy.

Keywords:  ARFI; CFLD; Cystic fibrosis; bile acids

DOI:  https://doi.org/10.1111/liv.15544
Eur J Med Res. 2023 Feb 11. 28(1): 74

Bile acid predicts congenital portosystemic venous shunt in patients with pulmonary arterial hypertension.

Yunyan Li, Xiaoxian Deng, Hongmei Zhou, Xuan Zheng, Gangcheng Zhang, Qingfeng Xiong.

  The etiology of pulmonary arterial hypertension (PAH) is complex, especially the investigation of rare pathogeny is difficult. Congenital portosystemic venous shunt (CPSS) is a rare congenital anomaly in which the portal blood completely or partially bypasses the liver through a congenital portosystemic shunt, and drains directly into the inferior vena cava (IVC) (Howard and Davenport in J Pediatr Surg 32:494-497, 1997).CPSS is an uncommon cause of PAH (Christiane et al. in J Pediatr Gastroenterol Nutr 56:675-681, 2013), and often covered by other pathogenic factors. The clinical manifestations of CPSS-associated PAH are not specific, thus making it difficult to distinguish from PAH caused by other pathogenetic factors based on clinical presentations alone. This is a retrospective analysis of data from six patients with CPSS at a single center. Of these, five were diagnosed as PAH: four were also associated with other predisposing factors of pulmonary hypertension (PH). All patients had high serum bile concentration and high cardiac output. The aim of this retrospective study was to investigate the clinical recognition of PAH secondary to CPSS. The concentration of serum bile acid and cardiac output can be used as two important non-invasive indicators in clinical practice. Thus far, few studies have reported the clinical outcomes of CPSS-associated PAH specifically (Anna et al. in Hepatology 71:658-669, 2020;Franchi-Abella et al. in J Pediatr Gastroenterol Nutr 51:322-330, 2010;Uike et al. in Pediatr Pulmonol 53:505-511, 2018;). In the current study, such patients carried a poor prognosis if left untreated, or treated with pulmonary vasodilators alone.

Keywords:  Bile acid; Congenital portosystemic venous shunt; Pulmonary arterial hypertension

DOI:  https://doi.org/10.1186/s40001-023-01039-0
JCI Insight. 2023 Feb 14. pii: e166618. [Epub ahead of print]

Gastric bypass alters diurnal feeding behavior and reprograms hepatic clock to regulate endogenous glucose flux.

Yuanchao Ye, Marwa Abu El Haija, Reine Obeid, Hussein Herz, Liping Tian, Benjamin Linden, Yi Chu, Deng Fu Guo, Daniel C Levine, Jonathan Cedernaes, Kamal Rahmouni, Joseph Bass, Mohamad Mokadem.

  The molecular clock machinery regulates several homeostatic rhythms, including glucose metabolism. We previously demonstrated that Roux-en Y Gastric Bypass (RYGB) has a weight-independent effect on glucose homeostasis, and transiently reduces food intake. In this study we investigate the effects of RYGB on diurnal eating behavior as well as its effects on the molecular clock, and its requirement for the metabolic effects of this bariatric procedure in obese mice. We find that RYGB reverses the high fat diet-induced disruption in diurnal eating pattern during the early post-surgery phase of food reduction. "Dark-cycle" pair-feeding experiments improved glucose tolerance to the level of bypass-operated animals during the physiologic "fasting" phase (Zeitgeber ZT2), but not the "feeding" phase (ZT14). Using a clock gene reporter mouse model (mPer2Luc), we reveal that RYGB induces a liver-specific phase shift in peripheral clock oscillation with no changes to the central clock activity within the suprachiasmatic nucleus (SCN). In addition, we show that weight loss effects are attenuated in obese ClockΔ19 mutant mice post-RYGB that also fail to improve glucose metabolism after surgery, specifically hepatic glucose production. We conclude that RYGB reprograms the peripheral clock within the liver early after surgery to alter diurnal eating behavior and regulate hepatic glucose flux.

Keywords:  Endocrinology; Gluconeogenesis; Glucose metabolism; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.166618