PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells

Rogue, Alexandra; Anthérieu, Sébastien; Vluggens, Aurore; Umbdenstock, Thierry; Claude, Nancy; Moureyre-Spire, Catherine de la; Weaver, Richard J.; Guillouzo, André

doi:10.1016/j.taap.2014.02.001

Cited by 52 publications

(43 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Rogue et al tested a battery of PPAR agonists (troglitazone, rosiglitazone, muraglitazar, tesaglitazar, fenofibrate, and bezafibrate) in oleic acid-overloaded HepaRG cells. Only troglitazone did not reduce the oleic acid-induced increased lipid load, demonstrating the potential of this model for the preclinical assessment of new anti-NAFLD compounds [83]. Yet, although harboring great applicability potential, none of the successfully tested drugs in the in vitro model showed convincing results during clinical studies [40,61].…”

Section: Ppar-targeted Preclinical Drug Testingmentioning

confidence: 97%

Anti-NASH Drug Development Hitches a Lift on PPAR Agonism

Boeckmans

Natale

Rombaut

et al. 2019

Cells

View full text Add to dashboard Cite

Non-alcoholic fatty liver disease (NAFLD) affects one-third of the population worldwide, of which a substantial number of patients suffer from non-alcoholic steatohepatitis (NASH). NASH is a severe condition characterized by steatosis and concomitant liver inflammation and fibrosis, for which no drug is yet available. NAFLD is also generally conceived as the hepatic manifestation of the metabolic syndrome. Consequently, well-established drugs that are indicated for the treatment of type 2 diabetes and hyperlipidemia are thought to exert effects that alleviate the pathological features of NASH. One class of these drugs targets peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors that play a regulatory role in lipid metabolism and inflammation. Therefore, PPARs are now also being investigated as potential anti-NASH druggable targets. In this paper, we review the mechanisms of action and physiological functions of PPARs and discuss the position of the different PPAR agonists in the therapeutic landscape of NASH. We particularly focus on the PPAR agonists currently under evaluation in clinical phase II and III trials. Preclinical strategies and how refinement and optimization may improve PPAR-targeted anti-NASH drug testing are also discussed. Finally, potential caveats related to PPAR agonism in anti-NASH therapy are stipulated.

show abstract

Section: Ppar-targeted Preclinical Drug Testingmentioning

confidence: 97%

Anti-NASH Drug Development Hitches a Lift on PPAR Agonism

Boeckmans

Natale

Rombaut

et al. 2019

Cells

View full text Add to dashboard Cite

show abstract

“…Their conclusions indicate pleiotropic effects of NAFLD and NASH on drugmetabolizing enzymes; however, these effects are not always consistent with results on the upregulation or downregulation of certain P450 isoforms under different conditions of experimental animal research or clinical studies. Previous studies suggest a negative influence of steatosis on various P450 activities in human primary hepatocytes in vitro (Donato et al, 2006), whereas in HepaRG cells, prolonged PPARa activation counteracts steatosis in these cells (Rogue et al, 2014). Inflammatory mediators, for example, interleukin 6 (IL-6), are known to broadly decrease the drug-metabolizing capacities of hepatocytes (Morgan et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Drug Metabolism by the Interplay of Inflammatory Signaling, Steatosis, and Xeno-Sensing Receptors in HepaRG Cells

et al. 2018

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (NAFLD), which is characterized by triglyceride deposition in hepatocytes resulting from imbalanced lipid homeostasis, is of increasing concern in Western countries, along with progression to nonalcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. Previous studies suggest a complex, mutual influence of hepatic fat accumulation, NASH-related inflammatory mediators, and drug-sensing receptors regulating xenobiotic metabolism. Here, we investigated the suitability of human HepaRG hepatocarcinoma cells as a model for NAFLD and NASH. Cells were incubated for up to 14 days with an oleate/palmitate mixture (125 M each) and/or with 10 ng/ml of the inflammatory mediator interleukin-6 (IL-6). Effects of these conditions on the regulation of drug metabolism were studied using xenobiotic agonists of the aryl hydrocarbon receptor (AHR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), nuclear factor (erythroid-derived 2)-like 2, and peroxisome proliferator-activated receptor (PPAR). Results underpin the suitability of HepaRG cells for NAFLD- and NASH-related research and constitute a broad-based analysis of the impact of hepatic fatty acid accumulation and inflammation on drug metabolism and its inducibility by xenobiotics. IL-6 exerted pronounced negative regulatory effects on basal as well as on PXR-, CAR-, and PPAR-, but not AHR-dependent induction of drug-metabolizing enzymes. This inhibition was related to diminished transactivation potential of the respective receptors rather than to reduced transcription of nuclear receptor-encoding mRNAs. The most striking effects of IL-6 and/or fatty acid treatment were observed in HepaRG cells after 14 days of treatment, making these cultures appear a suitable model for studying the relationship of fatty acid accumulation, inflammation, and xenobiotic-induced drug metabolism.

show abstract

“…However, metabolites located along the axes are specifically altered in the vehicle group ( studies showed that acyl-CoA oxidase 1 (ACOX1), pyruvate dehydrogenase kinase 4 (PDK4) and uncoupling proteins (including UCP1, UCP2 and UCP3) were downstream target genes of PPARα involved in lipid metabolism. 24,25 We observed significantly upregulated expression of ACOX1, PDK4 and UCP2 in the liver after apatinib treatment ( Figure 7A). In addition, apatinib could upregulate gene expression of ACOX1, PDK4 and UCP3 in HepG2 cells, but had no significant effect on the expression of UCP2 ( Figure 7B).…”

Section: Regulation Of Apatinib In Fatty Acid Metabolism and Ketogementioning

confidence: 94%

Apatinib induces 3‐hydroxybutyric acid production in the liver of mice by peroxisome proliferator‐activated receptor α activation to aid its antitumor effect

Feng

Wang

et al. 2019

Cancer Science

View full text Add to dashboard Cite

Apatinib, an antiangiogenic agent, shows efficient antitumor activity in a broad range of malignancies. Considering tumor is a type of metabolic disease, we investigated the metabolomics changes in serum and tumor after apatinib treatment and the molecular mechanism of characteristic changes associated with its antitumor efficacy. Molecules in serum and tumor tissue were extracted and analyzed by a gas chromatography‐mass spectrometry metabolic platform. Apatinib significantly inhibited e tumor growth and alleviated metabolic rearrangement in both serum and tumor of A549 xenograft mice. Among these endogenous metabolites, 3‐hydroxybutyric acid (3‐HB) was significantly increased in serum, tumor and liver after apatinib treatment. Interestingly, giving exogenous 3‐HB also inhibited tumor growth. Gene expression, dual luciferase reporter gene assay and molecular docking analysis all indicated that apatinib could induce 3‐HB production through the dependent activation of peroxisome proliferator‐activated receptor α (PPARα) and promotion of fatty acid utilization in the liver. Therefore, increased content of 3‐HB induced by PPARα activation in the liver partially contributed to the antitumor effect of apatinib. It may provide clues to another potential mechanism underlying the antitumor effect of apatinib besides its antiangiogenic effect through inhibiting vascular endothelial growth factor receptor 2.

show abstract

PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells

Cited by 52 publications

References 53 publications

Anti-NASH Drug Development Hitches a Lift on PPAR Agonism

Anti-NASH Drug Development Hitches a Lift on PPAR Agonism

Regulation of Drug Metabolism by the Interplay of Inflammatory Signaling, Steatosis, and Xeno-Sensing Receptors in HepaRG Cells

Apatinib induces 3‐hydroxybutyric acid production in the liver of mice by peroxisome proliferator‐activated receptor α activation to aid its antitumor effect

Contact Info

Product

Resources

About