Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
TL;DR: The dual PPAR‐α/δ agonist, GFT505, is a promising liver‐targeted drug for treatment of NAFLD/NASH and in animals, its protective effects are mediated by both PPar‐α‐dependent and ‐independent mechanisms.
About: This article is published in Hepatology.The article was published on 2013-12-01. It has received 339 citations till now. The article focuses on the topics: Nonalcoholic fatty liver disease & Peroxisome proliferator-activated receptor alpha.
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TL;DR: These findings reinforce the remarkable complexity and plasticity of HSC activation, and underscore the value of clarifying its regulation in hopes of advancing the development of novel diagnostics and therapies for liver disease.
Abstract: Activation of hepatic stellate cells (HSCs) in liver injury is the primary driver of hepatic fibrosis. In this Review, Tsuchida and Friedman detail the varied intracellular and extracellular signalling pathways leading to HSC activation, as well as the role of HSCs in liver fibrosis resolution and as therapeutic targets. Hepatic fibrosis is a dynamic process characterized by the net accumulation of extracellular matrix resulting from chronic liver injury of any aetiology, including viral infection, alcoholic liver disease and NASH. Activation of hepatic stellate cells (HSCs) — transdifferentiation of quiescent, vitamin-A-storing cells into proliferative, fibrogenic myofibroblasts — is now well established as a central driver of fibrosis in experimental and human liver injury. Yet, the continued discovery of novel pathways and mediators, including autophagy, endoplasmic reticulum stress, oxidative stress, retinol and cholesterol metabolism, epigenetics and receptor-mediated signals, reveals the complexity of HSC activation. Extracellular signals from resident and inflammatory cells including macrophages, hepatocytes, liver sinusoidal endothelial cells, natural killer cells, natural killer T cells, platelets and B cells further modulate HSC activation. Finally, pathways of HSC clearance have been greatly clarified, and include apoptosis, senescence and reversion to an inactivated state. Collectively, these findings reinforce the remarkable complexity and plasticity of HSC activation, and underscore the value of clarifying its regulation in hopes of advancing the development of novel diagnostics and therapies for liver disease.
1,578 citations
TL;DR: The transcriptional activation and repression mechanisms by PPAR α, the spectrum of target genes and chromatin-binding maps from recent genome-wide studies, are discussed, paying particular attention to PPARα-regulation of hepatic fatty acid and plasma lipoprotein metabolism during nutritional transition, and of the inflammatory response.
925 citations
Cites background from "Hepatoprotective effects of the dua..."
...Furthermore, GFT505 exerts anti-fibrotic activities on CCl4-induced fibrosis in rats [9]....
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...In phase II clinical trials, GFT505 treatment decreases plasma concentrations of ALT, cGT, and ALP, in MetS patients [9]....
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...PPARa activation, in combination with PPARb/d agonism, improves steatosis, inflammation and fibrosis in rodent models of NASH [9]....
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...Recently, GFT505 was shown to counteract multiple stages of NAFLD, as assessed in several animal models of NASH and fibrosis [9,146], effects likely due to the combined activation of the PPARa and d receptors....
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Pierre-and-Marie-Curie University1, French Institute of Health and Medical Research2, San Antonio Military Medical Center3, University of Antwerp4, Paris Diderot University5, University of Melbourne6, Catholic University of Leuven7, University of Angers8, Duke University9, University of Virginia10, Radboud University Nijmegen11, Newcastle University12, university of lille13, Virginia Commonwealth University14, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico15, Semmelweis University16
TL;DR: A post-hoc analysis of data from trial of patients with NASH showed that elafibranor (120 mg/d for 1 year) resolved NASH without fibrosis worsening, based on a modified definition, in the intention-to-treat analysis and in patients with moderate or severe NASH.
813 citations
Cites background from "Hepatoprotective effects of the dua..."
...Elafibranor (GFT505) is a dual PPARa/d agonist that has demonstrated efficacy in disease models of nonalcoholic fatty liver disease (NAFLD)/NASH and liver fibrosis.(16) Elafibranor confers liver protection by acting on several pathways involved in NASH pathogenesis, reducing steatosis, inflammation, and fibrosis....
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TL;DR: The past three decades of steady progress in understanding liver fibrosis have contributed to an emerging translational success story, with realistic hopes for antifibrotic therapies to treat patients with chronic liver disease in the near future.
Abstract: Reversibility of hepatic fibrosis and cirrhosis following antiviral therapy for hepatitis B or C has advanced the prospect of developing antifibrotic therapies for patients with chronic liver diseases, especially non-alcoholic steatohepatitis. Mechanisms of fibrosis have focused on hepatic stellate cells, which become fibrogenic myofibroblasts during injury through ‘activation’, and are at the nexus of efforts to define novel drug targets. Recent studies have clarified pathways of stellate cell gene regulation and epigenetics, emerging pathways of fibrosis regression through the recruitment and amplification of fibrolytic macrophages, nuanced responses of discrete inflammatory cell subsets and the identification of the ‘ductular reaction’ as a marker of severe injury and repair. Based on our expanded knowledge of fibrosis pathogenesis, attention is now directed towards strategies for antifibrotic therapies and regulatory challenges for conducting clinical trials with these agents. New therapies are attempting to: 1) Control or cure the primary disease or reduce tissue injury; 2) Target receptor-ligand interactions and intracellular signaling; 3) Inhibit fibrogenesis; and 4) Promote resolution of fibrosis. Progress is urgently needed in validating non-invasive markers of fibrosis progression and regression that can supplant biopsy and shorten the duration of clinical trials. Both scientific and clinical challenges remain, however the past three decades of steady progress in understanding liver fibrosis have contributed to an emerging translational success story, with realistic hopes for antifibrotic therapies to treat patients with chronic liver disease in the near future.
705 citations
TL;DR: Improved methods of analysis of the gut microbiome, and greater understanding of interactions between dysbiosis, diet, environmental factors and their effects on the gut–liver axis should improve the treatment of this common liver disease and its associated disorders.
Abstract: NAFLD is now the most common cause of liver disease in Western countries. This Review explores the links between NAFLD, the metabolic syndrome, dysbiosis, poor diet and gut health. Animal studies in which the gut microbiota are manipulated, and observational studies in patients with NAFLD, have provided considerable evidence that dysbiosis contributes to the pathogenesis of NAFLD. Dysbiosis increases gut permeability to bacterial products and increases hepatic exposure to injurious substances that increase hepatic inflammation and fibrosis. Dysbiosis, combined with poor diet, also changes luminal metabolism of food substrates, such as increased production of certain short-chain fatty acids and alcohol, and depletion of choline. Changes to the microbiome can also cause dysmotility, gut inflammation and other immunological changes in the gut that might contribute to liver injury. Evidence also suggests that certain food components and lifestyle factors, which are known to influence the severity of NAFLD, do so at least in part by changing the gut microbiota. Improved methods of analysis of the gut microbiome, and greater understanding of interactions between dysbiosis, diet, environmental factors and their effects on the gut-liver axis should improve the treatment of this common liver disease and its associated disorders.
623 citations
References
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TL;DR: Mortality among community-diagnosed NAFLD patients is higher than the general population and is associated with older age, impaired fasting glucose, and cirrhosis, although the absolute risk is low.
2,681 citations
Virginia Commonwealth University1, Indiana University – Purdue University Indianapolis2, Virginia Mason Medical Center3, Case Western Reserve University4, Duke University5, University of California, San Francisco6, Saint Louis University7, University of California, San Diego8, Johns Hopkins University9, Washington University in St. Louis10, National Institutes of Health11
TL;DR: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes, and significant benefits of pioglitazone were observed for some of the secondary outcomes.
Abstract: Background Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrho sis. Currently, there is no established treatment for this disease. Methods We randomly assigned 247 adults with nonalcoholic steatohepatitis and without dia betes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The pri mary outcome was an improvement in histologic features of nonalcoholic steato hepatitis, as assessed with the use of a composite of standardized scores for steato sis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indi cate statistical significance. Results Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P = 0. 001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P = 0. 04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pio glitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P = 0. 005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P = 0. 02 for vitamin E and P = 0. 004 for pioglitazone) but not with improvement in fibrosis scores (P = 0. 24 for vitamin E and P = 0. 12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. Conclusions Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT000 63622.)
2,632 citations
"Hepatoprotective effects of the dua..." refers result in this paper
...In two larger studies performed in patients with biopsyproven NASH, long-term treatment with pioglitazone led to clear metabolic and liver histological improvement, but did not significantly improve fibrosis.(36,37) Human studies performed with marketed PPAR-a agonists have generated inconsistent results on NAFLD/ NASH....
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TL;DR: The present “gold standard” management of NASH is modest weight reduction, particularly correction of central obesity achieved by combining dietary measures with increased physical activity, which improves insulin resistance and reverses steatosis, hepatocellular injury, inflammation, and fibrosis.
2,325 citations
"Hepatoprotective effects of the dua..." refers background in this paper
...NASH is defined by the presence of steatosis coexisting with hepatic inflammation and hepatocellular injury.(2) Although simple steatosis is generally a benign condition, NASH can have a dire prognosis resulting from concomitant evolving fibrosis(3) and progression to cirrhosis....
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...Although simple steatosis is generally a benign condition, NASH can have a dire prognosis resulting from concomitant evolving fibrosis(3) and progression to cirrhosis.(2) Patients with NASH have increased liverrelated mortality,(4) and NASH-induced cirrhosis can result in end-stage liver disease,(5) including the development of hepatocellular carcinoma....
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TL;DR: In this proof-of-concept study, the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis and larger controlled trials of longer duration are warranted to assess the long-term clinical benefit.
Abstract: BACKGROUND No pharmacologic therapy has conclusively proved to be effective for the treatment of nonalcoholic steatohepatitis, which is characterized by insulin resistance, steatosis, and necroinflammation with or without centrilobular fibrosis. Pioglitazone is a thiazolidinedione that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus. METHODS We randomly assigned 55 patients with impaired glucose tolerance or type 2 diabetes and liver biopsy–confirmed nonalcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet (a reduction of 500 kcal per day in relation to the calculated daily intake required to maintain body weight) plus pioglitazone (45 mg daily) or a hypocaloric diet plus placebo. Before and after treatment, we assessed hepatic histologic features, hepatic fat content by means of magnetic resonance spectroscopy, and glucose turnover during an oral glucose tolerance test ([ 14 C]glucose given with the oral glucose load and [ 3 H]glucose given by intravenous infusion). RESULTS Diet plus pioglitazone, as compared with diet plus placebo, improved glycemic control and glucose tolerance (P<0.001), normalized liver aminotransferase levels as it decreased plasma aspartate aminotransferase levels (by 40% vs. 21%, P = 0.04), decreased alanine aminotransferase levels (by 58% vs. 34%, P<0.001), decreased hepatic fat content (by 54% vs. 0%, P<0.001), and increased hepatic insulin sensitivity (by 48% vs. 14%, P = 0.008). Administration of pioglitazone, as compared with placebo, was associated with improvement in histologic findings with regard to steatosis (P = 0.003), ballooning necrosis (P = 0.02), and inflammation (P = 0.008). Subjects in the pioglitazone group had a greater reduction in necroinflammation (85% vs. 38%, P = 0.001), but the reduction in fibrosis did not differ significantly from that in the placebo group (P = 0.08). Fatigue and mild lower-extremity edema developed in one subject who received pioglitazone; no other adverse events were observed. CONCLUSIONS In this proof-of-concept study, the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis. Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone. (ClinicalTrials.gov number, NCT00227110.)
1,601 citations
"Hepatoprotective effects of the dua..." refers result in this paper
...In two larger studies performed in patients with biopsyproven NASH, long-term treatment with pioglitazone led to clear metabolic and liver histological improvement, but did not significantly improve fibrosis.(36,37) Human studies performed with marketed PPAR-a agonists have generated inconsistent results on NAFLD/ NASH....
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TL;DR: Features suggestive of NASH are more frequently observed in HCC arising in patients with CC than in age- and sex-matched HCC patients of well-defined viral or alcoholic etiology.
1,336 citations
"Hepatoprotective effects of the dua..." refers background in this paper
...Patients with NASH have increased liverrelated mortality,(4) and NASH-induced cirrhosis can result in end-stage liver disease,(5) including the development of hepatocellular carcinoma.(6) Efficacious therapeutic agents for the treatment of NASH are lacking....
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