scholarly journals Pharmacologic Modulation of Bile Acid-FXR-FGF15/FGF19 Pathway for the Treatment of Nonalcoholic Steatohepatitis

2019 ◽  
pp. 325-357 ◽  
Author(s):  
Justin D. Schumacher ◽  
Grace L. Guo
Keyword(s):  
Bile Acid ◽  
Nonalcoholic Steatohepatitis ◽  
Pharmacologic Modulation

scholarly journals Atorvastatin Modulates Bile Acid Homeostasis in Mice with Diet-Induced Nonalcoholic Steatohepatitis

2021 ◽  
Vol 22 (12) ◽  
pp. 6468
Author(s):  
Hana Lastuvkova ◽  
Fatemeh Alaei Faradonbeh ◽  
Jolana Schreiberova ◽  
Milos Hroch ◽  
Jaroslav Mokry ◽  
...  
Keyword(s):  
Bile Acid ◽  
Nonalcoholic Steatohepatitis ◽  
Plasma Concentrations ◽  
Liver Steatosis ◽  
Saturated Fat ◽  
Cardiovascular Complications ◽  
Biliary Secretion ◽  
Fecal Excretion ◽  
High Cholesterol Diet ◽  
Chow Diet

Bile acids (BA) play a significant role in the pathophysiology of nonalcoholic steatohepatitis (NASH). The present study evaluates the modulation of bile acid metabolomics by atorvastatin, a cholesterol-lowering agent commonly used to treat cardiovascular complications accompanying NASH. NASH was induced in mice by 24 weeks of consuming a high–saturated fat, high-fructose, and high-cholesterol diet (F), with atorvastatin administered orally (20 mg/kg/day) during the last three weeks. Biochemical and histological analyses confirmed the effectiveness of the F diet in inducing NASH. Untreated NASH animals had significantly reduced biliary secretion of BA and increased fecal excretion of BA via decreased apical sodium-dependent bile salt transporter (Asbt)-mediated reabsorption. Atorvastatin decreased liver steatosis and inflammation in NASH animals consistently with a reduction in crucial lipogenic enzyme stearoyl–coenzyme A (CoA) desaturase-1 and nuclear factor kappa light chain enhancer of activated B-cell pro-inflammatory signaling, respectively. In this group, atorvastatin also uniformly enhanced plasma concentration, biliary secretion and fecal excretion of the secondary BA, deoxycholic acid (DCA). However, in the chow diet–fed animals, atorvastatin decreased plasma concentrations of BA, and reduced BA biliary secretions. These changes stemmed primarily from the increased fecal excretion of BA resulting from the reduced Asbt-mediated BA reabsorption in the ileum and suppression of synthesis in the liver. In conclusion, our results reveal that atorvastatin significantly modulates BA metabolomics by altering their intestinal processing and liver synthesis in control and NASH mice.

scholarly journals Berberine Prevents Disease Progression of Nonalcoholic Steatohepatitis through Modulating Multiple Pathways

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 210
Author(s):  
Yanyan Wang ◽  
Yun-Ling Tai ◽  
Derrick Zhao ◽  
Yuan Zhang ◽  
Junkai Yan ◽  
...  
Keyword(s):  
Bile Acid ◽  
Mouse Model ◽  
Disease Progression ◽  
Nonalcoholic Steatohepatitis ◽  
Noncoding Rna ◽  
Metabolic Diseases ◽  
Immune Cell ◽  
Stellate Cell ◽  
Clinical Investigation ◽  
Beneficial Effects

Background and Aims: The disease progression of nonalcoholic fatty liver disease (NAFLD) from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is driven by multiple factors. Berberine (BBR) is an ancient Chinese medicine and has various beneficial effects on metabolic diseases, including NAFLD/NASH. However, the underlying mechanisms remain incompletely understood due to the limitation of the NASH animal models used. Methods: A high-fat and high-fructose diet-induced mouse model of NAFLD, the best available preclinical NASH mouse model, was used. RNAseq, histological, and metabolic pathway analyses were used to identify the potential signaling pathways modulated by BBR. LC–MS was used to measure bile acid levels in the serum and liver. The real-time RT-PCR and Western blot analysis were used to validate the RNAseq data. Results: BBR not only significantly reduced hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also restored the bile acid homeostasis by targeting multiple pathways. In addition, BBR markedly inhibited inflammation by reducing immune cell infiltration and inhibition of neutrophil activation and inflammatory gene expression. Furthermore, BBR was able to inhibit hepatic fibrosis by modulating the expression of multiple genes involved in hepatic stellate cell activation and cholangiocyte proliferation. Consistent with our previous findings, BBR’s beneficial effects are linked with the downregulation of microRNA34a and long noncoding RNA H19, which are two important players in promoting NASH progression and liver fibrosis. Conclusion: BBR is a promising therapeutic agent for NASH by targeting multiple pathways. These results provide a strong foundation for a future clinical investigation.

scholarly journals Obeticholic acid improves fetal bile acid profile in a mouse model of gestational hypercholanemia

2020 ◽  
Vol 319 (2) ◽  
pp. G197-G211
Author(s):  
Vanessa Pataia ◽  
Saraid McIlvride ◽  
Georgia Papacleovoulou ◽  
Caroline Ovadia ◽  
Julie A. K. McDonald ◽  
...  
Keyword(s):  
Bile Acid ◽  
Mouse Model ◽  
Nonalcoholic Steatohepatitis ◽  
Intrahepatic Cholestasis ◽  
Primary Biliary Cholangitis ◽  
Intrahepatic Cholestasis Of Pregnancy ◽  
Obeticholic Acid ◽  
Cholestasis Of Pregnancy

We used a mouse model of gestational hypercholanemia to investigate the use of obeticholic acid (OCA), a potent FXR agonist, as a treatment for the hypercholanemia of intrahepatic cholestasis of pregnancy (ICP). The results demonstrate that OCA can improve the fetal bile acid profile. This is relevant not only to women with ICP but also for women who become pregnant while receiving OCA treatment for other conditions such as primary biliary cholangitis and nonalcoholic steatohepatitis.

Bile acid modulators for the treatment of nonalcoholic steatohepatitis (NASH)

2020 ◽  
Vol 29 (6) ◽  
pp. 623-632 ◽  
Author(s):  
Stefano Fiorucci ◽  
Michele Biagioli ◽  
Valentina Sepe ◽  
Angela Zampella ◽  
Eleonora Distrutti
Keyword(s):  
Bile Acid ◽  
Nonalcoholic Steatohepatitis

scholarly journals Bile Acid Sequestrant, Sevelamer Ameliorates Hepatic Fibrosis with Reduced Overload of Endogenous Lipopolysaccharide in Experimental Nonalcoholic Steatohepatitis

2020 ◽  
Vol 8 (6) ◽  
pp. 925 ◽  
Author(s):  
Yuki Tsuji ◽  
Kosuke Kaji ◽  
Mitsuteru Kitade ◽  
Daisuke Kaya ◽  
Koh Kitagawa ◽  
...  
Keyword(s):  
Bile Acid ◽  
Hepatic Fibrosis ◽  
Nonalcoholic Steatohepatitis ◽  
Receptor Activation ◽  
Farnesoid X Receptor ◽  
Bile Acid Sequestrant ◽  
Intestinal Lumen ◽  
Fecal Excretion ◽  
Clinical Issue ◽  
Α Diversity

Despite the use of various pharmacotherapeutic strategies, fibrosis due to nonalcoholic steatohepatitis (NASH) remains an unsatisfied clinical issue. We investigated the effect of sevelamer, a hydrophilic bile acid sequestrant, on hepatic fibrosis in a murine NASH model. Male C57BL/6J mice were fed a choline-deficient, L-amino acid-defined, high-fat (CDHF) diet for 12 weeks with or without orally administered sevelamer hydrochloride (2% per diet weight). Histological and biochemical analyses revealed that sevelamer prevented hepatic steatosis, macrophage infiltration, and pericellular fibrosis in CDHF-fed mice. Sevelamer reduced the portal levels of total bile acid and inhibited both hepatic and intestinal farnesoid X receptor activation. Gut microbiome analysis demonstrated that sevelamer improved a lower α-diversity and prevented decreases in Lactobacillaceae and Clostridiaceae as well as increases in Desulfovibrionaceae and Enterobacteriaceae in the CDHF-fed mice. Additionally, sevelamer bound to lipopolysaccharide (LPS) in the intestinal lumen and promoted its fecal excretion. Consequently, the sevelamer treatment restored the tight intestinal junction proteins and reduced the portal LPS levels, leading to the suppression of hepatic toll-like receptor 4 signaling pathway. Furthermore, sevelamer inhibited the LPS-mediated induction of fibrogenic activity in human hepatic stellate cells in vitro. Collectively, sevelamer inhibited the development of murine steatohepatitis by reducing hepatic LPS overload.

scholarly journals Disruption of phospholipid and bile acid homeostasis in mice with nonalcoholic steatohepatitis

Hepatology ◽  
2012 ◽  
Vol 56 (1) ◽  
pp. 118-129 ◽  
Author(s):  
Naoki Tanaka ◽  
Tsutomu Matsubara ◽  
Kristopher W. Krausz ◽  
Andrew D. Patterson ◽  
Frank J. Gonzalez
Keyword(s):  
Bile Acid ◽  
Nonalcoholic Steatohepatitis

scholarly journals Organic solute transporter OSTα/β is overexpressed in nonalcoholic steatohepatitis and modulated by drugs associated with liver injury

2018 ◽  
Vol 314 (5) ◽  
pp. G597-G609 ◽  
Author(s):  
Melina M. Malinen ◽  
Izna Ali ◽  
Jacqueline Bezençon ◽  
James J. Beaudoin ◽  
Kim L. R. Brouwer
Keyword(s):  
Bile Acid ◽  
Liver Injury ◽  
Nonalcoholic Steatohepatitis ◽  
Liver Tissue ◽  
Primary Biliary Cholangitis ◽  
Drug Induced ◽  
Organic Solute Transporter ◽  
Organic Solute ◽  
Solute Transporter

The heteromeric steroid transporter organic solute transporter α/β (OSTα/β, SLC51A/B) was discovered over a decade ago, but its physiological significance in the liver remains uncertain. A major challenge has been the lack of suitable models expressing OSTα/β. Based on observations first reported here that hepatic OSTα/β is upregulated in nonalcoholic steatohepatitis, the aim of this research was to develop an in vitro model to evaluate OSTα/β function and interaction with drugs and bile acids. OSTα/β expression in human liver tissue was analyzed by quantitative RT-PCR, Western blotting, and immunofluorescence. Radiolabeled compounds were used to determine OSTα/β-mediated transport in the established in vitro model. The effect of bile acids and drugs, including those associated with cholestatic drug-induced liver injury, on OSTα/β-mediated transport was evaluated. Expression of OSTα/β was elevated in the liver of patients with nonalcoholic steatohepatitis and primary biliary cholangitis, whereas hepatocyte expression of OSTα/β was low in control liver tissue. Studies in the novel cell-based system showed rapid and linear OSTα/β-mediated transport for all tested compounds: dehydroepiandrosterone sulfate, digoxin, estrone sulfate, and taurocholate. The interaction study with 26 compounds revealed novel OSTα/β inhibitors: a biomarker for cholestasis, glycochenodeoxycholic acid; the major metabolite of troglitazone, troglitazone sulfate; and a macrocyclic antibiotic, fidaxomicin. Additionally, some drugs (e.g., digoxin) consistently stimulated taurocholate uptake in OSTα/β-overexpressing cells. Our findings demonstrate that OSTα/β is an important transporter in liver disease and imply a role for this transporter in bile acid-bile acid and drug-bile acid interactions, as well as cholestatic drug-induced liver injury. NEW & NOTEWORTHY The organic solute transporter OSTα/β is highly expressed in hepatocytes of liver tissue obtained from patients with nonalcoholic steatohepatitis and primary biliary cholangitis. OSTα/β substrates exhibit rapid, linear, and concentration-driven transport in an OSTα/β-overexpressing cell line. Drugs associated with hepatotoxicity modulate OSTα/β-mediated taurocholate transport. These data suggest that hepatic OSTα/β plays an essential role in patients with cholestasis and may have important clinical implications for bile acid and drug disposition.

P860 NUCLEAR RECEPTOR FXR UPREGULATES GENE EXPRESSION OF BILE ACID TRANSPORTERS IN NONALCOHOLIC STEATOHEPATITIS

2014 ◽  
Vol 60 (1) ◽  
pp. S358-S359
Author(s):  
N. Méndez-Sánchez ◽  
V. Sánchez-Valle ◽  
J.A. López-Velázquez ◽  
F. Chablé-Montero ◽  
N.C. Chávez-Tapia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bile Acid ◽  
Nuclear Receptor ◽  
Nonalcoholic Steatohepatitis ◽  
Bile Acid Transporters
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