Metabolic Profile of Obeticholic Acid and Endogenous Bile Acids in Rats with Decompensated Liver Cirrhosis

Roda, Aldo; Aldini, Rita; Camborata, Cecilia; Spinozzi, Silvia; Franco, Placido; Cont, Massimiliano; D’Errico, Antonietta; Vasuri, Francesco; Degiovanni, Alessio; Maroni, Lorenzo; Adorini, Luciano

doi:10.1111/cts.12468

Cited by 18 publications

(12 citation statements)

References 32 publications

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“…The results indicate that the nuclear receptors were highly expressed in hiPSC-Hep by day 7-9 compared with primary hepatocytes. FXR is agonistically controlled by bile acid to regulate a variety of target genes controlling lipid and sterol metabolism ( Roda, 2017 ). We validated our model with the clinical compound OCA, a semisynthetic bile acid analog and selective FXR agonist ( Neuschwander-Tetri et al, 2015 ).…”

Section: Resultsmentioning

confidence: 99%

A nonalcoholic fatty liver disease model in human induced pluripotent stem cell-derived hepatocytes, created by endoplasmic reticulum stress-induced steatosis

Parafati¹,

Kirby²,

Khorasanizadeh

et al. 2018

Disease Models &Amp; Mechanisms

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Hepatic steatosis, a reversible state of metabolic dysregulation, can promote the onset of nonalcoholic steatohepatitis (NASH), and its transition is thought to be critical in disease evolution. The association between endoplasmic reticulum (ER) stress response and hepatocyte metabolism disorders prompted us to characterize ER stress-induced hepatic metabolic dysfunction in human induced pluripotent stem cell-derived hepatocytes (hiPSC-Hep), to explore regulatory pathways and validate a phenotypic in vitro model for progression of liver steatosis. We treated hiPSC-Hep with a ratio of unsaturated and saturated fatty acids in the presence of an inducer of ER stress to synergistically promote triglyceride accumulation and dysregulate lipid metabolism. We monitored lipid accumulation by high-content imaging and measured gene regulation by RNA sequencing and reverse transcription quantitative PCR analyses. Our results show that ER stress potentiated intracellular lipid accumulation by 5-fold in hiPSC-Hep in the absence of apoptosis. Transcriptome pathway analysis identified ER stress pathways as the most significantly dysregulated of all pathways affected. Obeticholic acid dose dependently inhibited lipid accumulation and modulated gene expression downstream of the farnesoid X receptor. We were able to identify modulation of hepatic markers and gene pathways known to be involved in steatosis and nonalcoholic fatty liver disease (NAFLD), in support of a hiPSC-Hep disease model that is relevant to clinical data for human NASH. Our results show that the model can serve as a translational discovery platform for the understanding of molecular pathways involved in NAFLD, and can facilitate the identification of novel therapeutic molecules based on high-throughput screening strategies.

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Section: Resultsmentioning

confidence: 99%

A nonalcoholic fatty liver disease model in human induced pluripotent stem cell-derived hepatocytes, created by endoplasmic reticulum stress-induced steatosis

Parafati¹,

Kirby²,

Khorasanizadeh

et al. 2018

Disease Models &Amp; Mechanisms

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“…All the in vitro effects of OCA documented in the present study on iCCA cells occurred at concentrations compatible with the plasma concentrations reached by OCA in treated patients. We should also consider the marked down regulation of the bile acid transporter ASBT in iCCA cells; the relative hydrophobicity of OCA, however, allows passive entrance into the cell, as demonstrated in previous studies [38, 39].…”

Section: Discussionmentioning

confidence: 97%

The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma

et al. 2019

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Cholangiocarcinoma (CCA) is an aggressive cancer with high resistance to chemotherapeutics. CCA is enriched in cancer stem cells, which correlate with aggressiveness and prognosis. FXR, a member of the metabolic nuclear receptor family, is markedly down-regulated in human CCA. Our aim was to evaluate, in primary cultures of human intrahepatic CCA (iCCA), the effects of the FXR agonist obeticholic acid (OCA), a semisynthetic bile acid derivative, on their cancerogenic potential. Primary human iCCA cell cultures were prepared from surgical specimens of mucinous or mixed iCCA subtypes. Increasing concentrations (0–2.5 μM) of OCA were added to culture media and, after 3–10 days, effects on proliferation (MTS assay, cell population doubling time), apoptosis (annexin V-FITC/propidium iodide), cell migration and invasion (wound healing response and Matrigel invasion assay), and cancerogenic potential (spheroid formation, clonogenic assay, colony formation capacity) were evaluated. Results: FXR gene expression was downregulated (RT-qPCR) in iCCA cells vs normal human biliary tree stem cells (p < 0.05) and in mucinous iCCA vs mixed iCCA cells (p < 0.05) but was upregulated by addition of OCA. OCA significantly (p < 0.05) inhibited proliferation of both mucinous and mixed iCCA cells, starting at a concentration as low as 0.05 μM. Also, CDCA (but not UDCA) inhibited cell proliferation, although to a much lower extent than OCA, consistent with its different affinity for FXR. OCA significantly induced apoptosis of both iCCA subtypes and decreased their in vitro cancerogenic potential, as evaluated by impairment of colony and spheroid formation capacity and delayed wound healing and Matrigel invasion. In general, these effects were more evident in mixed than mucinous iCCA cells. When tested together with Gemcitabine and Cisplatin, OCA potentiated the anti-proliferative and pro-apoptotic effects of these chemotherapeutics, but mainly in mixed iCCA cells. OCA abolished the capacity of both mucinous and mixed iCCA cells to form colonies when administered together with Gemcitabine and Cisplatin. In subcutaneous xenografts of mixed iCCA cells, OCA alone or combined with Gemcitabine or Cisplatin markedly reduced the tumor size after 5 weeks of treatment by inducing necrosis of tumor mass and inhibiting cell proliferation. In conclusion, FXR is down-regulated in iCCA cells, and its activation by OCA results in anti-cancerogenic effects against mucinous and mixed iCCA cells, both in vitro and in vivo. The effects of OCA predominated in mixed iCCA cells, consistent with the lower aggressiveness and the higher FXR expression in this CCA subtype. These results, showing the FXR-mediated capacity of OCA to inhibit cholangiocarcinogenesis, represent the basis for testing OCA in clinical trials of CCA patients.

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“…Indeed, before being secreted in the bile canaliculi, primary BAs are conjugated with glycine or taurine by two enzymes, the BA-CoA synthetase (BACS; also known as BA CoA ligase) and the BA-CoA amino acid N-acetyltransferase, for the formation of amphipathic molecules used to emulsify and absorb lipids introduced with the diet [ 4 ]. The conjugation process is also required to allow an efficient BA secretion into bile, since the conjugates are more polar than the free form [ 8 , 9 ]. During the intestinal transit, about 95% of BAs are reabsorbed to maintain the 3-5 g of the physiological pool.…”

Section: Methodsmentioning

confidence: 99%

Role of bile acids in inflammatory bowel disease

Tiratterra

Franco

Porru

et al. 2018

aog

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Bile acids (BAs) are the end product of cholesterol catabolism. Their synthesis is regulated by the nuclear receptor farnesoid X receptor, also involved in the control of their enterohepatic circulation. Inflammatory bowel diseases (IBD), which include Crohn’s disease (CD) and ulcerative colitis (UC), are multifactorial diseases characterized by diarrhea. The pathogenesis of diarrhea in IBD is still debated. The most important factor is the inflammatory process of the intestinal wall, causing alterations of solute and water absorption/secretion, deterioration of epithelial cell integrity, disruption of the intestinal microflora homeostasis, and impairment of specific transport mechanisms within the gut (including that of BAs). In this review, we summarize the current state of the art in this area and we critically evaluate the alterations of BA metabolism in patients with CD and UC.

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Metabolic Profile of Obeticholic Acid and Endogenous Bile Acids in Rats with Decompensated Liver Cirrhosis

Cited by 18 publications

References 32 publications

A nonalcoholic fatty liver disease model in human induced pluripotent stem cell-derived hepatocytes, created by endoplasmic reticulum stress-induced steatosis

A nonalcoholic fatty liver disease model in human induced pluripotent stem cell-derived hepatocytes, created by endoplasmic reticulum stress-induced steatosis

The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma

Role of bile acids in inflammatory bowel disease

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