A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease

Fernández‐Miranda, Consuelo; Pérez-Carreras, M; Colina, Francisco; López-Alonso, G.; Vargas, Carmela; Solı́s-Herruzo, José A.

doi:10.1016/j.dld.2007.10.002

Cited by 220 publications

(175 citation statements)

References 31 publications

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“…It has been shown that the PPARα expression level in the liver negatively correlates with the severity of NASH 46. During a 48‐week clinical trial in patients with biopsy‐proven NASH, fenofibrate significantly decreased ballooning and improved metabolic parameters but not inflammation or steatosis 16. Selective PPARδ agonists have not been investigated in patients with NASH, but in overweight subjects GW501516 and MBX‐8025 improved metabolic parameters during a 2‐week and 8‐week duration trial, respectively 17, 18.…”

Section: Discussionmentioning

confidence: 99%

“…The selective PPARα agonist Wy14,643 improved steatosis, inflammation, and fibrosis in mice receiving a methionine‐ and choline‐deficient (MCD) diet and improved metabolic disorders, steatosis, and ballooning in high‐fat diet (HFD) fed foz/foz mice 14, 15. In patients, the PPARα agonist fenofibrate had limited efficacy on NASH but a significant effect on hepatocyte ballooning 16. Some but not all PPARδ agonists have had beneficial effects in preclinical models of NASH 17, 18.…”

Section: Introductionmentioning

confidence: 99%

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The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Wettstein

Luccarini

Poekes

et al. 2017

Hepatology Communications

113

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IVA337 is a pan‐peroxisome proliferator‐activated receptor (PPAR) agonist with moderate and well‐balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet‐induced obesity model (high‐fat/high‐sucrose diet); a methionine‐ and choline‐deficient diet; the foz/foz model; the CCl4‐induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of β‐oxidation‐related and fatty acid desaturation‐related genes in both the methionine‐ and choline‐deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARα, PPARδ, or PPARγ agonists. Conclusion: The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data. (Hepatology Communications 2017;1:524–537)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Wettstein

Luccarini

Poekes

et al. 2017

Hepatology Communications

113

View full text Add to dashboard Cite

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“…Fenofibrate was associated with significant improvement of the serum lipid profile and insulin sensitivity. Alkaline phosphatase and γGT activities were significantly reduced [101] . The proportion of patients with abnormal aminotransferase activities (> 45 IU/L) was also decreased: 93.7% at baseline vs 62.5% following treatment for ALT; 50% at baseline vs 18.7% following treatment for AST [101] .…”

Section: Clinical Evidencementioning

confidence: 98%

“…Alkaline phosphatase and γGT activities were significantly reduced [101] . The proportion of patients with abnormal aminotransferase activities (> 45 IU/L) was also decreased: 93.7% at baseline vs 62.5% following treatment for ALT; 50% at baseline vs 18.7% following treatment for AST [101] . Interestingly, a control liver biopsy at the end of the study showed a significantly decreased grade of hepatocellular ballooning degeneration compared with baseline.…”

Section: Clinical Evidencementioning

confidence: 98%

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Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease

Kostapanos

Kei²,

Elisaf³

2013

WJH

131

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Non-alcoholic fatty liver disease (NAFLD) is a common health problem with a high mortality burden due to its liver-and vascular-specific complications. It is associated with obesity, high-fat diet as well as with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). Impaired hepatic fatty acid (FA) turnover together with insulin resistance are key players in NAFLD pathogenesis. Peroxisome proliferator-activated receptors (PPARs) are involved in lipid and glucose metabolic pathways. The novel concept is that the activation of the PPARα subunit may protect from liver steatosis. Fenofibrate, by activating PPARα, effectively improves the atherogenic lipid profile associated with T2DM and MetS. Experimental evidence suggested various protective effects of the drug against liver steatosis. Namely, fenofibraterelated PPARα activation may enhance the expression of genes promoting hepatic FA β-oxidation. Furthermore, fenofibrate reduces hepatic insulin resistance. It also inhibits the expression of inflammatory mediators involved in non-alcoholic steatohepatitis pathogenesis. These include tumor necrosis factor-α, intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Consequently, fenofibrate can limit hepatic macrophage infiltration. Other liver-protective effects include decreased oxidative stress and improved liver microvasculature function. Experimental studies showed that fenofibrate can limit liver steatosis associated with high-fat diet, T2DM and obesity-related insulin resistance. Few studies showed that these benefits are also relevant even in the clinical setting. However, these have certain limitations. Namely, these were uncontrolled, their sample size was small, fenofibrate was used as a part of multifactorial approach, while histological data were absent. In this context, there is a need for large prospective studies, including proper control groups and full assessment of liver histology.

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Nonalcoholic Fatty Liver Disease

Siddiqui¹,

Sanyal²

2015

Yamada' S Textbook of Gastroenterology

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A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease

Cited by 220 publications

References 31 publications

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease

Nonalcoholic Fatty Liver Disease

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