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. However, the predefined end point was not met in the intention to treat population. Elafibranor was well tolerated and improved patients' cardiometabolic risk profile. ClinicalTrials.gov number: NCT01694849.

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Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies.

Nowadays, liver cancer, cirrhosis and other liver-related diseases are the fifth most common cause of mortality in the UK. Furthermore, chronic liver diseases (CLDs) are one of the major causes of death, which are still increasing year-on-year. Therefore, knowledge about the pathophysiology of CLDs and its complications is of uttermost importance. The goal of this review is to clarify the role of angiogenesis in the disease progression of various liver diseases. Looking closer at the pathophysiology of portal hypertension (PH), fibrosis, cirrhosis, non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), we find that angiogenesis is a recurring factor in the disease progression. In PH, several factors involved in its pathogenesis, such as hypoxia, oxidative stress, inflammation and shear stress are potential mediators for the angiogenic response. The progression from fibrosis to cirrhosis, the end-point of CLDs, is distinguished by a prolonged inflammatory and fibrogenic process that leads to an abnormal angioarchitecture distinctive for cirrhosis. In several stages of NASH, a link might be made between the disease progression and hepatic microvasculature changes. HCC is one of the most vascular solid tumours in which angiogenesis plays an important role in its development, progression and metastasis. The close relationship between the progression of CLDs and angiogenesis emphasises the need for anti-angiogenic therapy as a tool for blocking or slowing down the disease progression. The fact that angiogenesis plays a pivotal role in CLDs gives rise to new opportunities for treating CLDs and its complications.

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Angiogenesis contributes to the development of nonalcoholic steatohepatitis (NASH) and promotes inflammation, fibrosis, and progression to hepatocellular carcinoma (HCC). Angiopoietin‐2 (Ang‐2) is a key regulator of angiogenesis. We aimed to investigate the role of Ang‐2 and its potential as a therapeutic target in NASH using human samples, in vivo mouse models, and in vitro assays. Serum Ang‐2 levels were determined in 104 obese patients undergoing bariatric surgery and concomitant liver biopsy. The effect of the Ang‐2/Tie2 receptor inhibiting peptibody L1‐10 was evaluated in the methionine‐choline deficient (MCD) and streptozotocin‐western diet nonalcoholic fatty liver disease mouse models, and in vitro on endothelial cells and bone marrow–derived macrophages. The hepatic vasculature was visualized with µCT scans and scanning electron microscopy of vascular casts. Serum Ang‐2 levels were increased in patients with histological NASH compared with patients with simple steatosis and correlated with hepatic CD34 immunoreactivity as a marker of hepatic angiogenesis. Serum and hepatic Ang‐2 levels were similarly increased in mice with steatohepatitis. Both preventive and therapeutic L1‐10 treatment reduced hepatocyte ballooning and fibrosis in MCD diet‐fed mice and was associated with reduced hepatic angiogenesis and normalization of the vascular micro‐architecture. Liver‐isolated endothelial cells and monocytes from MCD‐fed L1‐10–treated mice showed reduced expression of leukocyte adhesion and inflammatory markers, respectively, compared with cells from untreated MCD diet‐fed mice. In the streptozotocin‐western diet model, therapeutic Ang‐2 inhibition was able to reverse NASH and attenuate HCC progression. In vitro, L1‐10 treatment mitigated increased cytokine production in lipopolysaccharide‐stimulated endothelial cells but not in macrophages. Conclusion: Our findings provide evidence for Ang‐2 inhibition as a therapeutic strategy to target pathological angiogenesis in NASH.

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The pathophysiology of nonalcoholic steatohepatitis (NASH) should be approached as a multifactorial process. In several stages of NASH, a link between disease progression and hepatic microvasculature changes can be made. In this study we investigated the role of angiogenesis in two mouse models for NASH, and the effect of a preventive and therapeutic antiangiogenic treatment in a diet-induced mouse model for NASH. Protein and RNA levels of angiogenic and inflammatory factors were significantly up-regulated in the liver of C56BL/6 and db/db mice with NASH at different timepoints. To examine the effect of angiogenic factors on the disease progression of NASH, a prevention and treatment study was set up, blocking the placental growth factor (PlGF) or vascular endothelial growth factor receptor 2 (VEGFR2). Our study showed that treatment prevents the progression of NASH by attenuating steatosis and inflammation, both in a preventive and therapeutic setting, thereby confirming the hypothesis that angiogenic factors play an early role in the disease progression from steatosis to NASH. Anti-PlGF (aPlGF) did not significantly improve liver histology. Vascular corrosion casting showed a more disrupted liver vasculature in mice with NASH compared to controls. Treatment with aVEGFR2 showed an improvement of the liver vasculature. Moreover, fat-laden primary hepatocytes treated with aVEGFR2 stored significantly less lipids. Conclusion: Our results demonstrate that there is an increased expression of angiogenic factors in the liver in different mouse models for NASH. We found that VEGFR2 blockage attenuates steatosis and inflammation in a diet-induced mouse model for NASH in a preventive and therapeutic setting. Our findings warrant further investigation of the role of angiogenesis in the pathophysiology in NASH.