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Liraglutide Decreases Hepatic Inflammation and Injury in Advanced Lean Non-Alcoholic Steatohepatitis.
Basic Clin Pharmacol Toxicol. 2018 Dec; 123(6):704-713.BC

Abstract

Although commonly associated with obesity, non-alcoholic fatty liver disease (NAFLD) is also present in the lean population representing a unique disease phenotype. Affecting 25% of the world's population, NAFLD is associated with increased mortality especially when progressed to non-alcoholic steatohepatitis (NASH). However, no approved pharmacological treatments exist. Current research focuses mainly on NASH associated with obesity, leaving the effectiveness of promising treatments in lean NASH virtually unknown. This study therefore aimed to evaluate the effect of liraglutide (glucagon-like peptide 1 analogue) and dietary intervention, alone and in combination, in guinea pigs with non-obese NASH. After 20 weeks of high-fat feeding (20% fat, 15% sucrose, 0.35% cholesterol), 40 female guinea pigs were block-randomized based on weight into four groups receiving one of four treatments for 4 weeks: continued high-fat diet (HF, control), high-fat diet and liraglutide treatment (HFL), chow diet (4% fat, 0% sucrose, 0% cholesterol; HFC) or chow diet and liraglutide treatment (HFCL). High-fat feeding induced NASH with severe fibrosis. Liraglutide decreased inflammation (p < 0.05) and hepatocyte ballooning (p < 0.05), while increasing hepatic α-tocopherol (p = 0.0154). Dietary intervention did not improve liver histopathology significantly, but decreased liver weight (p = 0.004), plasma total cholesterol (p = 0.0175), LDL-cholesterol (p = 0.0063), VLDL-cholesterol (p = 0.0034), hepatic cholesterol (p < 0.0001) and increased hepatic vitamin C (p = 0.0099). Combined liraglutide and dietary intervention induced a rapid weight loss, necessitating periodical liraglutide dose adjustment/discontinuation, limiting the strength of the findings from this group. Collectively, this pre-clinical study supports the beneficial effect of liraglutide on NASH and extends this notion to lean NASH.

Authors+Show Affiliations

Department of Veterinary & Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.Diabetes and Cardiovascular Pharmacology, Global Research, Novo Nordisk A/S, Måløv, Denmark.Diabetes and Cardiovascular Pharmacology, Global Research, Novo Nordisk A/S, Måløv, Denmark.Department of Veterinary & Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.Department of Veterinary & Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.Department of Veterinary & Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.Department of Veterinary & Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.Department of Veterinary & Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.Department of Veterinary & Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.Department of Veterinary & Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29953740

Citation

Ipsen, David H., et al. "Liraglutide Decreases Hepatic Inflammation and Injury in Advanced Lean Non-Alcoholic Steatohepatitis." Basic & Clinical Pharmacology & Toxicology, vol. 123, no. 6, 2018, pp. 704-713.
Ipsen DH, Rolin B, Rakipovski G, et al. Liraglutide Decreases Hepatic Inflammation and Injury in Advanced Lean Non-Alcoholic Steatohepatitis. Basic Clin Pharmacol Toxicol. 2018;123(6):704-713.
Ipsen, D. H., Rolin, B., Rakipovski, G., Skovsted, G. F., Madsen, A., Kolstrup, S., Schou-Pedersen, A. M., Skat-Rørdam, J., Lykkesfeldt, J., & Tveden-Nyborg, P. (2018). Liraglutide Decreases Hepatic Inflammation and Injury in Advanced Lean Non-Alcoholic Steatohepatitis. Basic & Clinical Pharmacology & Toxicology, 123(6), 704-713. https://doi.org/10.1111/bcpt.13082
Ipsen DH, et al. Liraglutide Decreases Hepatic Inflammation and Injury in Advanced Lean Non-Alcoholic Steatohepatitis. Basic Clin Pharmacol Toxicol. 2018;123(6):704-713. PubMed PMID: 29953740.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Liraglutide Decreases Hepatic Inflammation and Injury in Advanced Lean Non-Alcoholic Steatohepatitis. AU - Ipsen,David H, AU - Rolin,Bidda, AU - Rakipovski,Günaj, AU - Skovsted,Gry F, AU - Madsen,Anette, AU - Kolstrup,Stefanie, AU - Schou-Pedersen,Anne Marie, AU - Skat-Rørdam,Josephine, AU - Lykkesfeldt,Jens, AU - Tveden-Nyborg,Pernille, Y1 - 2018/07/30/ PY - 2018/04/10/received PY - 2018/06/26/accepted PY - 2018/6/29/pubmed PY - 2019/1/30/medline PY - 2018/6/29/entrez SP - 704 EP - 713 JF - Basic & clinical pharmacology & toxicology JO - Basic Clin. Pharmacol. Toxicol. VL - 123 IS - 6 N2 - Although commonly associated with obesity, non-alcoholic fatty liver disease (NAFLD) is also present in the lean population representing a unique disease phenotype. Affecting 25% of the world's population, NAFLD is associated with increased mortality especially when progressed to non-alcoholic steatohepatitis (NASH). However, no approved pharmacological treatments exist. Current research focuses mainly on NASH associated with obesity, leaving the effectiveness of promising treatments in lean NASH virtually unknown. This study therefore aimed to evaluate the effect of liraglutide (glucagon-like peptide 1 analogue) and dietary intervention, alone and in combination, in guinea pigs with non-obese NASH. After 20 weeks of high-fat feeding (20% fat, 15% sucrose, 0.35% cholesterol), 40 female guinea pigs were block-randomized based on weight into four groups receiving one of four treatments for 4 weeks: continued high-fat diet (HF, control), high-fat diet and liraglutide treatment (HFL), chow diet (4% fat, 0% sucrose, 0% cholesterol; HFC) or chow diet and liraglutide treatment (HFCL). High-fat feeding induced NASH with severe fibrosis. Liraglutide decreased inflammation (p < 0.05) and hepatocyte ballooning (p < 0.05), while increasing hepatic α-tocopherol (p = 0.0154). Dietary intervention did not improve liver histopathology significantly, but decreased liver weight (p = 0.004), plasma total cholesterol (p = 0.0175), LDL-cholesterol (p = 0.0063), VLDL-cholesterol (p = 0.0034), hepatic cholesterol (p < 0.0001) and increased hepatic vitamin C (p = 0.0099). Combined liraglutide and dietary intervention induced a rapid weight loss, necessitating periodical liraglutide dose adjustment/discontinuation, limiting the strength of the findings from this group. Collectively, this pre-clinical study supports the beneficial effect of liraglutide on NASH and extends this notion to lean NASH. SN - 1742-7843 UR - https://www.unboundmedicine.com/medline/citation/29953740/Liraglutide_Decreases_Hepatic_Inflammation_and_Injury_in_Advanced_Lean_Non_Alcoholic_Steatohepatitis_ L2 - https://doi.org/10.1111/bcpt.13082 DB - PRIME DP - Unbound Medicine ER -