New therapeutic perspectives in non-alcoholic steatohepatitis

Ampuero, Javier; Sánchez‐Torrijos, Yolanda; Aguilera, Virginia; Bellido, Francisco Mazuelos; Romero–Gómez, Manuel

doi:10.1016/j.gastre.2017.07.016

Cited by 10 publications

(12 citation statements)

References 84 publications

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“…For treatment of NASH, the reversal of fibrosis is a key unmet need and data suggests > 10% body weight loss is necessary for an optimal result 9 , an objective difficult to reach and maintain by lifestyle modification alone. Bariatric surgery remains the most effective route to achieve longer-term, definitive weight loss and reversal of obesity-driven comorbidities such as NAFLD/NASH 10 , 11 .…”

Section: Introductionmentioning

confidence: 99%

Effects of ALT-801, a GLP-1 and glucagon receptor dual agonist, in a translational mouse model of non-alcoholic steatohepatitis

Nestor

Parkes

Feigh

et al. 2022

Sci Rep

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Body weight loss of ≥ 10% improves the metabolic derangements and liver disease in the majority of non-alcoholic steatohepatitis (NASH) patients, suggesting metabolic modulators may be effective in controlling disease. The pharmacodynamics of ALT-801, a GLP-1/glucagon receptor dual agonist optimized for NASH and weight loss, were compared to semaglutide (GLP-1 receptor agonist) and elafibranor (peroxisome proliferator-activated receptor, PPAR-α/δ, agonist) in a biopsy-confirmed, diet-induced obese (DIO) mouse model of NASH (DIO-NASH). Male C57BL/6J mice were fed Amylin Liver NASH (AMLN) diet for 32 weeks. Animals with biopsy-confirmed steatosis and fibrosis received ALT-801, semaglutide, elafibranor, or vehicle daily for 12 weeks while maintained on the AMLN diet. Study endpoints included body and liver weight, liver and plasma total cholesterol and triglycerides, plasma aminotransferases, histological analysis of liver steatosis, inflammation (galectin-3) and fibrosis (collagen type 1 alpha 1), and evaluation of individual animal changes in composite Non-alcoholic Fatty Liver Disease Activity Score (NAS), and fibrosis stage. ALT-801 demonstrated significant reductions in body weight (approx. 25%), plasma aminotransferases, plasma total cholesterol and liver triglycerides/total cholesterol in conjunction with improved liver steatosis, with greater reductions (p < 0.05) compared to semaglutide and elafibranor. ALT-801 significantly reduced the inflammation marker galectin-3 and the fibrosis marker collagen type 1 alpha 1 vs. vehicle (p < 0.05), with ALT-801 producing greater reductions in galectin-3 vs. elafibranor (p < 0.05). Importantly, all animals treated with ALT-801 significantly improved composite NAS compared to the active controls. This study provides evidence for a potential role for ALT-801 in the therapeutic treatment of NASH.

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Section: Introductionmentioning

confidence: 99%

Effects of ALT-801, a GLP-1 and glucagon receptor dual agonist, in a translational mouse model of non-alcoholic steatohepatitis

Nestor

Parkes

Feigh

et al. 2022

Sci Rep

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“…Moreover, several studies have demonstrated that healthy changes in dietary habits can promote a clinically meaningful regression of disease status [ 19 ]. For this reason, life-style interventions based on nutritional changes is considered the first line therapy in preventing or ameliorating MAFLD [ 20 ]. In this way, plant peptide such as those from soy have been shown not only to lower the MAFLD status in animals [ 21 ] and humans [ 18 ] but also to be able to decrease the main obesity risk factors [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Lupinus angustifolius Protein Hydrolysates Reduce Abdominal Adiposity and Ameliorate Metabolic Associated Fatty Liver Disease (MAFLD) in Western Diet Fed-ApoE−/− Mice

et al. 2021

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Metabolic-associated fatty liver disease (MAFLD) is the most important cause of liver disease worldwide. It is characterized by the accumulation of fat in the liver and is closely associated with abdominal obesity. In addition, oxidative stress and inflammation are significant features involved in MAFLD. Recently, our group demonstrated that lupin protein hydrolysates (LPHs) had lipid lowering, antioxidant, and anti-inflammatory effects. Sixty male mice fed with a Western diet were intragastrically treated with LPHs (or vehicle) for 12 weeks. Liver and adipose tissue lipid accumulation and hepatic inflammatory and oxidant status were evaluated. A significant decrease in steatosis was observed in LPHs-treated mice, which presented a decreased gene expression of CD36 and LDL-R, crucial markers in MAFLD. In addition, LPHs increased the hepatic total antioxidant capacity and reduced the hepatic inflammatory status. Moreover, LPHs-treated mice showed a significant reduction in abdominal adiposity. This is the first study to show that the supplementation with LPHs markedly ameliorates the generation of the steatotic liver caused by the intake of a Western diet and reduces abdominal obesity in ApoE−/− mice. Future clinical trials should shed light on the effects of LPHs on MAFLD.

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“…We are now in a race to identify the first drug able to prevent NAFLD or reverse the disease course in patients at more advanced stages. 3 Clinical trials for NAFLD pose many challenges. 4 On the one hand, some problems relate to recruitment.…”

Section: Current Challenges In Nafld Clinical Trialsmentioning

confidence: 99%

“…11 In this review, we analyse the existing literature on the impact of metabolic comorbidities and lifestyle on treatment response, how this is reported in the different published clinical trials, and how we can use this information to optimise stratification. 1 Hospital Universitario Virgen del Rocío, Sevilla, Spain; 2 SeLiver Group, Instituto de Biomedicina de Sevilla, Sevilla, Spain; 3 CIBERehd, Spain…”

Section: Current Challenges In Nafld Clinical Trialsmentioning

confidence: 99%

Stratification of patients in NASH clinical trials: A pitfall for trial success

Ampuero

Romero–Gómez

2020

JHEP Reports

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Identifying the most effective therapeutic intervention in patients with NAFLD is challenging. Precise stratification in clinical trials is key to ensuring the inclusion of patients who will benefit (and not those who will be harmed) and/or in whom the natural history can be improved. Clinical trials in NAFLD can provide useful information about the individual components that underlie this complex metabolic disorder and the concomitant medications that could interfere with responses to an experimental intervention. However, to date, clinical trial reporting for NAFLD has been suboptimal, limiting our understanding. Frequently dysmetabolic comorbidities and/or daily habits are not reported or adequately accounted for. Herein, we suggest new strategies to integrate the spectra of comorbidities usually present in patients with NAFLD, accounting for the impact of lifestyle, to develop personalised therapeutic approaches. First, the mechanism of action of the drug being explored should be considered. Second, the same proportion of patients with relevant metabolic comorbidities should be maintained from phase II to III clinical trials, if such comorbidities are expected to impact on the treatment response. Third, innovative trial designs, such as the adaptative, umbrella or basket strategies, could be used to increase the efficiency of clinical trials, potentially benefiting patients while reducing costs and enhancing the likelihood of finding a real benefit of the therapy being studied. Finally, alcohol intake and daily exercise should be assessed objectively not only in the screening period but also during follow-up.

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New therapeutic perspectives in non-alcoholic steatohepatitis

Cited by 10 publications

References 84 publications

Effects of ALT-801, a GLP-1 and glucagon receptor dual agonist, in a translational mouse model of non-alcoholic steatohepatitis

Effects of ALT-801, a GLP-1 and glucagon receptor dual agonist, in a translational mouse model of non-alcoholic steatohepatitis

Lupinus angustifolius Protein Hydrolysates Reduce Abdominal Adiposity and Ameliorate Metabolic Associated Fatty Liver Disease (MAFLD) in Western Diet Fed-ApoE−/− Mice

Stratification of patients in NASH clinical trials: A pitfall for trial success

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