Mechanistic insights into the inhibition of NTCP by myrcludex B

Donkers, Joanne M.; Appelman, Monique D.; Graaf, Stan F.J. van de

doi:10.1016/j.jhepr.2019.07.006

Cited by 31 publications

(23 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The increase in plasma bile acids was temporary, as they completely normalized within 24 hours after the injection. 21 , 23 Inhibition of NTCP by Myrcludex B increased fasting GLP-1 levels 4-fold ( Figure 1 B ). Next, we evaluated if the Myrcludex B–mediated GLP-1 increase affected glycemic control.…”

Section: Resultsmentioning

confidence: 96%

Inhibition of Hepatic Bile Acid Uptake by Myrcludex B Promotes Glucagon-Like Peptide-1 Release and Reduces Obesity

Donkers

Abbing

Weeghel

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

Self Cite

View full text Add to dashboard Cite

Background & Aims Bile acids are important metabolic signaling molecules. Bile acid receptor activation promotes body weight loss and improves glycemic control. The incretin hormone GLP-1 and thyroid hormone activation of T4 to T3 have been suggested as important contributors. Here, we identify the hepatic bile acid uptake transporter Na + taurocholate co-transporting polypeptide (NTCP) as target to prolong postprandial bile acid signaling. Methods Organic anion transporting polypeptide (OATP)1a/1b KO mice with or without reconstitution with human OATP1B1 in the liver were treated with the NTCP inhibitor Myrcludex B for 3.5 weeks after the onset of obesity induced by high fat diet-feeding. Furthermore, radiolabeled T4 was injected to determine the role of NTCP and OATPs in thyroid hormone clearance from plasma. Results Inhibition of NTCP by Myrcludex B in obese Oatp1a/1b KO mice inhibited hepatic clearance of bile acids from portal and systemic blood, stimulated GLP-1 secretion, reduced body weight, and decreased (hepatic) adiposity. NTCP inhibition did not affect hepatic T4 uptake nor lead to increased thyroid hormone activation. Myrcludex B treatment increased fecal energy output, explaining body weight reductions amongst unaltered food intake and energy expenditure. Conclusions Pharmacologically targeting hepatic bile acid uptake to increase bile acid signaling is a novel approach to treat obesity and induce GLP1- secretion.

show abstract

Section: Resultsmentioning

confidence: 96%

Inhibition of Hepatic Bile Acid Uptake by Myrcludex B Promotes Glucagon-Like Peptide-1 Release and Reduces Obesity

Donkers

Abbing

Weeghel

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, this cell line could not stimulate the identification and entry of HBV particles ( 25 , 36 ). NTCP has been demonstrated to be the receptor for HBV ( 25 , 36 , 37 ). The present study constructed a NTCP-Huh7.5.1 cell line by transfecting NTCP into Huh7.5.1 cells, a derivative of hepatocellular carcinoma cells.…”

Section: Discussionmentioning

confidence: 97%

HBV induces liver fibrosis via the TGF‑β1/miR‑21‑5p pathway

Chen

et al. 2020

Exp Ther Med

View full text Add to dashboard Cite

MicroRNA (miR)-21-5p is a newly discovered factor that mediates TGF-β1 signaling. The present study was designed to investigate the role of TGF-β1/miR-21-5p in hepatitis B virus (HBV)-induced liver fibrosis. HBV-infected sodium taurocholate co -t ra nspor ting polypeptide (NTCP)-transfected Huh7.5.1 cells were co-cultured with LX2 cells to simulate HBV infection in the present study. A total of 29 patients with chronic HBV infection were enrolled. Cells were transfected with miR-21-5p mimic or inhibitor with or without TGF-β1 stimulation. The demographic, biochemical and virological data from the 29 patients were analyzed and liver tissues were collected. miR-21-5p levels and the mRNA and protein expression of α-smooth muscle actin (SMA), collagen type 1 α 1 (CoL1A1), tissue inhibitor of metalloproteinase (TIMP)-1 and Smad from liver cells or tissues were detected by quantitative PCR analysis and western blotting, respectively. Cell viability was observed, and the liver fibrosis score was evaluated. The association between miR-21-5p and liver fibrosis was evaluated by correlation analysis. HBV infection upregulated TGF-β1/miR-21-5p mRNA expression in NTCP-Huh7.5.1 cells compared with mock infection (P<0.05). TGF-β1 incubation significantly increased miR-21-5p levels, as well as the mRNA and protein expression of α-SMA, CoL1A1 and TIMP-1, and reduced Smad7 expression in LX2 cells compared with the normal group, and these effects were counteracted by miR-21-5p inhibitor (P<0.05). miR-21-5p overexpression also contributed to TGF-β1-induced α-SMA, CoL1A1 and TIMP-1 expression in LX2 cells (P<0.05). Co-culture with HBV-infected NTCP-Huh7.5.1 cells upregulated TGF-β1/miR-21-5p activity and CoL1A1 expression in LX2 cells compared with normal control, which were significantly reduced by miR-21-5p inhibitor (P<0.05). miR-21-5p levels were significantly correlated with the liver fibrosis score (r=0.888; P<0.05). These data demonstrated that HBV induced liver fibrosis via the TGF-β1/miR-21-5p pathway and suggested that miR-21-5p may be an effective anti-fibrosis target.

show abstract

“…After bile acid is discharged into the small intestine, approximately 95% of the conjugated bile acid is reabsorbed through the apical sodiumdependent bile acid transporter, ileum bile acid binding protein, and terminal apical sodiumdependent bile acid transporter. sodium/ taurocholate cotransporting polypeptide(Ntcp) mediates approximately 80% of bile acids into liver cells [16,17], which are again secreted into the bile to formate enterohepatic circulation of bile acids [18][19][20].…”

Section: Discussionmentioning

confidence: 99%

FXR expression in a rat model of hilar cholangiocarcinoma

Zhang

Wang

2020

Preprint

View full text Add to dashboard Cite

AIM: To develop a rat model of hilar cholangiocarcinoma and detect Farnesyl X receptor (FXR) expression in hilar cholangiocarcinoma tissues of this model, in order to provide a new method for the treatment of hilar cholangiocarcinoma. METHODS: Forty male Wistar rats (body weight, 185 ± 5 g) were randomly divided into two groups (n = 20 each) as follows: The control group was fed a standard diet, and the experimental group was injected by cholangiocarcinoma QBC939 cell suspension along the hilar bile duct into the bile duct bifurcation with microsyringe. Every day note the rats’ mental state, diet, and fur condition. At 4 weeks, one rat of the experimental group was sacrificed after it was administered anesthesia, and we recorded changes in hilar bile duct size, texture, and form. This procedure was repeated at 6 weeks. After 6 weeks, , hilar cholangiocarcinoma developed only in the experimental group, thereby establishing an experimental model for studying QBC939-induced hilar cholangiocarcinoma. Tumor formation was confirmed by pathological examination, and hilar bile duct tissues were harvested from both the groups. A real-time polymerase chain reaction assay and an immunohistochemical assay were used to analyze the expression of FXR in hilar cholangiocarcinoma and normal hilar bile duct tissues. RESULTS: From the second week, the rats in experimental group began to eat less, and their body mass decreased compared with controls. After 6 weeks, we detected hilar cholangiocarcinoma in 17 rats (85%) in the experimental group. In the experimental group with hilar cholangiocarcinoma, we found that the levels of total cholesterol, total bilirubin, and direct bilirubin were higher compared with those of the control group. Simultaneously, muddy stones emerged from the bile ducts of rats in the experimental group. The FXR /Gapdh mRNA ratio in hilar cholangiocarcinoma and normal hilar bile duct tissues differed markedly (16 and 35, respectively). Light microscopy revealed a granular pattern of FXR expression which reacted with the anti- FXR antibody. Each section was randomly divided into six regions, with 80 cells were observed in every region. Sections with >10% positive cells were designated positive, Sections with <10% positive cells were designated negative. Each group included 4,800 cells. In the experimental group, 1,196 cells (24.9%) were positive and 3,538 cells (73.7%) were positive in the control group, and this difference was statistically significant (χ2 = 10.35, P < 0.05). CONCLUSION: FXR expression significantly decreased in hilar cholangiocarcinoma of rats than in those of controls, suggesting that drugs targeting FXR may be a new strategy for hilar cholangiocarcinoma.

show abstract

Mechanistic insights into the inhibition of NTCP by myrcludex B

Cited by 31 publications

References 26 publications

Inhibition of Hepatic Bile Acid Uptake by Myrcludex B Promotes Glucagon-Like Peptide-1 Release and Reduces Obesity

Inhibition of Hepatic Bile Acid Uptake by Myrcludex B Promotes Glucagon-Like Peptide-1 Release and Reduces Obesity

HBV induces liver fibrosis via the TGF‑β1/miR‑21‑5p pathway

FXR expression in a rat model of hilar cholangiocarcinoma

Contact Info

Product

Resources

About